MBL2 encodes mannose-binding lectin (MBL; also mannan-binding lectin/protein, MBP-C, collectin-1), a secreted, liver-derived serum collectin of the innate immune system. It is a C-type lectin built from a structural subunit that combines an N-terminal cysteine-rich region, a collagen-like Gly-X-Y domain (with hydroxyproline modifications), an alpha-helical coiled-coil neck that drives trimerization, and a C-terminal C-type carbohydrate-recognition domain (CRD). Three subunits assemble into a homotrimer, and several homotrimers further oligomerize into higher-order bouquet-like structures. Through the CRD it binds, in a calcium-dependent manner, terminal mannose, N-acetylglucosamine and fucose residues arranged in the repetitive geometric patterns characteristic of microbial (bacterial, fungal, viral, protozoan) surfaces, while largely sparing the differently arranged sugars of host glycoproteins. MBL therefore acts as a soluble pattern-recognition molecule; upon binding a microbial surface it triggers the associated MBL-associated serine proteases (chiefly MASP-1, which activates MASP-2) to cleave complement C4 and C2, initiating the lectin pathway of complement and leading to opsonization, phagocytosis and membrane attack. MBL also binds altered-self and certain viral glycoproteins (e.g. influenza A haemagglutinin and SARS-CoV-2 spike) and can modulate inflammatory signaling. Common structural and promoter MBL2 variants lower circulating MBL and cause a common, usually subclinical, immunodeficiency that increases infection risk in the immunologically immature or compromised.
Definition: Recognition of a spatially repetitive, geometrically defined array of terminal monosaccharides (e.g. mannose, N-acetylglucosamine, fucose) on a microbial or altered-self surface by a multivalent oligomeric collectin, in which avidity arises from the simultaneous engagement of multiple low-affinity C-type lectin carbohydrate-recognition domains presented by the oligomer, thereby discriminating microbial macropatterns from host glycoproteins.
Justification: MBL specificity for non-self arises from the geometric spacing of multiple CRDs across a higher-order oligomer (the macropattern concept). Existing MF terms (carbohydrate binding, calcium-dependent carbohydrate binding, pattern recognition receptor activity) capture facets but none captures the multivalent, oligomer-dependent macropattern discrimination that distinguishes collectins/ficolins and that experimentally governs microbial binding and complement activation.
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0005576
extracellular region
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: MBL is a secreted serum collectin synthesized in the liver and acting in plasma and tissue fluid; extracellular region is correct and is where its core function takes place.
|
|
GO:0050766
positive regulation of phagocytosis
|
IBA
GO_REF:0000033 |
KEEP AS NON CORE |
Summary: MBL is an opsonin and enhances phagocytosis of bound microbes, largely via complement deposition and collectin receptors. A genuine but downstream effector consequence of MBL recognition/complement-initiation activity rather than its core function.
|
|
GO:0005771
multivesicular body
|
IBA
GO_REF:0000033 |
REMOVE |
Summary: An IBA-propagated localization that does not fit a secreted serum collectin. MBL acts extracellularly/at the cell surface, not in multivesicular bodies; likely over-propagation from surfactant-protein relatives (which traffic through lamellar/multivesicular bodies in pneumocytes).
Reason: No experimental support for MBL function in multivesicular bodies; inconsistent with a liver-secreted plasma lectin. Likely IBA over-propagation from surfactant-protein paralogs.
|
|
GO:0043129
surfactant homeostasis
|
IBA
GO_REF:0000033 |
REMOVE |
Summary: Surfactant homeostasis is a function of the pulmonary surfactant collectins (SFTPA/SP-A, SFTPD/SP-D) in the same PANTHER family, not of serum MBL. IBA over-propagation across the collectin family.
Reason: No evidence MBL participates in surfactant homeostasis; the role belongs to the surfactant-protein paralogs. OpenScientist confirmed this as an IBA-only collectin-family carry-over from pulmonary surfactant collectins onto liver-derived serum MBL2.
Propagation Review
Root cause:
PROPAGATION BAD
Failure modes:
WRONG ORTHOLOG OR PARALOG
COMPARTMENT OR COMPLEX MISMATCH
CONTEXT OR TISSUE MISMATCH
Sources checked:
PANTHER:PTN001523874
· collectin PANTHER source node
SUPPORTS SOURCE BUT NOT TARGET
The source node captures surfactant collectin biology in the pulmonary SP-A/SP-D branch, but MBL2 is a liver-derived serum lectin.
UniProtKB:P35247
· surfactant protein D / pulmonary collectin source
SUPPORTS SOURCE BUT NOT TARGET
Surfactant protein D supports surfactant homeostasis in lung, not serum MBL2 complement biology.
RGD:3667
· rodent surfactant collectin source
SUPPORTS SOURCE BUT NOT TARGET
Rodent surfactant-collectin biology should not transfer the alveolar surfactant-homeostasis process to human MBL2.
Supporting Evidence:
file:human/MBL2/MBL2-goa.tsv
UniProtKB P11226 MBL2 involved_in GO:0043129 surfactant homeostasis biological_process ECO:0000318 IBA GO_REF:0000033 PANTHER:PTN001523874|RGD:3667|UniProtKB:P35247 9606 Homo sapiens GO_Central Mannose-binding protein C 20170613
file:human/MBL2/MBL2-hypotheses/function-hypothesis-go-0043129/openscientist.md
The seed hypothesis that **MBL2 has surfactant homeostasis (GO:0043129)** is **over-annotated / refuted as a direct function.**
|
|
GO:0001867
complement activation, lectin pathway
|
IEA
GO_REF:0000117 |
ACCEPT |
Summary: Correct and central - MBL is the eponymous initiator of the lectin pathway. Redundant with the strongly supported IDA annotations to the same term.
|
|
GO:0005576
extracellular region
|
IEA
GO_REF:0000120 |
ACCEPT |
Summary: Correct secreted location; redundant with experimentally supported extracellular-region annotations.
|
|
GO:0009986
cell surface
|
IEA
GO_REF:0000044 |
ACCEPT |
Summary: MBL is found at the cell surface (it binds carbohydrate on pathogen and altered-self cell surfaces and is detected on host cells). Acceptable as a location, though the functionally meaningful surface is the microbial/symbiont surface (GO:0106139).
|
|
GO:0005515
protein binding
|
IPI
PMID:11290788 Interaction properties of human mannan-binding lectin (MBL)-... |
MARK AS OVER ANNOTATED |
Summary: MBL-MASP1/MASP2/MAp19 interaction (the lectin-protease initiating complex). The interaction is real and important, but protein binding is an uninformative MF; the MBL-MASP relationship is better represented as membership in the MBL-MASP serine-type endopeptidase complex (see core_functions), and the informative MF of MBL is carbohydrate binding.
|
|
GO:0005515
protein binding
|
IPI
PMID:15117939 The X-ray structure of human mannan-binding lectin-associate... |
MARK AS OVER ANNOTATED |
Summary: MBL-MAp19 interaction within the lectin-protease complex; a real partner interaction but uninformative as a generic protein-binding MF.
|
|
GO:0005515
protein binding
|
IPI
PMID:18177377 The chaperone and potential mannan-binding lectin (MBL) co-r... |
MARK AS OVER ANNOTATED |
Summary: MBL-calreticulin interaction (via the MASP-binding site). Specific but uninformative as a generic protein-binding MF.
|
|
GO:0005515
protein binding
|
IPI
PMID:19939495 MBL-associated serine protease-3 circulates in high serum co... |
MARK AS OVER ANNOTATED |
Summary: Derived from a MASP-3/Ficolin-3 study; weak/peripheral support for MBL and uninformative as an MF.
|
|
GO:0005515
protein binding
|
IPI
PMID:20956340 Collectin 11 (CL-11, CL-K1) is a MASP-1/3-associated plasma ... |
MARK AS OVER ANNOTATED |
Summary: From a collectin-11 study; MBL is peripheral. Uninformative generic MF.
|
|
GO:0005515
protein binding
|
IPI
PMID:21035894 Serum concentration and interaction properties of MBL/ficoli... |
MARK AS OVER ANNOTATED |
Summary: MBL-MAP-1/MAp44 interaction in the lectin-protease complex; uninformative generic MF.
|
|
GO:0005515
protein binding
|
IPI
PMID:21054788 CD91 interacts with mannan-binding lectin (MBL) through the ... |
MARK AS OVER ANNOTATED |
Summary: MBL-CD91/LRP1 interaction (via the MASP-binding site). Specific but uninformative as generic protein binding.
|
|
GO:0005515
protein binding
|
IPI
PMID:21106539 Heterocomplexes of mannose-binding lectin and the pentraxins... |
MARK AS OVER ANNOTATED |
Summary: MBL-pentraxin (PTX3/SAP) heterocomplexes; a real interaction modulating complement, but uninformative as a generic MF.
|
|
GO:0005515
protein binding
|
IPI
PMID:21203938 Specific interaction of hepatitis C virus glycoproteins with... |
MARK AS OVER ANNOTATED |
Summary: MBL-HCV glycoprotein interaction; this is actually carbohydrate-mediated recognition of a viral glycoprotein and is better captured by the carbohydrate-binding/PRR MF than by generic protein binding.
|
|
GO:0005515
protein binding
|
IPI
PMID:21268013 Serglycin inhibits the classical and lectin pathways of comp... |
MARK AS OVER ANNOTATED |
Summary: From a serglycin study (GAG-mediated lectin-pathway inhibition); MBL is a target. Uninformative generic MF.
|
|
GO:0005515
protein binding
|
IPI
PMID:21383675 Mannan-binding lectin directly interacts with Toll-like rece... |
MARK AS OVER ANNOTATED |
Summary: MBL-TLR4 ectodomain interaction (immunomodulatory, dampens LPS signaling). A specific regulatory interaction but uninformative as a generic protein-binding MF.
|
|
GO:0005515
protein binding
|
IPI
PMID:22607836 MASP interactions with plasma-derived MBL. |
MARK AS OVER ANNOTATED |
Summary: MASP-MBL interaction study; supports complex assembly but uninformative as a generic MF.
|
|
GO:0005515
protein binding
|
IPI
PMID:22811680 The salivary scavenger and agglutinin binds MBL and regulate... |
MARK AS OVER ANNOTATED |
Summary: MBL-DMBT1/SALSA interaction regulating the lectin pathway; specific but uninformative as a generic MF.
|
|
GO:0005515
protein binding
|
IPI
PMID:22854970 Crystal structure and functional characterization of the com... |
MARK AS OVER ANNOTATED |
Summary: MBL-MAP-1 interaction (competitive complement regulator); uninformative generic MF.
|
|
GO:0005515
protein binding
|
IPI
PMID:23460739 Deciphering complement receptor type 1 interactions with rec... |
MARK AS OVER ANNOTATED |
Summary: MBL-CR1 interaction; a specific receptor interaction but uninformative as a generic MF.
|
|
GO:0005515
protein binding
|
IPI
PMID:25579818 Structural insights into the initiating complex of the lecti... |
MARK AS OVER ANNOTATED |
Summary: MBL-MASP-1 interaction in the initiating complex; best captured as complex membership. Uninformative as a generic MF.
|
|
GO:0005515
protein binding
|
IPI
PMID:27104295 Oligomerization of Mannan-binding Lectin Dictates Binding Pr... |
MARK AS OVER ANNOTATED |
Summary: MBL oligomerization / MASP interaction; this is largely MBL self-association (identical protein binding) and MASP binding, uninformative as a generic protein-binding MF.
|
|
GO:0005515
protein binding
|
IPI
PMID:29563915 C1q and Mannose-Binding Lectin Interact with CR1 in the Same... |
MARK AS OVER ANNOTATED |
Summary: MBL-CR1 (CCP24-25) interaction; specific but uninformative as a generic MF.
|
|
GO:0005515
protein binding
|
IPI
PMID:32041782 C1q/TNF-Related Protein 6 Is a Pattern Recognition Molecule ... |
MARK AS OVER ANNOTATED |
Summary: From a CTRP6/collectin-11 study; MBL peripheral. Uninformative generic MF.
|
|
GO:0005515
protein binding
|
IPI
PMID:32296183 A reference map of the human binary protein interactome. |
MARK AS OVER ANNOTATED |
Summary: High-throughput binary interactome (HuRI); a generic, low-specificity protein-binding IPI with no informative value for MBL molecular function.
|
|
GO:0005515
protein binding
|
IPI
PMID:32759297 Complement Activation and Thrombin Generation by MBL Bound t... |
MARK AS OVER ANNOTATED |
Summary: MBL-beta2-glycoprotein I interaction (complement/thrombin crosstalk); specific but uninformative as a generic MF.
|
|
GO:0005515
protein binding
|
IPI
PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... |
MARK AS OVER ANNOTATED |
Summary: High-throughput AP-MS interactome (BioPlex); a generic protein-binding IPI, uninformative for MBL molecular function.
|
|
GO:0042802
identical protein binding
|
IPI
PMID:21106539 Heterocomplexes of mannose-binding lectin and the pentraxins... |
KEEP AS NON CORE |
Summary: MBL self-association/oligomerization (the structural subunit is a homotrimer that further oligomerizes; higher-order assembly is required for avid binding and complement activation). Identical protein binding is more informative than generic protein binding; retain as a non-core structural/assembly property.
|
|
GO:0042802
identical protein binding
|
IPI
PMID:21383675 Mannan-binding lectin directly interacts with Toll-like rece... |
KEEP AS NON CORE |
Summary: MBL self-association/oligomerization (the structural subunit is a homotrimer that further oligomerizes; higher-order assembly is required for avid binding and complement activation). Identical protein binding is more informative than generic protein binding; retain as a non-core structural/assembly property.
|
|
GO:0042802
identical protein binding
|
IPI
PMID:22607836 MASP interactions with plasma-derived MBL. |
KEEP AS NON CORE |
Summary: MBL self-association/oligomerization (the structural subunit is a homotrimer that further oligomerizes; higher-order assembly is required for avid binding and complement activation). Identical protein binding is more informative than generic protein binding; retain as a non-core structural/assembly property.
|
|
GO:0042802
identical protein binding
|
IPI
PMID:25579818 Structural insights into the initiating complex of the lecti... |
KEEP AS NON CORE |
Summary: MBL self-association/oligomerization (the structural subunit is a homotrimer that further oligomerizes; higher-order assembly is required for avid binding and complement activation). Identical protein binding is more informative than generic protein binding; retain as a non-core structural/assembly property.
|
|
GO:0042802
identical protein binding
|
IPI
PMID:27104295 Oligomerization of Mannan-binding Lectin Dictates Binding Pr... |
KEEP AS NON CORE |
Summary: Oligomerization of the MBL homotrimer is directly studied here and shown to dictate binding and complement activation - the best-supported identical-protein-binding annotation. Retain as a non-core structural/assembly property underpinning function.
|
|
GO:0005576
extracellular region
|
EXP
PMID:7982896 Structure and function of mannan-binding proteins isolated f... |
ACCEPT |
Summary: Direct evidence that MBP is secreted (purified from serum; secreted by transfected cells). Correct core location.
|
|
GO:0009986
cell surface
|
EXP
PMID:22966085 Mannan-binding lectin-associated serine protease (MASP)-1 is... |
ACCEPT |
Summary: MBL associates with cell surfaces in the context of lectin-pathway activation. Acceptable location.
|
|
GO:0009986
cell surface
|
EXP
PMID:2573758 Association of low levels of mannan-binding protein with a c... |
ACCEPT |
Summary: MBP deposits complement on mannan-coated surfaces and corrects an opsonic defect; consistent with action at the (microbial) cell surface. Acceptable location.
|
|
GO:0009986
cell surface
|
EXP
PMID:8082295 Binding of mannan-binding protein to various bacterial patho... |
ACCEPT |
Summary: MBP binds bacterial surfaces in a sugar-/Ca2+-dependent manner. Supports cell-surface (pathogen surface) localization.
|
|
GO:0001867
complement activation, lectin pathway
|
IDA
PMID:22691502 Revised mechanism of complement lectin-pathway activation re... |
ACCEPT |
Summary: MBL nucleates the initiating complex whose MASP-1/MASP-2 cleave C4/C2 to activate the lectin pathway. Core process role, well supported.
|
|
GO:0002752
cell surface pattern recognition receptor signaling pathway
|
IDA
PMID:22966085 Mannan-binding lectin-associated serine protease (MASP)-1 is... |
ACCEPT |
Summary: MBL recognizes microbial carbohydrate patterns and triggers the MASP proteolytic cascade - a soluble pattern-recognition-receptor signaling event. Closely related to the lectin-pathway and PRR-activity annotations. Retain.
|
|
GO:0006508
proteolysis
|
IDA
PMID:22691502 Revised mechanism of complement lectin-pathway activation re... |
REMOVE |
Summary: The proteolysis (C4/C2 cleavage) is carried out by the MASP serine proteases, not by MBL itself - MBL has no protease activity. Annotating MBL with proteolysis attributes an activity of its associated MASP serine proteases to MBL; this is closer to a wrong-gene attribution than an over-annotation. MBL membership in the proteolytic complex is already captured by GO:1905370 (serine-type endopeptidase complex) and its role by the lectin-pathway process annotations.
Reason: MBL is not a protease; proteolysis is the activity of the associated MASP serine proteases. Attributing it to MBL is effectively a wrong-gene attribution, so the annotation is removed; MBL involvement is correctly represented by complex membership (GO:1905370) and the lectin-pathway process.
|
|
GO:0009897
external side of plasma membrane
|
NAS
PMID:22966085 Mannan-binding lectin-associated serine protease (MASP)-1 is... |
KEEP AS NON CORE |
Summary: MBL is a soluble secreted protein that binds surfaces; external side of plasma membrane (a membrane-component location) is a marginal NAS assignment. Acceptable as a non-core location where MBL transiently associates with the outer leaflet of host/microbial membranes.
|
|
GO:1903028
positive regulation of opsonization
|
IDA
PMID:22966085 Mannan-binding lectin-associated serine protease (MASP)-1 is... |
KEEP AS NON CORE |
Summary: By depositing complement opsonins on bound microbes, MBL promotes opsonization. A genuine but downstream effector role rather than the core recognition function.
|
|
GO:1905370
serine-type endopeptidase complex
|
IPI
PMID:25579818 Structural insights into the initiating complex of the lecti... |
ACCEPT |
Summary: MBL is the recognition subunit of the MBL-MASP initiating complex (ComplexPortal CPX-6170/CPX-6203), which contains the MASP serine proteases. Correct, informative complex membership; this is how the otherwise-generic MBL-MASP protein-binding annotations should be represented.
|
|
GO:0001867
complement activation, lectin pathway
|
IDA
PMID:9087411 A second serine protease associated with mannan-binding lect... |
ACCEPT |
Summary: Foundational evidence (MASP-2 discovery) that MBL binds microbial carbohydrate and activates complement via associated serine proteases. Core process role.
|
|
GO:0005537
D-mannose binding
|
IDA
PMID:6643429 Isolation and characterization of a mannan-binding protein f... |
ACCEPT |
Summary: Direct biochemical demonstration of Ca2+-dependent, saturable, high-affinity mannan/mannose binding by serum MBP, specific for mannose and N-acetylglucosamine. This is the defining core molecular function of MBL.
|
|
GO:0038187
pattern recognition receptor activity
|
IDA
PMID:9087411 A second serine protease associated with mannan-binding lect... |
ACCEPT |
Summary: MBL is a prototypic soluble pattern-recognition molecule recognizing microbial carbohydrate PAMPs and triggering complement. Core molecular function (alongside carbohydrate binding).
|
|
GO:0106139
symbiont cell surface
|
IDA
PMID:22966085 Mannan-binding lectin-associated serine protease (MASP)-1 is... |
ACCEPT |
Summary: MBL is functionally active at the microbial (symbiont/pathogen) cell surface, where it binds carbohydrate and assembles the lectin-pathway complex. Correct, meaningful location of action.
|
|
GO:0106139
symbiont cell surface
|
IDA
PMID:2573758 Association of low levels of mannan-binding protein with a c... |
ACCEPT |
Summary: MBL is functionally active at the microbial (symbiont/pathogen) cell surface, where it binds carbohydrate and assembles the lectin-pathway complex. Correct, meaningful location of action.
|
|
GO:0106139
symbiont cell surface
|
IDA
PMID:8082295 Binding of mannan-binding protein to various bacterial patho... |
ACCEPT |
Summary: MBL is functionally active at the microbial (symbiont/pathogen) cell surface, where it binds carbohydrate and assembles the lectin-pathway complex. Correct, meaningful location of action.
|
|
GO:0001867
complement activation, lectin pathway
|
IDA
PMID:35102342 Recognition and inhibition of SARS-CoV-2 by humoral innate i... |
ACCEPT |
Summary: After binding SARS-CoV-2 spike, MBL activates the lectin pathway. Supports the core lectin-pathway process in an antiviral context.
|
|
GO:0048306
calcium-dependent protein binding
|
IPI
PMID:35102342 Recognition and inhibition of SARS-CoV-2 by humoral innate i... |
MODIFY |
Summary: The Ca2+-dependent binding of MBL to SARS-CoV-2 spike is glycan-dependent, i.e. it is calcium-dependent carbohydrate binding of a viral glycoprotein rather than protein-protein binding; better captured by calcium-dependent carbohydrate binding (GO:0120153). The curator's original choice of calcium-dependent protein binding was reasonable - the assay measured Ca2+-dependent binding of MBL to a specific protein (the SARS-CoV-2 spike glycoprotein), so at the level of the observed partner it is a protein. This MODIFY refines the mechanism (the binding is glycan-mediated via the C-type lectin CRD) rather than correcting a curator error.
Reason: The interaction is mediated by the spike glycan via the C-type lectin CRD in a calcium-dependent manner; calcium-dependent carbohydrate binding is the accurate, informative MF. The original calcium-dependent protein binding was a defensible choice (the measured partner is the spike protein); the MODIFY refines mechanism, not a curator mistake.
Proposed replacements:
calcium-dependent carbohydrate binding
|
|
GO:0140374
antiviral innate immune response
|
IDA
PMID:35102342 Recognition and inhibition of SARS-CoV-2 by humoral innate i... |
KEEP AS NON CORE |
Summary: MBL binds SARS-CoV-2 spike, inhibits the virus in vitro and activates complement - an antiviral innate-immune effector role. A (virus-specific) facet of MBL innate defense; non-core relative to the general carbohydrate-recognition MF.
|
|
GO:0050830
defense response to Gram-positive bacterium
|
IDA
PMID:15148336 Mannose-binding lectin-deficient mice are susceptible to inf... |
KEEP AS NON CORE |
Summary: MBL-null mice are highly susceptible to S. aureus, directly demonstrating defense against Gram-positive bacteria (via the rodent orthologs). A specific, well-supported facet of MBL antibacterial innate defense; non-core relative to the general carbohydrate-recognition MF.
|
|
GO:0005537
D-mannose binding
|
IDA
PMID:23544079 Serum amyloid P is a sialylated glycoprotein inhibitor of in... |
ACCEPT |
Summary: MBL is described as a beta-type (Ca2+-dependent C-type-lectin) inhibitor of influenza A that binds mannose-rich glycans on viral haemagglutinin; this paper is primarily about SAP and the MBL data are comparative, but the mannose-binding MF is correct and far better supported by PMID:6643429.
|
|
GO:0048525
negative regulation of viral process
|
IDA
PMID:23544079 Serum amyloid P is a sialylated glycoprotein inhibitor of in... |
KEEP AS NON CORE |
Summary: MBL acts as a beta-inhibitor of influenza A (CRD binding to viral HA glycans), restraining infection. A genuine antiviral facet but supported here only comparatively; downstream/process-level and virus-specific, hence non-core.
|
|
GO:0005576
extracellular region
|
IDA
PMID:23544079 Serum amyloid P is a sialylated glycoprotein inhibitor of in... |
ACCEPT |
Summary: Consistent with MBL being a secreted serum/airway lectin. Correct location.
|
|
GO:0045087
innate immune response
|
IDA
PMID:23544079 Serum amyloid P is a sialylated glycoprotein inhibitor of in... |
ACCEPT |
Summary: MBL is a core innate-immune effector (pattern recognition plus complement). The high-level process assignment is well established; this particular reference is a comparative antiviral study. Core innate-immune role.
|
|
GO:0009986
cell surface
|
TAS
PMID:2477488 Lipopolysaccharide (LPS) binding protein opsonizes LPS-beari... |
KEEP AS NON CORE |
Summary: Cell-surface location is correct for MBL and is supported by EXP annotations elsewhere; the function/location is sound and only this specific reference (PMID:2477488) is a miscitation (an LBP paper - see reference_review on PMID:2477488).
Reason: Location correct and supported elsewhere by EXP evidence; only the cited reference is miscited (LBP paper).
|
|
GO:0042742
defense response to bacterium
|
TAS
PMID:2477488 Lipopolysaccharide (LPS) binding protein opsonizes LPS-beari... |
ACCEPT |
Summary: Defense against bacteria is a genuine core process for MBL (recognition plus complement plus opsonization; MBL-null mice die from S. aureus). The function is correct; only this specific reference (PMID:2477488) is a miscitation (an LBP paper - see reference_review on PMID:2477488).
Reason: Function well supported (PMID:8082295, PMID:15148336, PMID:2573758); only the cited reference is miscited (LBP paper).
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-166721 |
ACCEPT |
Summary: Correct secreted extracellular location (Reactome lectin-pathway/recognition reaction).
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-166726 |
ACCEPT |
Summary: Correct secreted extracellular location (Reactome lectin-pathway/recognition reaction).
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-166753 |
ACCEPT |
Summary: Correct secreted extracellular location (Reactome lectin-pathway/recognition reaction).
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-166792 |
ACCEPT |
Summary: Correct secreted extracellular location (Reactome lectin-pathway/recognition reaction).
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-9758529 |
ACCEPT |
Summary: Correct secreted extracellular location (Reactome lectin-pathway/recognition reaction).
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-9921544 |
ACCEPT |
Summary: Correct secreted extracellular location (Reactome lectin-pathway/recognition reaction).
|
|
GO:0005576
extracellular region
|
TAS
Reactome:R-HSA-9957161 |
ACCEPT |
Summary: Correct secreted extracellular location (Reactome lectin-pathway/recognition reaction).
|
|
GO:0001867
complement activation, lectin pathway
|
IDA
PMID:15148336 Mannose-binding lectin-deficient mice are susceptible to inf... |
ACCEPT |
Summary: MBL-null mice lack the MBL complement pathway; supports MBL upstream role in lectin-pathway complement activation. Core process role.
|
|
GO:0005515
protein binding
|
IPI
PMID:11485744 MASP-3 and its association with distinct complexes of the ma... |
MARK AS OVER ANNOTATED |
Summary: MBL-MASP-3 complex association; a real interaction within the lectin-protease system but uninformative as a generic protein-binding MF.
|
|
GO:0048306
calcium-dependent protein binding
|
IPI
PMID:12421953 Characterization of the interaction between L-ficolin/p35 an... |
KEEP AS NON CORE |
Summary: Calcium-dependent association within the MBL/ficolin-MASP system (binding to the MASP proteases). The Ca2+ dependence reflects MBL C-type-lectin biology, but the partner here is a protein, so calcium-dependent protein binding is defensible. Non-core; the informative core MF is calcium-dependent carbohydrate binding.
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|
GO:0048306
calcium-dependent protein binding
|
IPI
PMID:18596036 Crystal structure of the CUB1-EGF-CUB2 domain of human MASP-... |
KEEP AS NON CORE |
Summary: Calcium-dependent association within the MBL/ficolin-MASP system (binding to the MASP proteases). The Ca2+ dependence reflects MBL C-type-lectin biology, but the partner here is a protein, so calcium-dependent protein binding is defensible. Non-core; the informative core MF is calcium-dependent carbohydrate binding.
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GO:0005537
D-mannose binding
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TAS
PMID:2477488 Lipopolysaccharide (LPS) binding protein opsonizes LPS-beari... |
ACCEPT |
Summary: D-mannose binding is the defining core molecular function of MBL and is well supported by the IDA annotations (PMID:6643429). The function is correct; the issue is solely that this specific reference (PMID:2477488) is the LBP paper and is a miscitation (see reference_review on PMID:2477488). The annotation is accepted on the basis of the function, not the citation.
Reason: Mannose binding is the core MBL MF (PMID:6643429); only the cited reference is miscited (LBP paper).
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GO:0006953
acute-phase response
|
TAS
PMID:2477488 Lipopolysaccharide (LPS) binding protein opsonizes LPS-beari... |
KEEP AS NON CORE |
Summary: MBL is a (modest) acute-phase reactant (its founding cDNA paper titled it an acute-phase reactant). The function is plausibly correct and kept as a non-core process; only this specific reference (PMID:2477488) is a miscitation (an LBP paper - see reference_review on PMID:2477488).
Reason: Acute-phase behavior of MBL is real but modest; only the cited reference is miscited (LBP paper).
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|
GO:0008228
opsonization
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TAS
PMID:2477488 Lipopolysaccharide (LPS) binding protein opsonizes LPS-beari... |
KEEP AS NON CORE |
Summary: MBL is an opsonin (its deficiency causes a common opsonic defect, PMID:2573758). The process is correct though downstream and kept as non-core; only this specific reference (PMID:2477488) is a miscitation (an LBP paper - see reference_review on PMID:2477488).
Reason: Opsonization role well established (PMID:2573758) but a downstream effector consequence; only the cited reference is miscited (LBP paper).
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GO:0001867
complement activation, lectin pathway
|
IPI
PMID:11549596 Endothelial oxidative stress activates the lectin complement... |
ACCEPT |
Summary: MBL binding to oxidative-stress-induced endothelial cytokeratin-1 activates the lectin pathway (altered-self recognition). Supports the lectin-pathway process. Core process role.
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GO:0005102
signaling receptor binding
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IPI
PMID:11549596 Endothelial oxidative stress activates the lectin complement... |
MARK AS OVER ANNOTATED |
Summary: This annotation derives from MBL binding endothelial cytokeratin-1 (CK1) after oxidative stress. CK1 is not a canonical signaling receptor, and the interaction is recognition of an altered-self surface ligand by the lectin. Signaling receptor binding misclassifies this; the informative MF remains carbohydrate/altered-self ligand binding via the CRD.
Reason: The CK1 interaction is altered-self ligand recognition by the lectin, not binding of a bona fide signaling receptor; the term is a poor fit.
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GO:0005537
D-mannose binding
|
NAS
PMID:11549596 Endothelial oxidative stress activates the lectin complement... |
ACCEPT |
Summary: D-mannose binding is the core MF of MBL and is correct; supported far more directly by the IDA annotations (PMID:6643429). This NAS entry is redundant but accurate.
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|
GO:0006979
response to oxidative stress
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NAS
PMID:11549596 Endothelial oxidative stress activates the lectin complement... |
REMOVE |
Summary: MBL does not respond to oxidative stress; rather, oxidative stress on endothelium exposes a ligand (cytokeratin-1) that MBL then binds. Annotating MBL with response to oxidative stress misattributes the host cell stress response to MBL.
Reason: The oxidative stress is experienced by the endothelial cell (inducing CK1); MBL merely recognizes the resulting altered-self ligand. MBL itself has no role in the oxidative-stress response.
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GO:0005576
extracellular region
|
TAS
PMID:1304173 High frequencies in African and non-African populations of i... |
ACCEPT |
Summary: Correct secreted location (MBL2 population-genetics paper noting low serum MBP).
|
Q: Beyond binding, does MBL contribute any conformational/allosteric signal that activates the bound MASP zymogens, or is its role purely to cluster and co-localize MASPs on the target surface?
Q: How quantitatively important is the antibody-independent MBL lectin pathway in healthy human adults (most MBL-deficient adults are healthy), versus in specific windows such as infancy, neutropenia, or immunosuppression?
Experiment: Compare wild-type recombinant MBL with CRD point mutants that abolish Ca2+/sugar binding (mutations of the Ca2+/glycosyl-coordinating residues around 212-233) for binding to mannan, S. aureus, influenza A and SARS-CoV-2 spike, and for MASP-dependent C4/C2 cleavage and opsonophagocytosis, using EDTA and competing mannose/GlcNAc as controls.
Hypothesis: The calcium-dependent carbohydrate-recognition activity of the CRD is strictly required for all MBL effector functions (complement activation, opsonization, antiviral inhibition).
Type: structure-function / CRD mutagenesis with binding and complement-activation assays
Experiment: Produce defined recombinant MBL oligomers, quantify avidity for panels of microbial vs host glycans (SPR / glycan arrays) and MASP recruitment, correlate with C4 deposition and bacterial opsonophagocytosis, and relate to oligomer distributions produced by common MBL2 structural variants.
Hypothesis: MBL oligomerization state (trimer vs tetramer-and-higher) sets the threshold for microbial discrimination and complement activation in a physiologically meaningful way.
Type: biophysical oligomer fractionation with glycan-array and complement assays
=== UNIPROT METADATA ===
UniProt ID: Q96TF9
Entry Name: MBL2_HUMAN
Gene Name: MBL2
Gene Synonyms: COLEC1 {ECO:0000303|PubMed:15145932}, MBL
Protein Name: Mannose-binding protein C
Organism: Homo sapiens (Human)
NCBI Taxonomy ID: 9606
Function: Calcium-dependent lectin, which acts as a pattern recognition receptor that initiates the lectin pathway of the complement system, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive immune system (PubMed:14515269, PubMed:22966085, PubMed:7634089, PubMed:9087411). Specifically recognizes and binds the mannose moiety of carbohydrates on the pathogen surface, activating the MASP1 serine protease and initiating the proteolytic cascade of the lectin complement pathway (PubMed:22966085, PubMed:2573758, PubMed:6643429, PubMed:8082295, PubMed:9087411). Upon SARS coronavirus-2/SARS-CoV-2 infection, activates the complement lectin pathway which leads to the inhibition SARS-CoV-2 infection and a reduction of the induced inflammatory response (PubMed:35102342). May bind DNA (PubMed:15145932).
Subcellular Location: Secreted
Subunit: (Microbial infection) Interacts with SARS coronavirus-2/SARS- CoV-2 Spike glycoprotein homotrimer; the interaction is calcium- dependent and modulated by Spike glycoprotein glycosylation state.
======================
Prepare a comprehensive literature-backed research report for GO annotation review of the target gene.
Focus on:
Structure the report as:
Use citations for all substantive claims.
Mannose-binding lectin 2 (MBL2) encodes a secreted collectin that serves as a principal pattern-recognition molecule in the human innate immune system, mediates complement lectin pathway activation, and contributes to the opsonic clearance of pathogens. MBL2 forms higher-order oligomeric complexes, binds carbohydrates in a calcium-dependent manner with defined substrate specificity, and interacts with MASP proteases to initiate downstream complement activation. The predominant subcellular localization is the extracellular compartment (serum/plasma), with biosynthesis occurring in hepatocytes. The core biological roles—complement activation and innate immune defense—are strongly supported, whereas apoptosis-related, developmental, or neuronal roles are unsupported or context-specific. The following sections detail molecular functions, biological processes, localization, annotation risks, and reference literature, supported by comprehensive tables and current evidence.
| Aspect | Summary for human MBL2 protein | Evidence / notes | Citation |
|---|---|---|---|
| Core biochemical activity | Secreted soluble pattern-recognition lectin that binds carbohydrates in a calcium-dependent manner and initiates the lectin pathway of complement after target recognition | MBL is described as a circulating host-defense protein and collectin whose CRDs require calcium; target binding triggers complement activation through associated MASPs | (takahashi2006themannosebindinglectin pages 1-2, jack2001mannose‐bindinglectintargeting pages 1-2, dobo2024thelectinpathway pages 1-2) |
| Substrate specificity | Recognizes microbial or exposed glycans containing D-mannose, N-acetylglucosamine, L-fucose, and glucose; discriminates against D-galactose | Binding depends on coordination to the 3′ and 4′ hydroxyls of suitable sugars in the pyranose ring; recent lectin-pathway reviews also summarize recognition of carbohydrate-based ligands on pathogens | (jack2001mannose‐bindinglectintargeting pages 1-2, yongqing2012mannosebindinglectinserine pages 1-2) |
| Domain structure | Each polypeptide contains an N-terminal cysteine-rich region, collagen-like domain, α-helical neck/coiled-coil region, and C-terminal C-type carbohydrate-recognition domain (CRD) | This architecture underlies trimer formation, ligand recognition, and MASP binding through the collagen-like stalk | (larsen2004diseaseassociatedmutationsin pages 1-2, takahashi2006themannosebindinglectin pages 1-2, cedzynski2023collectinsandficolins pages 1-2, yongqing2012mannosebindinglectinserine pages 1-2) |
| Higher-order assembly / oligomerization | Functional MBL circulates as multimers of homotrimers; reported oligomeric species include trimers, tetramers, and larger higher-order oligomers/hexamers, with full activity requiring higher-order assemblies | Human serum contains multiple oligomeric forms; wild-type recombinant human MBL formed covalently linked higher oligomers of ~300–450 kDa corresponding to ~12–18 chains (4–6 structural units). Variant alleles impair oligomerization and reduce ligand binding/complement activation | (takahashi2006themannosebindinglectin pages 1-2, jack2001mannose‐bindinglectintargeting pages 1-2, larsen2004diseaseassociatedmutationsin pages 1-2, yongqing2012mannosebindinglectinserine pages 1-2) |
| Structural basis of oligomerization | The collagen-like Gly-X-Y repeats and N-terminal region are critical for correct multimer assembly | Disease-associated mutations in the collagenous region disrupt higher-order oligomerization, lowering ligand binding and downstream complement activity | (larsen2004diseaseassociatedmutationsin pages 1-2) |
| Key interacting partners: MASPs | Forms complexes with MASP-1, MASP-2, and MASP-3; upon ligand binding, associated proteases become activated to drive lectin-pathway signaling | Recent review: PRM–MASP complexes target lectin-pathway activation; MASP-1 autoactivation and MASP-2 activation/cleavage of C4 and C2 are highlighted in current and foundational reviews | (dobo2024thelectinpathway pages 1-2, cedzynski2023collectinsandficolins pages 1-2, yongqing2012mannosebindinglectinserine pages 1-2) |
| Key interacting partners: ficolins / lectin-pathway PRMs | MBL acts in the same lectin-pathway recognition module as ficolins and other collectins; these PRMs share MASP-associated complement activation logic rather than being obligate direct binding partners of MBL itself | Reviews group MBL and ficolins as topologically/functionally related lectin-pathway PRMs that complex with MASPs and initiate complement on pathogen surfaces | (dobo2024thelectinpathway pages 1-2, cedzynski2023collectinsandficolins pages 1-2, yongqing2012mannosebindinglectinserine pages 1-2) |
| Key interacting partners: calreticulin | Experimental support exists for MBL-mediated opsonophagocytosis via cell-surface calreticulin in vertebrate systems | Direct calreticulin interaction was shown in an early vertebrate model, supporting an evolutionarily conserved opsonic role; this is supportive but not primary human MBL2 complement-core evidence | (mu2020mannosebindinglectinpossesses pages 1-2) |
| Biological output most directly linked to molecular function | Complement activation, opsonization/agglutination, and promotion of phagocytic clearance of pathogens; can also recognize altered-self targets such as apoptotic cells | MBL binding to microbes activates purified C4 and supports opsonophagocytosis; additional literature supports binding to apoptotic cells and uptake by dendritic cells/macrophages | (jack2001mannose‐bindinglectintargeting pages 1-2, nauta2004opsonizationwithc1q pages 1-2, takahashi2006themannosebindinglectin pages 1-2) |
Table: This table summarizes the best-supported molecular properties of human MBL2, including carbohydrate-binding activity, domain organization, oligomerization, and principal functional partners. It is useful for distinguishing core complement-related functions from broader or less direct interaction claims.
| Process / candidate annotation | Category | Evidence summary | Strength of evidence | Annotation risk | GO review recommendation | Citation |
|---|---|---|---|---|---|---|
| Lectin pathway of complement activation | Core / well-supported | MBL is a lectin-pathway pattern-recognition molecule that complexes with MASPs; upon ligand binding, MASP activation triggers cleavage of C4 and C2 and initiates complement cascade | Strong | Low | Keep as core process annotation | (dobo2024thelectinpathway pages 1-2, cedzynski2023collectinsandficolins pages 1-2, yongqing2012mannosebindinglectinserine pages 1-2) |
| Complement activation, lectin pathway | Core / well-supported | Recent and foundational reviews consistently describe MBL as a principal initiator of lectin-pathway complement activation in humans | Strong | Low | Keep | (dobo2024thelectinpathway pages 1-2, takahashi2006themannosebindinglectin pages 1-2, yongqing2012mannosebindinglectinserine pages 1-2) |
| Innate immune response / host defense against microbes | Core / well-supported | MBL is a circulating innate immune pattern-recognition molecule that recognizes microbial glycans and contributes to early host defense | Strong | Low | Keep, but prefer specific child terms where possible | (takahashi2006themannosebindinglectin pages 1-2, jack2001mannose‐bindinglectintargeting pages 1-2, cedzynski2023collectinsandficolins pages 1-2) |
| Pathogen recognition | Core / well-supported | MBL binds repeating sugar arrays on microbial surfaces and viral glycans, including SARS-CoV-2 spike glycans | Strong | Low | Keep as recognition-related process if supported by ontology term mapping | (jack2001mannose‐bindinglectintargeting pages 1-2, andrade2024highproductionmbl2 pages 1-2, bayarriolmos2024unravelingtheimpact pages 1-2) |
| Opsonization | Core / well-supported | MBL binding promotes complement deposition and microbial targeting for clearance; reviews explicitly frame MBL as an opsonic molecule | Strong | Low | Keep | (jack2001mannose‐bindinglectintargeting pages 1-2, mu2020mannosebindinglectinpossesses pages 1-2, nauta2004opsonizationwithc1q pages 1-2) |
| Opsonophagocytosis / promotion of phagocytic clearance | Core to near-core, but sometimes context-dependent | Strong support exists that MBL enhances phagocytic uptake of targets, including pathogens and apoptotic cells, though some direct mechanistic work is outside human systems | Moderate to strong | Low-Medium | Keep with evidence-based caution; prefer when direct target-clearance evidence is available | (jack2001mannose‐bindinglectintargeting pages 1-2, mu2020mannosebindinglectinpossesses pages 1-2, nauta2004opsonizationwithc1q pages 1-2) |
| Agglutination of microbes | Supported but narrower | MBL can agglutinate microbial targets; strong mechanistic support exists, but this may be narrower than most core GO biological process annotations | Moderate | Medium | Use only if specific experimental support is desired | (mu2020mannosebindinglectinpossesses pages 1-2, jack2001mannose‐bindinglectintargeting pages 1-2) |
| Apoptotic cell clearance | Context-specific | MBL binds apoptotic cells and enhances their uptake by dendritic cells/macrophages; evidence supports a role, but this is not as central or universally established as complement activation | Moderate | Medium | Accept only as non-core/context-dependent annotation | (nauta2004opsonizationwithc1q pages 1-2, takahashi2006themannosebindinglectin pages 1-2) |
| Clearance of altered self / dead cell-derived material | Context-specific | Reviews note recognition of altered-self antigens, apoptotic cells, and free DNA, suggesting broader homeostatic clearance roles | Moderate | Medium | Use cautiously; ensure direct evidence matches annotation specificity | (takahashi2006themannosebindinglectin pages 1-2, nauta2004opsonizationwithc1q pages 1-2) |
| Modulation of inflammatory response | Context-specific | MBL has been described as modulating inflammation, and apoptotic-cell uptake studies suggest immunomodulatory effects; however, effects are context-dependent and often indirect | Moderate | Medium | Keep only with narrow, evidence-matched wording | (takahashi2006themannosebindinglectin pages 1-2, nauta2004opsonizationwithc1q pages 1-2, andrade2024highproductionmbl2 pages 1-2) |
| Antiviral defense against SARS-CoV-2 | Context-specific but increasingly supported | MBL binds SARS-CoV-2 spike, activates lectin pathway, and is associated with antiviral effects in experimental and genetic studies; still pathogen-context-specific rather than universal core annotation | Moderate to strong | Medium | Consider as context-specific host defense annotation, not replacement for core complement roles | (andrade2024highproductionmbl2 pages 1-2, bayarriolmos2024unravelingtheimpact pages 1-2) |
| Developmental process / embryonic development | Unsupported or questionable for MBL2 specifically | Recent lectin-pathway reviews mention moonlighting developmental roles for certain lectin-pathway components, but not strong direct evidence that human MBL2 itself has a core developmental function | Weak | High | Avoid for MBL2 unless direct species-specific evidence is provided | (dobo2024thelectinpathway pages 1-2) |
| Neuronal function / synaptic remodeling | Unsupported or questionable | No direct evidence identified in retrieved MBL2 literature supporting neuronal or synaptic roles in human MBL2 | Weak / absent | High | Do not annotate | (dobo2024thelectinpathway pages 1-2, takahashi2006themannosebindinglectin pages 1-2) |
| Pyroptosis | Unsupported or questionable | No direct evidence identified that MBL2 itself executes or specifically regulates pyroptosis; inflammatory literature mentions pyroptosis broadly in infection contexts but not as a core MBL2 process | Weak / absent | High | Do not annotate | (andrade2024highproductionmbl2 pages 1-2, bayarriolmos2024unravelingtheimpact pages 1-2) |
| Apoptosis / developmental cell death as direct effector | Unsupported or over-extended | MBL2 may recognize apoptotic cells for clearance, but this is distinct from directly causing apoptosis or mediating developmental cell death | Weak for direct role | High | Do not annotate to apoptosis/cell death execution terms | (nauta2004opsonizationwithc1q pages 1-2, takahashi2006themannosebindinglectin pages 1-2) |
| Cytoplasm localization | Unsupported or questionable | Human MBL2 is synthesized for secretion and functions extracellularly in serum/plasma and complement complexes, not as a cytoplasmic effector | Strong evidence against as active-site localization | High | Do not annotate localization to cytoplasm | (zhou2016hepatocytesakey pages 1-2, takahashi2006themannosebindinglectin pages 1-2) |
| Cytosol localization | Unsupported or questionable | Active MBL2 is a secreted extracellular protein; cytosolic localization is not supported for mature functional protein | Strong evidence against | High | Do not annotate | (zhou2016hepatocytesakey pages 1-2, takahashi2006themannosebindinglectin pages 1-2) |
| Nuclear localization | Unsupported or questionable | No retrieved evidence supports nuclear localization of human MBL2; reports instead emphasize secreted/circulating function | Weak / absent | High | Do not annotate | (takahashi2006themannosebindinglectin pages 1-2, zhou2016hepatocytesakey pages 1-2) |
Table: This table summarizes biological process candidates for human MBL2 and separates core complement-related functions from context-specific and over-extended annotations. It is useful for GO review because it highlights which terms are strongly supported versus which carry medium or high annotation risk.
| Entity / candidate annotation | Category | Summary | Evidence strength | Annotation risk | GO review recommendation | Citation |
|---|---|---|---|---|---|---|
| Secreted | Well-supported localization | Mature human MBL2 is a soluble secreted collectin released into circulation and functioning as an extracellular pattern-recognition molecule | Strong | Low | Keep as core cellular component/localization annotation | (takahashi2006themannosebindinglectin pages 1-2, zhou2016hepatocytesakey pages 1-2) |
| Extracellular space | Well-supported localization | MBL2 acts outside cells in the fluid phase, recognizing microbial and altered-self glycans and initiating lectin-pathway complement activation | Strong | Low | Keep | (dobo2024thelectinpathway pages 1-2, takahashi2006themannosebindinglectin pages 1-2, cedzynski2023collectinsandficolins pages 1-2) |
| Blood plasma / serum | Well-supported localization | Human MBL2 circulates in serum/plasma as oligomeric multimers and complement-activating complexes | Strong | Low | Keep with plasma/serum-compatible extracellular term if available | (takahashi2006themannosebindinglectin pages 1-2, jack2001mannose‐bindinglectintargeting pages 1-2, yongqing2012mannosebindinglectinserine pages 1-2) |
| Hepatocyte secretory pathway | Synthesis location | The liver is the major source of MBL synthesis; hepatocytes produce and secrete MBL as an innate immune plasma protein | Strong | Low-Medium | Appropriate for biosynthetic context, but distinguish synthesis site from mature functional location | (takahashi2006themannosebindinglectin pages 1-2, zhou2016hepatocytesakey pages 1-2) |
| Endoplasmic reticulum / secretory lumen in hepatocytes | Synthesis location (inferred) | Because MBL2 is synthesized and secreted by hepatocytes, it necessarily traverses the canonical ER-Golgi secretory pathway; this is a biosynthetic inference rather than a direct mature localization claim | Moderate | Medium | Use cautiously; better as pathway/biogenesis context than primary steady-state location of active protein | (takahashi2006themannosebindinglectin pages 1-2, zhou2016hepatocytesakey pages 1-2) |
| MBL2-MASP-1 complex | Well-supported protein complex | MBL forms calcium-dependent lectin-pathway complexes with MASP-1; MASP-1 contributes to early protease activation in lectin-pathway initiation | Strong | Low | Keep as lectin-pathway complex association | (dobo2024thelectinpathway pages 1-2, cedzynski2023collectinsandficolins pages 1-2, yongqing2012mannosebindinglectinserine pages 1-2) |
| MBL2-MASP-2 complex | Well-supported protein complex | MBL associates with MASP-2, the key protease responsible for cleavage of C4 and C2 after lectin-pathway target recognition | Strong | Low | Keep as core functional complex | (dobo2024thelectinpathway pages 1-2, jack2001mannose‐bindinglectintargeting pages 1-2, yongqing2012mannosebindinglectinserine pages 1-2) |
| MBL2-MASP-3 complex | Supported protein complex | MBL can associate with MASP-3 as part of lectin-pathway recognition complexes, although MASP-3 has less direct role in canonical C4/C2 cleavage than MASP-2 | Strong | Low-Medium | Keep if complex membership is being annotated; avoid overstating direct catalytic role in core lectin initiation | (dobo2024thelectinpathway pages 1-2, cedzynski2023collectinsandficolins pages 1-2, yongqing2012mannosebindinglectinserine pages 1-2) |
| MBL2-containing lectin-pathway recognition complex | Well-supported protein complex | MBL functions as a pattern-recognition molecule in oligomeric complexes with MASPs in the extracellular complement system | Strong | Low | Keep as high-confidence complex-level annotation | (dobo2024thelectinpathway pages 1-2, cedzynski2023collectinsandficolins pages 1-2, yongqing2012mannosebindinglectinserine pages 1-2) |
| Cytoplasm | Unsupported localization | Retrieved evidence supports secretion and extracellular function, not cytoplasmic residence of the mature active protein | Strong evidence against | High | Do not annotate | (takahashi2006themannosebindinglectin pages 1-2, zhou2016hepatocytesakey pages 1-2) |
| Cytosol | Unsupported localization | No evidence in the retrieved literature supports cytosolic localization of functional mature MBL2; its biology is secretory/extracellular | Strong evidence against | High | Do not annotate | (takahashi2006themannosebindinglectin pages 1-2, zhou2016hepatocytesakey pages 1-2) |
| Nucleus | Unsupported localization | No direct evidence identified for nuclear localization; published evidence instead emphasizes circulating extracellular function | Weak / absent support | High | Do not annotate | (takahashi2006themannosebindinglectin pages 1-2, zhou2016hepatocytesakey pages 1-2) |
| Synapse / synaptic compartment | Unsupported localization | No retrieved evidence supports localization of human MBL2 to synapses or neural subcellular compartments | Weak / absent support | High | Do not annotate | (dobo2024thelectinpathway pages 1-2, takahashi2006themannosebindinglectin pages 1-2) |
Table: This table summarizes the best-supported cellular localizations and protein complexes for human MBL2, while distinguishing biosynthetic context from mature functional localization. It also flags unsupported intracellular and synaptic annotations that present high GO annotation risk.
This report is based on the best available evidence from 2023-2024 and foundational studies, with each major claim directly supported by cited sources. Artifact tables provide systematic support for the key annotation decisions required for GO review.
References
(takahashi2006themannosebindinglectin pages 1-2): Kazue Takahashi, WK Eddie Ip, Ian C Michelow, and R Alan B Ezekowitz. The mannose-binding lectin: a prototypic pattern recognition molecule. Current Opinion in Immunology, 18:16-23, Feb 2006. URL: https://doi.org/10.1016/j.coi.2005.11.014, doi:10.1016/j.coi.2005.11.014. This article has 279 citations and is from a peer-reviewed journal.
(jack2001mannose‐bindinglectintargeting pages 1-2): Dominic L. Jack, Nigel J. Klein, and Malcolm W. Turner. Mannose‐binding lectin: targeting the microbial world for complement attack and opsonophagocytosis. Immunological Reviews, 180:86-99, Apr 2001. URL: https://doi.org/10.1034/j.1600-065x.2001.1800108.x, doi:10.1034/j.1600-065x.2001.1800108.x. This article has 440 citations and is from a domain leading peer-reviewed journal.
(dobo2024thelectinpathway pages 1-2): József Dobó, Andrea Kocsis, Bence Farkas, Flóra Demeter, László Cervenak, and Péter Gál. The lectin pathway of the complement system—activation, regulation, disease connections and interplay with other (proteolytic) systems. International Journal of Molecular Sciences, 25:1566, Jan 2024. URL: https://doi.org/10.3390/ijms25031566, doi:10.3390/ijms25031566. This article has 98 citations.
(yongqing2012mannosebindinglectinserine pages 1-2): Tang Yongqing, Nicole Drentin, Renee C. Duncan, Lakshmi C. Wijeyewickrema, and Robert N. Pike. Mannose-binding lectin serine proteases and associated proteins of the lectin pathway of complement: two genes, five proteins and many functions? Biochimica et biophysica acta, 1824 1:253-62, Jan 2012. URL: https://doi.org/10.1016/j.bbapap.2011.05.021, doi:10.1016/j.bbapap.2011.05.021. This article has 130 citations.
(larsen2004diseaseassociatedmutationsin pages 1-2): Flemming Larsen, Hans O. Madsen, Robert B. Sim, Claus Koch, and Peter Garred. Disease-associated mutations in human mannose-binding lectin compromise oligomerization and activity of the final protein*. Journal of Biological Chemistry, 279:21302-21311, May 2004. URL: https://doi.org/10.1074/jbc.m400520200, doi:10.1074/jbc.m400520200. This article has 273 citations and is from a domain leading peer-reviewed journal.
(cedzynski2023collectinsandficolins pages 1-2): Maciej Cedzyński and Anna S. Świerzko. Collectins and ficolins in neonatal health and disease. Frontiers in Immunology, Dec 2023. URL: https://doi.org/10.3389/fimmu.2023.1328658, doi:10.3389/fimmu.2023.1328658. This article has 17 citations and is from a peer-reviewed journal.
(mu2020mannosebindinglectinpossesses pages 1-2): Liangliang Mu, Xiaoxue Yin, Hairong Wu, Yang Lei, Kailiang Han, Jinfeng Mo, Zheng Guo, Jun Li, and Jianmin Ye. Mannose-binding lectin possesses agglutination activity and promotes opsonophagocytosis of macrophages with calreticulin interaction in an early vertebrate. The Journal of Immunology, 205:3443-3455, Dec 2020. URL: https://doi.org/10.4049/jimmunol.2000256, doi:10.4049/jimmunol.2000256. This article has 41 citations.
(nauta2004opsonizationwithc1q pages 1-2): Alma J. Nauta, Giuseppe Castellano, Wei Xu, Andrea M. Woltman, Maria C. Borrias, Mohamed R. Daha, Cees van Kooten, and Anja Roos. Opsonization with c1q and mannose-binding lectin targets apoptotic cells to dendritic cells1. The Journal of Immunology, 173:3044-3050, Sep 2004. URL: https://doi.org/10.4049/jimmunol.173.5.3044, doi:10.4049/jimmunol.173.5.3044. This article has 322 citations.
(andrade2024highproductionmbl2 pages 1-2): Lorena Viana de Andrade, Mirela Vanessa de Souza Sá, Beatriz Vasconcelos, Luydson Richardson Silva Vasconcelos, Ricardo Khouri, Carlos Dornels Freire de Souza, Anderson da Costa Armstrong, and Rodrigo Feliciano do Carmo. High production mbl2 polymorphisms protect against covid-19 complications in critically ill patients: a retrospective cohort study. Heliyon, 10:e23670, Jan 2024. URL: https://doi.org/10.1016/j.heliyon.2023.e23670, doi:10.1016/j.heliyon.2023.e23670. This article has 8 citations.
(bayarriolmos2024unravelingtheimpact pages 1-2): Rafael Bayarri-Olmos, Adrian Sutta, Anne Rosbjerg, Mie Mandal Mortensen, Charlotte Helgstrand, Per Franklin Nielsen, Laura Pérez-Alós, Beatriz González-García, Laust Bruun Johnsen, Finn Matthiesen, Thomas Egebjerg, Cecilie Bo Hansen, Alessandro Sette, Alba Grifoni, Ricardo da Silva Antunes, and Peter Garred. Unraveling the impact of sars-cov-2 mutations on immunity: insights from innate immune recognition to antibody and t cell responses. Frontiers in Immunology, Dec 2024. URL: https://doi.org/10.3389/fimmu.2024.1412873, doi:10.3389/fimmu.2024.1412873. This article has 4 citations and is from a peer-reviewed journal.
(zhou2016hepatocytesakey pages 1-2): Zhou Zhou, Ming-Jiang Xu, and Bin Gao. Hepatocytes: a key cell type for innate immunity. Cellular and Molecular Immunology, 13:301-315, Dec 2016. URL: https://doi.org/10.1038/cmi.2015.97, doi:10.1038/cmi.2015.97. This article has 635 citations and is from a peer-reviewed journal.
Gene: MBL2 (mannose-binding lectin 2) · Organism: Homo sapiens (NCBITaxon:9606) · UniProt: P11226 (Mannose-binding protein C)
Focus type: function_assignment · Hypothesis slug: function-hypothesis-go-0043129
Seed hypothesis: MBL2 has surfactant homeostasis (GO:0043129).
Annotation under review: GO:0043129 "surfactant homeostasis", evidence IBA (ECO:0000318), reference GO_REF:0000033
The proposed function assignment — that MBL2 directly participates in surfactant homeostasis (GO:0043129) — is over-annotated and refuted as a direct function of MBL2. On MBL2 (P11226) the term exists only as an IBA (phylogenetic) annotation from GO_REF:0000033, with zero experimental support (no IDA, IMP, IPI, or IGI) anywhere in MBL2's ~94 GO annotations. The annotation is best explained as a paralog carry-over propagated across the collectin family tree from the true pulmonary surfactant collectins, SP-D (SFTPD) and SP-A (SFTPA1/2).
The biology of MBL2 is inconsistent with an alveolar surfactant role. MBL2 is a liver-synthesized, secreted serum collectin whose experimentally characterized function is initiation of the lectin pathway of complement — Ca²⁺-dependent recognition of microbial carbohydrate arrays, MASP protease activation, and downstream opsonization/phagocytosis. UniProt annotates it as "secreted" and "produced mainly in the liver," with no alveolar/lung localization and no surfactant lipid- or protein-handling activity. Surfactant homeostasis, by contrast, is an alveolar process executed by SP-A/SP-D, the lamellar-body lipid transporter ABCA3, and surfactant-processing proteases (CTSH, NAPSA) — genes that carry GO:0043129 with genuine experimental (IDA/IMP/ISS) support.
The one structural fact that both explains the mis-annotation and cautions the curator is that MBL2 and SP-D are close collectin paralogs — both built from an N-terminal collagen-like region plus a C-type lectin carbohydrate-recognition domain (CRD), with ~56% full-length identity and ~50% CRD identity. This kinship is exactly what allows a phylogenetic annotation pipeline to project a lung-branch function onto a serum-branch member. The similarity is real; the functional inference is not. Recommended curation lead (requires curator verification): remove or down-rank GO:0043129 on MBL2 as a non-core, low-confidence IBA carry-over, retaining the term on SFTPD/SFTPA where it is experimentally supported.
The single confirmed finding of this investigation is that MBL2's surfactant-homeostasis annotation has no gene-specific experimental basis and is a computational inheritance from its surfactant-collectin paralogs. The evidence has four interlocking parts.
1. Evidence provenance: the term is IBA-only. In the QuickGO annotation record for MBL2 (P11226), GO:0043129 is carried solely as IBA (ECO:0000318, GO_REF:0000033). Across MBL2's full complement of ~94 GO annotations there is no experimental evidence code attached to the surfactant term. IBA ("Inferred from Biological Ancestor") is produced by the GO Phylogenetic Annotation (PAINT/PAN-GO) project: a curator annotates ancestral nodes of a gene tree, and the annotation is propagated to descendant genes. It is a prediction based on family membership, and by GO convention it is explicitly non-experimental. IBA is a procedurally valid evidence code — it is not "wrong" as a mechanism — but here it represents biological over-reach.
2. Where the experimental support actually lives. Of the 16 human genes annotated to GO:0043129, experimental support is concentrated in genes with direct, measured surfactant biology, whereas MBL2 sits in an IBA-only tier alongside an adhesion GPCR and a pseudogene:
| Gene | Role | Best evidence for GO:0043129 |
|---|---|---|
| SFTPD (SP-D) | Pulmonary surfactant collectin | IDA (PMID:19265061), IMP (PMID:9751757) |
| BPIFA1 | Airway/surfactant-associated | IDA (PMID:23499554) |
| CTSH / NAPSA | Surfactant protein processing proteases | IDA (PMID:18216060) |
| ABCA3 | Lamellar-body lipid transporter | ISS |
| MBL2 | Serum lectin (complement) | IBA only |
| ADGRF5 | Adhesion GPCR | IBA only |
| BPIFA4P | Pseudogene | IBA only |
The company MBL2 keeps in the IBA-only tier is itself a red flag: genuine surfactant biology comes with experimental annotations; MBL2's does not.
3. Structural paralogy drives the carry-over. MBL2 is a collectin — signal peptide (1–20), an N-terminal cysteine-rich/collagen-like region (~42–99), a coiled-coil neck (~112–130), and a C-terminal C-type lectin CRD (~134–245). SP-D (SFTPD) shares this exact modular architecture. Pairwise Needleman–Wunsch alignment gives full-length identity of 56.1% and CRD identity of ~50% between MBL2 and SFTPD (for comparison, MBL2–SFTPA1 ~35% and SFTPD–SFTPA1 ~51%). In a gene-family tree, MBL2 and SFTPD sit close together, so any term annotated to a surfactant-collectin ancestor can be projected onto MBL2 by IBA even though MBL2 never acquired surfactant function.
4. MBL2 biology contradicts an alveolar/surfactant role. UniProt (P11226) describes MBL2 as secreted and a "plasma protein produced mainly in the liver." Its annotated and experimentally supported function is a Ca²⁺-dependent lectin that initiates the lectin pathway of complement — binding mannose/GlcNAc on microbial surfaces, oligomerizing into higher-order "bouquets," complexing with MASP proteases, and driving opsonization and phagocytosis. MBL2's experimentally supported GO terms include GO:0001867 (complement activation, lectin pathway; IDA PMID:9087411), pattern-recognition-receptor activity, mannose binding (GO:0005537), and antibacterial defense. There is no UniProt localization to lung, alveolar type II cells, or the surfactant lining layer, and no annotated participation in surfactant lipid/protein turnover.
Interpretation. GO:0043129 on MBL2 reflects family-level inference, not gene-level function. The term is legitimately experimental on SP-D/SP-A and legitimately propagates within the pulmonary-collectin subfamily, but MBL2 is a serum complement collectin in a different compartment performing a different process. The annotation is therefore an over-annotation on MBL2.
The crux of this case is distinguishing shared architecture from shared function. Collectins are a family defined by a collagen-like stalk plus a C-type lectin CRD, but different collectins are deployed in different anatomical compartments for different biological jobs.
COLLECTIN FAMILY (collagen region + C-type lectin CRD)
|
------------------------------------------------------------------------
| | |
SERUM / COMPLEMENT PULMONARY / SURFACTANT OTHER (CL-L1, CL-K1...)
| |
MBL2 (P11226) SFTPD (SP-D), SFTPA1/2 (SP-A)
liver-derived, secreted alveolar type II / Clara cells
| |
Ca2+-dependent binding to Ca2+-dependent binding to surfactant
microbial sugar arrays lipids/proteins + pathogens
| |
MASP-1/2/3 complexes regulate surfactant pool size,
-> lectin complement pathway structure, and reuptake
-> opsonization / phagocytosis -> SURFACTANT HOMEOSTASIS (GO:0043129)
| |
[INNATE IMMUNITY core] [SURFACTANT HOMEOSTASIS core]
|
└── GO:0043129 attaches to MBL2 ONLY by IBA (phylogenetic carry-over),
NOT by any experimental measurement of MBL2.
Both branches share a Ca²⁺-dependent CRD and a collagen stalk, so a phylogenetic annotation pipeline readily projects a term from the pulmonary branch onto the serum branch. But the compartment (serum vs. alveolus), the cellular source (hepatocyte vs. alveolar type II/Clara cell), and the downstream effector system (MASP/complement vs. surfactant lipid turnover) all differ. Surfactant homeostasis is a property of the SP-D/SP-A branch; its appearance on MBL2 is a false positive of family-level inference.
A useful mental test for the curator: Would loss of MBL2 perturb alveolar surfactant pool size or composition? The published MBL2 loss-of-function literature centers on infection susceptibility, complement activity, and immune modulation — not on pulmonary surfactant metabolism, and not on alveolar proteinosis (the SP-D knockout phenotype). MBL2 shares the molecular tool (a Ca²⁺-dependent CRD) but not the biological process.
The evidence matrix below summarizes the most decision-relevant items. A striking pattern emerges: every experimentally grounded description of MBL2 function points to the lectin complement pathway and innate immunity, and none describes MBL2 participating in surfactant metabolism. The experimental home of GO:0043129 is SP-D, not MBL2.
| # | Citation | Evidence type | Supports/Refutes/Qualifies/Competing | Claim tested | Key finding | Context | Confidence & limitations |
|---|---|---|---|---|---|---|---|
| 1 | QuickGO (P11226), GO_REF:0000033 (ECO:0000318) | Review/database (provenance) | Refutes (as direct) | Is GO:0043129 on MBL2 experimentally supported? | GO:0043129 on MBL2 is IBA-only; 0 experimental codes among ~94 annotations | Human, database-level | High for provenance; database snapshot |
| 2 | SFTPD: PMID:19265061(https://pubmed.ncbi.nlm.nih.gov/19265061/) (IDA), PMID:9751757(https://pubmed.ncbi.nlm.nih.gov/9751757/) (IMP) | Direct assay / mutant phenotype | Qualifies (localizes true function) | Which gene truly owns surfactant homeostasis? | Experimental GO:0043129 belongs to SP-D, not MBL2 | Human/mouse lung | High; establishes correct term-holder |
| 3 | UniProt P11226 (curated) | Review/database | Refutes | Is MBL2 a lung surfactant protein? | "Secreted"; "produced mainly in the liver"; function = Ca²⁺-dependent lectin initiating lectin complement pathway | Human, plasma/liver | High |
| 4 | Sequence analysis (this run, NW alignment) | Structural/evolutionary (computed) | Explains mechanism of error | Is MBL2 a paralog of SP-D? | MBL2–SFTPD 56.1% full-length, ~50% CRD; same collagen+C-type-lectin architecture | Human collectins | High |
| 5 | PMID:9087411(https://pubmed.ncbi.nlm.nih.gov/9087411/) | Direct assay | Competing (correct function) | What is MBL2's assayed activity? | MBL2 → complement activation, lectin pathway (GO:0001867) = innate-immunity core | Human serum | High (snippet not independently re-fetched this run) |
| 6 | PMID:15060079(https://pubmed.ncbi.nlm.nih.gov/15060079/) | Direct assay / mechanism | Competing | MBL molecular mechanism | MBP (MBL) binds surface carbohydrates and activates MASP-1/2/3 → C4/C2 cleavage → complement | Serum biochemistry | High |
| 7 | PMID:21091907(https://pubmed.ncbi.nlm.nih.gov/21091907/) | Mutant/phenotype (human deficiency) | Competing | MBL2 loss-of-function phenotype | MBL deficiency alters dendritic-cell innate/antigen-presenting function (immune, not pulmonary) | Human blood | Medium |
| 8 | PMID:16410008(https://pubmed.ncbi.nlm.nih.gov/16410008/), PMID:18952132(https://pubmed.ncbi.nlm.nih.gov/18952132/) | Genetic | Competing | MBL2 functional variation | Exon-1 SNPs → impaired polymerization, low serum MBL, ↑ infection susceptibility | Human populations | Medium |
| 9 | PMID:32335925(https://pubmed.ncbi.nlm.nih.gov/32335925/), PMID:19606686(https://pubmed.ncbi.nlm.nih.gov/19606686/) | Association | Competing | MBL2 physiological correlates | Low serum MBL associates with adverse pregnancy outcomes / gastritis via innate immunity/opsonization | Human serum | Low/medium; correlational |
| 10 | PMID:22475410(https://pubmed.ncbi.nlm.nih.gov/22475410/), PMID:23814060(https://pubmed.ncbi.nlm.nih.gov/23814060/) | Review / direct assay | Qualifies | Collectin family compartmentalization | Collectins share architecture but differ in tissue/role; CL-L1 binds mannose via CRD, forms MASP complexes → lectin pathway | Human plasma / review | Medium; orientation |
| 11 | PMID:10589993(https://pubmed.ncbi.nlm.nih.gov/10589993/), PMID:10931846(https://pubmed.ncbi.nlm.nih.gov/10931846/) | Structural/biochemical | Qualifies | CRD specificity divergence | Serum- vs. liver-type MBP CRDs differ in oligosaccharide affinity; CRD specificity is modular/tunable | Rat MBPs, crystallography | High for mechanism; non-human |
Across the retrieved primary literature, every experimentally grounded description of MBL2 function points to the lectin complement pathway and innate immunity — carbohydrate recognition, MASP association, opsonization, phagocytosis, and infection/disease susceptibility (PMID:15060079(https://pubmed.ncbi.nlm.nih.gov/15060079/), PMID:21091907(https://pubmed.ncbi.nlm.nih.gov/21091907/), PMID:16410008(https://pubmed.ncbi.nlm.nih.gov/16410008/), PMID:18952132(https://pubmed.ncbi.nlm.nih.gov/18952132/)). None describes MBL2 participating in alveolar surfactant metabolism. Family reviews (PMID:22475410(https://pubmed.ncbi.nlm.nih.gov/22475410/)) and CL-L1 work (PMID:23814060(https://pubmed.ncbi.nlm.nih.gov/23814060/)) reinforce that collectins share architecture but are compartmentalized into distinct functional niches — the structural basis for why an IBA pipeline mis-assigns the surfactant term to MBL2. The experimental home of GO:0043129 is SP-D (PMID:19265061(https://pubmed.ncbi.nlm.nih.gov/19265061/), PMID:9751757(https://pubmed.ncbi.nlm.nih.gov/9751757/)), not MBL2.
Term: GO:0043129 "surfactant homeostasis" (Biological Process).
Current action on MBL2: annotated, IBA (ECO:0000318), GO_REF:0000033.
Recommended curation action (lead — requires curator verification):
MF / BP / CC judgment: GO:0043129 is a BP term. The evidence does not support this BP for MBL2. It supports a different BP (lectin complement pathway) plus specific MF/CC terms. The surfactant BP should be removed/generalized-away on MBL2, not retained as core.
The immediate molecular activity under interrogation is whether MBL2's Ca²⁺-dependent C-type lectin CRD participates in surfactant homeostasis — regulation of the pool size, composition, or turnover of pulmonary surfactant lipids/proteins in the alveolar lining layer.
The distinction matters because IBA can conflate a shared molecular tool (a Ca²⁺-dependent CRD) with a shared biological process (surfactant homeostasis). MBL2 shares the tool but not the process.
No retrieved evidence conflicts with the refutation; all alternatives point the same way (family carry-over, not a real MBL2 surfactant function).
To decisively separate "MBL2 has surfactant homeostasis" from "MBL2 is a serum complement lectin mis-annotated by paralogy":
For the curator (immediate, low-cost):
- Re-pull the QuickGO annotation for P11226 and confirm GO:0043129 is IBA-only; if so, flag for removal/down-ranking on MBL2.
- Verify that the SFTPD references (PMID:19265061, PMID:9751757) support GO:0043129 on SFTPD, and retain the term there.
- Retrieve PMID:9087411 and extract the exact snippet documenting MBL2's lectin-pathway experimental annotation before using it as MBL2's core BP support.
- Also scrutinize MBL2's other IBA-only terms — GO:0005771 (multivesicular body, CC) and GO:0050766 (positive regulation of phagocytosis, the latter biologically plausible via opsonization and possibly upgradeable to experimental).
Computational provenance to run/record:
- MBL2 vs. SFTPD global and CRD-only NW alignment, saving the alignment and percent-identity table.
- MBL2 tissue-expression pull (GTEx/HPA), saving the expression table showing liver dominance.
- PANTHER/PAINT node inspection to document the ancestral origin of the IBA propagation.
Curation Leads (require curator verification):
| Lead | Detail |
|---|---|
| Action change | Remove or down-rank GO:0043129 (surfactant homeostasis, IBA, GO_REF:0000033) on MBL2 as an over-annotation. |
| Retain elsewhere | Keep GO:0043129 on SFTPD/SFTPA (experimentally supported IDA/IMP). |
| Candidate core terms for MBL2 | BP: GO:0001867 (complement activation, lectin pathway), GO:0050830 (defense to Gram-positive bacterium); MF: GO:0005537 (mannose binding), GO:0038187 (PRR activity); CC: GO:0005576 (extracellular region, secreted). |
| Candidate references to verify (exact snippets) | MBL2 lectin-pathway IDA PMID:9087411; SFTPD surfactant homeostasis IDA PMID:19265061, IMP PMID:9751757. |
| Suggested question | "Is any MBL2 experimental paper reporting a pulmonary-surfactant function? If none, GO:0043129 should not be propagated to MBL2." |
| Suggested experiment | Comparative KO phenotype + tissue-expression audit (MBL2 vs. SFTPD) to confirm functional divergence. |
The seed hypothesis that MBL2 has surfactant homeostasis (GO:0043129) is over-annotated / refuted as a direct function. The annotation is an IBA (phylogenetic) paralog carry-over with zero MBL2-specific experimental support, propagated from the true pulmonary surfactant collectins SP-D/SP-A across a structurally similar but functionally distinct family. MBL2's experimentally established role is initiating the lectin pathway of complement as a liver-derived, secreted serum lectin in innate immunity. The recommended lead is to remove or down-rank GO:0043129 on MBL2 while retaining it on the genuine surfactant genes, and to anchor the MBL2 review on its complement/innate-immunity core functions.
UniProt: P11226 (MBL2_HUMAN). HGNC:6922. Chr 10. 248 aa precursor (chain 21-248).
MBL2 encodes the secreted, liver-derived serum collectin "mannose-binding lectin" (MBL,
mannan-binding protein, MBP-C). It is a Ca2+-dependent C-type lectin pattern-recognition
molecule of innate immunity that recognizes terminal mannose/GlcNAc/fucose on microbial
surfaces and, via associated MASP serine proteases, initiates the LECTIN PATHWAY of complement.
GO mapping: GO:0005537 D-mannose binding (MF, verified active), GO:0030246 carbohydrate
binding (MF parent, verified), GO:0120153 calcium-dependent carbohydrate binding (MF,
verified active 2026-06; definition "capability to attach to a carbohydrate molecule when
calcium ions are present"). The Ca2+-dependent sugar binding is the defining, evolutionarily
conserved core MF; this should be the apex of core_functions rather than "protein binding".
GO mapping: GO:0038187 pattern recognition receptor activity (MF, IDA); GO:0001867 complement
activation, lectin pathway (BP, IDA — strongly supported); GO:0045087 innate immune response;
GO:0042742 defense response to bacterium. These are core.
Most GO:0005515 "protein binding" / GO:0042802 "identical protein binding" /
GO:0048306 "calcium-dependent protein binding" IPI annotations come from a coherent body of
interaction studies, NOT from random partners:
- MASP-1, MASP-2, MASP-3, MAp19/MAp44, MAP-1 (the lectin-protease complex): PMID:11290788, 9087411, 15117939, 18177377 (calreticulin co-receptor via MASP-binding site), 19939495, 20956340 (CL-11), 21035894 (MAP-1), 21054788 (CD91/LRP1 via MASP-binding site), 22607836, 22854970 (MAP-1 structure), 25579818 (initiating complex).
- CR1 (complement receptor 1, CCP24-25): PMID:23460739, 29563915.
- Cross-talk / pentraxins: PMID:21106539 (PTX3/SAP heterocomplexes), 32041782 (CTRP6/collectin-11), 32759297 (β2-glycoprotein I).
- TLR4: PMID:21383675 (MBL binds TLR4 ectodomain, suppresses LPS-induced cytokines) — a regulatory/immunomodulatory interaction.
- SRGN serglycin: PMID:21268013 (GAG-mediated inhibition of LP). DMBT1/SALSA/gp340: PMID:22811680.
- HCV glycoproteins: PMID:21203938 (inhibits HCV entry). High-throughput interactome: PMID:32296183, 33961781 (HuRI / BioPlex; generic, low specificity).
These IPI "protein binding" terms are real but UNINFORMATIVE as MF. Per curation guidelines
they should not be the gene's representative MF. The MASP-binding interactions are best captured
in core_functions via complex membership (GO:1905370 serine-type endopeptidase complex /
ComplexPortal CPX-6170, CPX-6203) plus the carbohydrate-binding MF, rather than retained as
generic "protein binding". Action plan: MARK_AS_OVER_ANNOTATED most generic GO:0005515 IPI
(keep, but non-representative); ACCEPT/KEEP the MASP-relevant identical/Ca2+-dependent protein
binding that documents complex assembly; downgrade in core_functions toward carbohydrate binding.
Structural variants in exon 1 (codon 52 R>C, 54 G>D [rs1800450], 57 G>E [rs1800451]) disrupt the
collagen helix and lower serum MBL; promoter variants modulate levels. MBL deficiency (~5% of
Europeans, ~10% sub-Saharan Africans) predisposes to infection in toddlers, neutropenic
chemotherapy and transplant patients; associations with HBV recovery, COVID-19 severity,
M. africanum TB protection [UniProt POLYMORPHISM; PMID:1675710, 1304173, 15994813, 21695215,
35102342]. These are downstream susceptibility/pleiotropy, not the core molecular function.
FutureHouse Falcon deep-research report generated 2026-06-21 (genes/human/MBL2/MBL2-deep-research-falcon.md,
template gene_research_go_focused_compat.md). Verified its claims against the primary literature.
Findings USED (corroborated, concordant with primary literature):
- Core MF = Ca2+-dependent carbohydrate binding; substrate specificity D-mannose / GlcNAc / L-fucose /
glucose, discriminating against D-galactose (consistent with C-type-lectin 3'/4'-OH coordination).
- Domain architecture (N-terminal Cys-rich + collagen-like + neck/coiled-coil + CRD) and oligomerization
(multimers of homotrimers; higher-order assembly required for full activity); disease variants impair
oligomerization (Larsen 2004 J Biol Chem, real DOI). Reinforces my oligomer/macropattern proposed term.
- Core BP = lectin-pathway complement activation, innate defense, opsonization; MBL-MASP1/2/3 complexes.
- Explicitly flags cytoplasm / cytosol / nucleus / synapse / apoptosis-execution / pyroptosis / neuronal /
developmental roles as UNSUPPORTED, high-risk. (None of these are in the MBL2 GOA, so no action needed,
but this independently supports my REMOVE of multivesicular body and surfactant homeostasis as off-target.)
- Apoptotic-cell clearance (Nauta 2004 J Immunol) noted as a context-specific role — consistent with UniProt
RN[18] PubMed:14515269; not present in the current GOA so not annotated, recorded here as context.
Falcon citations checked: all 11 key references resolve to real, peer-reviewed published papers with valid
DOIs (Takahashi 2006, Jack 2001, Dobó 2024, Yongqing 2012, Larsen 2004, Cedzyński 2023, Mu 2020, Zhou 2016,
Andrade 2024, Bayarri-Olmos 2024, Nauta 2004). No preprint-only or unresolvable-PMID claims were found.
Findings NOT used / treated with caution:
- The report's own citation keys (e.g. "mu2020...", "nauta2004...") are not PMIDs and several of these papers
are not in our publications/ cache, so I did NOT add them as YAML supporting_text references (which require a
verbatim cached substring). The Falcon report itself is cited as a file: reference with a verbatim quote, and
flagged MEDIUM relevance / VERIFIED in reference_review.
- Mu 2020 (calreticulin/opsonophagocytosis) is in an "early vertebrate" (teleost) model — cross-species; used
only as context, not to drive a human MBL2 annotation.
- No new GO annotations were created solely on Falcon's say-so; every accepted/added term is grounded in the
primary literature and verified GO IDs.
id: P11226
gene_symbol: MBL2
product_type: PROTEIN
status: DRAFT
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: MBL2 encodes mannose-binding lectin (MBL; also mannan-binding lectin/protein, MBP-C, collectin-1),
a secreted, liver-derived serum collectin of the innate immune system. It is a C-type lectin built from
a structural subunit that combines an N-terminal cysteine-rich region, a collagen-like Gly-X-Y domain
(with hydroxyproline modifications), an alpha-helical coiled-coil neck that drives trimerization, and
a C-terminal C-type carbohydrate-recognition domain (CRD). Three subunits assemble into a homotrimer,
and several homotrimers further oligomerize into higher-order bouquet-like structures. Through the CRD
it binds, in a calcium-dependent manner, terminal mannose, N-acetylglucosamine and fucose residues arranged
in the repetitive geometric patterns characteristic of microbial (bacterial, fungal, viral, protozoan)
surfaces, while largely sparing the differently arranged sugars of host glycoproteins. MBL therefore
acts as a soluble pattern-recognition molecule; upon binding a microbial surface it triggers the associated
MBL-associated serine proteases (chiefly MASP-1, which activates MASP-2) to cleave complement C4 and
C2, initiating the lectin pathway of complement and leading to opsonization, phagocytosis and membrane
attack. MBL also binds altered-self and certain viral glycoproteins (e.g. influenza A haemagglutinin
and SARS-CoV-2 spike) and can modulate inflammatory signaling. Common structural and promoter MBL2 variants
lower circulating MBL and cause a common, usually subclinical, immunodeficiency that increases infection
risk in the immunologically immature or compromised.
existing_annotations:
- term:
id: GO:0005576
label: extracellular region
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: is_active_in
review:
summary: MBL is a secreted serum collectin synthesized in the liver and acting in plasma and tissue
fluid; extracellular region is correct and is where its core function takes place.
action: ACCEPT
- term:
id: GO:0050766
label: positive regulation of phagocytosis
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: involved_in
review:
summary: MBL is an opsonin and enhances phagocytosis of bound microbes, largely via complement deposition
and collectin receptors. A genuine but downstream effector consequence of MBL recognition/complement-initiation
activity rather than its core function.
action: KEEP_AS_NON_CORE
- term:
id: GO:0005771
label: multivesicular body
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: is_active_in
review:
summary: An IBA-propagated localization that does not fit a secreted serum collectin. MBL acts extracellularly/at
the cell surface, not in multivesicular bodies; likely over-propagation from surfactant-protein
relatives (which traffic through lamellar/multivesicular bodies in pneumocytes).
action: REMOVE
reason: No experimental support for MBL function in multivesicular bodies; inconsistent with a liver-secreted
plasma lectin. Likely IBA over-propagation from surfactant-protein paralogs.
- term:
id: GO:0043129
label: surfactant homeostasis
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: involved_in
review:
summary: Surfactant homeostasis is a function of the pulmonary surfactant collectins (SFTPA/SP-A,
SFTPD/SP-D) in the same PANTHER family, not of serum MBL. IBA over-propagation across the collectin
family.
action: REMOVE
reason: No evidence MBL participates in surfactant homeostasis; the role belongs to the surfactant-protein
paralogs. OpenScientist confirmed this as an IBA-only collectin-family carry-over
from pulmonary surfactant collectins onto liver-derived serum MBL2.
additional_reference_ids:
- file:human/MBL2/MBL2-goa.tsv
- file:human/MBL2/MBL2-hypotheses/function-hypothesis-go-0043129/openscientist.md
propagation_review:
root_cause: PROPAGATION_BAD
failure_modes:
- WRONG_ORTHOLOG_OR_PARALOG
- COMPARTMENT_OR_COMPLEX_MISMATCH
- CONTEXT_OR_TISSUE_MISMATCH
source_entities:
- source_id: PANTHER:PTN001523874
source_label: collectin PANTHER source node
source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
comment: The source node captures surfactant collectin biology in the
pulmonary SP-A/SP-D branch, but MBL2 is a liver-derived serum lectin.
- source_id: UniProtKB:P35247
source_label: surfactant protein D / pulmonary collectin source
source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
comment: Surfactant protein D supports surfactant homeostasis in lung,
not serum MBL2 complement biology.
- source_id: RGD:3667
source_label: rodent surfactant collectin source
source_status: SUPPORTS_SOURCE_BUT_NOT_TARGET
comment: Rodent surfactant-collectin biology should not transfer the
alveolar surfactant-homeostasis process to human MBL2.
supported_by:
- reference_id: file:human/MBL2/MBL2-goa.tsv
supporting_text: "UniProtKB\tP11226\tMBL2\tinvolved_in\tGO:0043129\tsurfactant homeostasis\tbiological_process\tECO:0000318\tIBA\tGO_REF:0000033\tPANTHER:PTN001523874|RGD:3667|UniProtKB:P35247\t9606\tHomo sapiens\tGO_Central\tMannose-binding protein C\t20170613"
- reference_id: file:human/MBL2/MBL2-hypotheses/function-hypothesis-go-0043129/openscientist.md
supporting_text: The seed hypothesis that **MBL2 has surfactant homeostasis (GO:0043129)** is **over-annotated / refuted as a direct function.**
- term:
id: GO:0001867
label: complement activation, lectin pathway
evidence_type: IEA
original_reference_id: GO_REF:0000117
qualifier: involved_in
review:
summary: Correct and central - MBL is the eponymous initiator of the lectin pathway. Redundant with
the strongly supported IDA annotations to the same term.
action: ACCEPT
- term:
id: GO:0005576
label: extracellular region
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: located_in
review:
summary: Correct secreted location; redundant with experimentally supported extracellular-region annotations.
action: ACCEPT
- term:
id: GO:0009986
label: cell surface
evidence_type: IEA
original_reference_id: GO_REF:0000044
qualifier: located_in
review:
summary: MBL is found at the cell surface (it binds carbohydrate on pathogen and altered-self cell
surfaces and is detected on host cells). Acceptable as a location, though the functionally meaningful
surface is the microbial/symbiont surface (GO:0106139).
action: ACCEPT
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:11290788
qualifier: enables
review:
summary: MBL-MASP1/MASP2/MAp19 interaction (the lectin-protease initiating complex). The interaction
is real and important, but protein binding is an uninformative MF; the MBL-MASP relationship is
better represented as membership in the MBL-MASP serine-type endopeptidase complex (see core_functions),
and the informative MF of MBL is carbohydrate binding.
action: MARK_AS_OVER_ANNOTATED
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:15117939
qualifier: enables
review:
summary: MBL-MAp19 interaction within the lectin-protease complex; a real partner interaction but
uninformative as a generic protein-binding MF.
action: MARK_AS_OVER_ANNOTATED
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:18177377
qualifier: enables
review:
summary: MBL-calreticulin interaction (via the MASP-binding site). Specific but uninformative as a
generic protein-binding MF.
action: MARK_AS_OVER_ANNOTATED
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:19939495
qualifier: enables
review:
summary: Derived from a MASP-3/Ficolin-3 study; weak/peripheral support for MBL and uninformative
as an MF.
action: MARK_AS_OVER_ANNOTATED
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:20956340
qualifier: enables
review:
summary: From a collectin-11 study; MBL is peripheral. Uninformative generic MF.
action: MARK_AS_OVER_ANNOTATED
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:21035894
qualifier: enables
review:
summary: MBL-MAP-1/MAp44 interaction in the lectin-protease complex; uninformative generic MF.
action: MARK_AS_OVER_ANNOTATED
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:21054788
qualifier: enables
review:
summary: MBL-CD91/LRP1 interaction (via the MASP-binding site). Specific but uninformative as generic
protein binding.
action: MARK_AS_OVER_ANNOTATED
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:21106539
qualifier: enables
review:
summary: MBL-pentraxin (PTX3/SAP) heterocomplexes; a real interaction modulating complement, but uninformative
as a generic MF.
action: MARK_AS_OVER_ANNOTATED
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:21203938
qualifier: enables
review:
summary: MBL-HCV glycoprotein interaction; this is actually carbohydrate-mediated recognition of a
viral glycoprotein and is better captured by the carbohydrate-binding/PRR MF than by generic protein
binding.
action: MARK_AS_OVER_ANNOTATED
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:21268013
qualifier: enables
review:
summary: From a serglycin study (GAG-mediated lectin-pathway inhibition); MBL is a target. Uninformative
generic MF.
action: MARK_AS_OVER_ANNOTATED
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:21383675
qualifier: enables
review:
summary: MBL-TLR4 ectodomain interaction (immunomodulatory, dampens LPS signaling). A specific regulatory
interaction but uninformative as a generic protein-binding MF.
action: MARK_AS_OVER_ANNOTATED
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:22607836
qualifier: enables
review:
summary: MASP-MBL interaction study; supports complex assembly but uninformative as a generic MF.
action: MARK_AS_OVER_ANNOTATED
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:22811680
qualifier: enables
review:
summary: MBL-DMBT1/SALSA interaction regulating the lectin pathway; specific but uninformative as
a generic MF.
action: MARK_AS_OVER_ANNOTATED
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:22854970
qualifier: enables
review:
summary: MBL-MAP-1 interaction (competitive complement regulator); uninformative generic MF.
action: MARK_AS_OVER_ANNOTATED
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:23460739
qualifier: enables
review:
summary: MBL-CR1 interaction; a specific receptor interaction but uninformative as a generic MF.
action: MARK_AS_OVER_ANNOTATED
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:25579818
qualifier: enables
review:
summary: MBL-MASP-1 interaction in the initiating complex; best captured as complex membership. Uninformative
as a generic MF.
action: MARK_AS_OVER_ANNOTATED
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:27104295
qualifier: enables
review:
summary: MBL oligomerization / MASP interaction; this is largely MBL self-association (identical protein
binding) and MASP binding, uninformative as a generic protein-binding MF.
action: MARK_AS_OVER_ANNOTATED
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:29563915
qualifier: enables
review:
summary: MBL-CR1 (CCP24-25) interaction; specific but uninformative as a generic MF.
action: MARK_AS_OVER_ANNOTATED
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32041782
qualifier: enables
review:
summary: From a CTRP6/collectin-11 study; MBL peripheral. Uninformative generic MF.
action: MARK_AS_OVER_ANNOTATED
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32296183
qualifier: enables
review:
summary: High-throughput binary interactome (HuRI); a generic, low-specificity protein-binding IPI
with no informative value for MBL molecular function.
action: MARK_AS_OVER_ANNOTATED
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32759297
qualifier: enables
review:
summary: MBL-beta2-glycoprotein I interaction (complement/thrombin crosstalk); specific but uninformative
as a generic MF.
action: MARK_AS_OVER_ANNOTATED
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:33961781
qualifier: enables
review:
summary: High-throughput AP-MS interactome (BioPlex); a generic protein-binding IPI, uninformative
for MBL molecular function.
action: MARK_AS_OVER_ANNOTATED
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:21106539
qualifier: enables
review:
summary: MBL self-association/oligomerization (the structural subunit is a homotrimer that further
oligomerizes; higher-order assembly is required for avid binding and complement activation). Identical
protein binding is more informative than generic protein binding; retain as a non-core structural/assembly
property.
action: KEEP_AS_NON_CORE
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:21383675
qualifier: enables
review:
summary: MBL self-association/oligomerization (the structural subunit is a homotrimer that further
oligomerizes; higher-order assembly is required for avid binding and complement activation). Identical
protein binding is more informative than generic protein binding; retain as a non-core structural/assembly
property.
action: KEEP_AS_NON_CORE
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:22607836
qualifier: enables
review:
summary: MBL self-association/oligomerization (the structural subunit is a homotrimer that further
oligomerizes; higher-order assembly is required for avid binding and complement activation). Identical
protein binding is more informative than generic protein binding; retain as a non-core structural/assembly
property.
action: KEEP_AS_NON_CORE
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:25579818
qualifier: enables
review:
summary: MBL self-association/oligomerization (the structural subunit is a homotrimer that further
oligomerizes; higher-order assembly is required for avid binding and complement activation). Identical
protein binding is more informative than generic protein binding; retain as a non-core structural/assembly
property.
action: KEEP_AS_NON_CORE
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:27104295
qualifier: enables
review:
summary: Oligomerization of the MBL homotrimer is directly studied here and shown to dictate binding
and complement activation - the best-supported identical-protein-binding annotation. Retain as a
non-core structural/assembly property underpinning function.
action: KEEP_AS_NON_CORE
- term:
id: GO:0005576
label: extracellular region
evidence_type: EXP
original_reference_id: PMID:7982896
qualifier: located_in
review:
summary: Direct evidence that MBP is secreted (purified from serum; secreted by transfected cells).
Correct core location.
action: ACCEPT
- term:
id: GO:0009986
label: cell surface
evidence_type: EXP
original_reference_id: PMID:22966085
qualifier: located_in
review:
summary: MBL associates with cell surfaces in the context of lectin-pathway activation. Acceptable
location.
action: ACCEPT
- term:
id: GO:0009986
label: cell surface
evidence_type: EXP
original_reference_id: PMID:2573758
qualifier: located_in
review:
summary: MBP deposits complement on mannan-coated surfaces and corrects an opsonic defect; consistent
with action at the (microbial) cell surface. Acceptable location.
action: ACCEPT
- term:
id: GO:0009986
label: cell surface
evidence_type: EXP
original_reference_id: PMID:8082295
qualifier: located_in
review:
summary: MBP binds bacterial surfaces in a sugar-/Ca2+-dependent manner. Supports cell-surface (pathogen
surface) localization.
action: ACCEPT
- term:
id: GO:0001867
label: complement activation, lectin pathway
evidence_type: IDA
original_reference_id: PMID:22691502
qualifier: involved_in
review:
summary: MBL nucleates the initiating complex whose MASP-1/MASP-2 cleave C4/C2 to activate the lectin
pathway. Core process role, well supported.
action: ACCEPT
- term:
id: GO:0002752
label: cell surface pattern recognition receptor signaling pathway
evidence_type: IDA
original_reference_id: PMID:22966085
qualifier: involved_in
review:
summary: MBL recognizes microbial carbohydrate patterns and triggers the MASP proteolytic cascade
- a soluble pattern-recognition-receptor signaling event. Closely related to the lectin-pathway
and PRR-activity annotations. Retain.
action: ACCEPT
- term:
id: GO:0006508
label: proteolysis
evidence_type: IDA
original_reference_id: PMID:22691502
qualifier: involved_in
review:
summary: The proteolysis (C4/C2 cleavage) is carried out by the MASP serine proteases, not by MBL
itself - MBL has no protease activity. Annotating MBL with proteolysis attributes an activity of
its associated MASP serine proteases to MBL; this is closer to a wrong-gene attribution than an
over-annotation. MBL membership in the proteolytic complex is already captured by GO:1905370 (serine-type
endopeptidase complex) and its role by the lectin-pathway process annotations.
action: REMOVE
reason: MBL is not a protease; proteolysis is the activity of the associated MASP serine proteases.
Attributing it to MBL is effectively a wrong-gene attribution, so the annotation is removed; MBL
involvement is correctly represented by complex membership (GO:1905370) and the lectin-pathway process.
- term:
id: GO:0009897
label: external side of plasma membrane
evidence_type: NAS
original_reference_id: PMID:22966085
qualifier: located_in
review:
summary: MBL is a soluble secreted protein that binds surfaces; external side of plasma membrane (a
membrane-component location) is a marginal NAS assignment. Acceptable as a non-core location where
MBL transiently associates with the outer leaflet of host/microbial membranes.
action: KEEP_AS_NON_CORE
- term:
id: GO:1903028
label: positive regulation of opsonization
evidence_type: IDA
original_reference_id: PMID:22966085
qualifier: involved_in
review:
summary: By depositing complement opsonins on bound microbes, MBL promotes opsonization. A genuine
but downstream effector role rather than the core recognition function.
action: KEEP_AS_NON_CORE
- term:
id: GO:1905370
label: serine-type endopeptidase complex
evidence_type: IPI
original_reference_id: PMID:25579818
qualifier: part_of
review:
summary: MBL is the recognition subunit of the MBL-MASP initiating complex (ComplexPortal CPX-6170/CPX-6203),
which contains the MASP serine proteases. Correct, informative complex membership; this is how the
otherwise-generic MBL-MASP protein-binding annotations should be represented.
action: ACCEPT
- term:
id: GO:0001867
label: complement activation, lectin pathway
evidence_type: IDA
original_reference_id: PMID:9087411
qualifier: involved_in
review:
summary: Foundational evidence (MASP-2 discovery) that MBL binds microbial carbohydrate and activates
complement via associated serine proteases. Core process role.
action: ACCEPT
- term:
id: GO:0005537
label: D-mannose binding
evidence_type: IDA
original_reference_id: PMID:6643429
qualifier: enables
review:
summary: Direct biochemical demonstration of Ca2+-dependent, saturable, high-affinity mannan/mannose
binding by serum MBP, specific for mannose and N-acetylglucosamine. This is the defining core molecular
function of MBL.
action: ACCEPT
- term:
id: GO:0038187
label: pattern recognition receptor activity
evidence_type: IDA
original_reference_id: PMID:9087411
qualifier: enables
review:
summary: MBL is a prototypic soluble pattern-recognition molecule recognizing microbial carbohydrate
PAMPs and triggering complement. Core molecular function (alongside carbohydrate binding).
action: ACCEPT
- term:
id: GO:0106139
label: symbiont cell surface
evidence_type: IDA
original_reference_id: PMID:22966085
qualifier: is_active_in
review:
summary: MBL is functionally active at the microbial (symbiont/pathogen) cell surface, where it binds
carbohydrate and assembles the lectin-pathway complex. Correct, meaningful location of action.
action: ACCEPT
- term:
id: GO:0106139
label: symbiont cell surface
evidence_type: IDA
original_reference_id: PMID:2573758
qualifier: is_active_in
review:
summary: MBL is functionally active at the microbial (symbiont/pathogen) cell surface, where it binds
carbohydrate and assembles the lectin-pathway complex. Correct, meaningful location of action.
action: ACCEPT
- term:
id: GO:0106139
label: symbiont cell surface
evidence_type: IDA
original_reference_id: PMID:8082295
qualifier: is_active_in
review:
summary: MBL is functionally active at the microbial (symbiont/pathogen) cell surface, where it binds
carbohydrate and assembles the lectin-pathway complex. Correct, meaningful location of action.
action: ACCEPT
- term:
id: GO:0001867
label: complement activation, lectin pathway
evidence_type: IDA
original_reference_id: PMID:35102342
qualifier: involved_in
review:
summary: After binding SARS-CoV-2 spike, MBL activates the lectin pathway. Supports the core lectin-pathway
process in an antiviral context.
action: ACCEPT
- term:
id: GO:0048306
label: calcium-dependent protein binding
evidence_type: IPI
original_reference_id: PMID:35102342
qualifier: enables
review:
summary: The Ca2+-dependent binding of MBL to SARS-CoV-2 spike is glycan-dependent, i.e. it is calcium-dependent
carbohydrate binding of a viral glycoprotein rather than protein-protein binding; better captured
by calcium-dependent carbohydrate binding (GO:0120153). The curator's original choice of calcium-dependent
protein binding was reasonable - the assay measured Ca2+-dependent binding of MBL to a specific
protein (the SARS-CoV-2 spike glycoprotein), so at the level of the observed partner it is a protein.
This MODIFY refines the mechanism (the binding is glycan-mediated via the C-type lectin CRD) rather
than correcting a curator error.
action: MODIFY
reason: The interaction is mediated by the spike glycan via the C-type lectin CRD in a calcium-dependent
manner; calcium-dependent carbohydrate binding is the accurate, informative MF. The original calcium-dependent
protein binding was a defensible choice (the measured partner is the spike protein); the MODIFY
refines mechanism, not a curator mistake.
proposed_replacement_terms:
- id: GO:0120153
label: calcium-dependent carbohydrate binding
- term:
id: GO:0140374
label: antiviral innate immune response
evidence_type: IDA
original_reference_id: PMID:35102342
qualifier: involved_in
review:
summary: MBL binds SARS-CoV-2 spike, inhibits the virus in vitro and activates complement - an antiviral
innate-immune effector role. A (virus-specific) facet of MBL innate defense; non-core relative to
the general carbohydrate-recognition MF.
action: KEEP_AS_NON_CORE
- term:
id: GO:0050830
label: defense response to Gram-positive bacterium
evidence_type: IDA
original_reference_id: PMID:15148336
qualifier: acts_upstream_of_or_within
review:
summary: MBL-null mice are highly susceptible to S. aureus, directly demonstrating defense against
Gram-positive bacteria (via the rodent orthologs). A specific, well-supported facet of MBL antibacterial
innate defense; non-core relative to the general carbohydrate-recognition MF.
action: KEEP_AS_NON_CORE
- term:
id: GO:0005537
label: D-mannose binding
evidence_type: IDA
original_reference_id: PMID:23544079
qualifier: enables
review:
summary: MBL is described as a beta-type (Ca2+-dependent C-type-lectin) inhibitor of influenza A that
binds mannose-rich glycans on viral haemagglutinin; this paper is primarily about SAP and the MBL
data are comparative, but the mannose-binding MF is correct and far better supported by PMID:6643429.
action: ACCEPT
- term:
id: GO:0048525
label: negative regulation of viral process
evidence_type: IDA
original_reference_id: PMID:23544079
qualifier: involved_in
review:
summary: MBL acts as a beta-inhibitor of influenza A (CRD binding to viral HA glycans), restraining
infection. A genuine antiviral facet but supported here only comparatively; downstream/process-level
and virus-specific, hence non-core.
action: KEEP_AS_NON_CORE
- term:
id: GO:0005576
label: extracellular region
evidence_type: IDA
original_reference_id: PMID:23544079
qualifier: located_in
review:
summary: Consistent with MBL being a secreted serum/airway lectin. Correct location.
action: ACCEPT
- term:
id: GO:0045087
label: innate immune response
evidence_type: IDA
original_reference_id: PMID:23544079
qualifier: involved_in
review:
summary: MBL is a core innate-immune effector (pattern recognition plus complement). The high-level
process assignment is well established; this particular reference is a comparative antiviral study.
Core innate-immune role.
action: ACCEPT
- term:
id: GO:0009986
label: cell surface
evidence_type: TAS
original_reference_id: PMID:2477488
qualifier: located_in
review:
summary: Cell-surface location is correct for MBL and is supported by EXP annotations elsewhere; the
function/location is sound and only this specific reference (PMID:2477488) is a miscitation (an
LBP paper - see reference_review on PMID:2477488).
action: KEEP_AS_NON_CORE
reason: Location correct and supported elsewhere by EXP evidence; only the cited reference is miscited
(LBP paper).
- term:
id: GO:0042742
label: defense response to bacterium
evidence_type: TAS
original_reference_id: PMID:2477488
qualifier: involved_in
review:
summary: Defense against bacteria is a genuine core process for MBL (recognition plus complement plus
opsonization; MBL-null mice die from S. aureus). The function is correct; only this specific reference
(PMID:2477488) is a miscitation (an LBP paper - see reference_review on PMID:2477488).
action: ACCEPT
reason: Function well supported (PMID:8082295, PMID:15148336, PMID:2573758); only the cited reference
is miscited (LBP paper).
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-166721
qualifier: located_in
review:
summary: Correct secreted extracellular location (Reactome lectin-pathway/recognition reaction).
action: ACCEPT
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-166726
qualifier: located_in
review:
summary: Correct secreted extracellular location (Reactome lectin-pathway/recognition reaction).
action: ACCEPT
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-166753
qualifier: located_in
review:
summary: Correct secreted extracellular location (Reactome lectin-pathway/recognition reaction).
action: ACCEPT
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-166792
qualifier: located_in
review:
summary: Correct secreted extracellular location (Reactome lectin-pathway/recognition reaction).
action: ACCEPT
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9758529
qualifier: located_in
review:
summary: Correct secreted extracellular location (Reactome lectin-pathway/recognition reaction).
action: ACCEPT
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9921544
qualifier: located_in
review:
summary: Correct secreted extracellular location (Reactome lectin-pathway/recognition reaction).
action: ACCEPT
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9957161
qualifier: located_in
review:
summary: Correct secreted extracellular location (Reactome lectin-pathway/recognition reaction).
action: ACCEPT
- term:
id: GO:0001867
label: complement activation, lectin pathway
evidence_type: IDA
original_reference_id: PMID:15148336
qualifier: acts_upstream_of_or_within
review:
summary: MBL-null mice lack the MBL complement pathway; supports MBL upstream role in lectin-pathway
complement activation. Core process role.
action: ACCEPT
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:11485744
qualifier: enables
review:
summary: MBL-MASP-3 complex association; a real interaction within the lectin-protease system but
uninformative as a generic protein-binding MF.
action: MARK_AS_OVER_ANNOTATED
- term:
id: GO:0048306
label: calcium-dependent protein binding
evidence_type: IPI
original_reference_id: PMID:12421953
qualifier: enables
review:
summary: Calcium-dependent association within the MBL/ficolin-MASP system (binding to the MASP proteases).
The Ca2+ dependence reflects MBL C-type-lectin biology, but the partner here is a protein, so calcium-dependent
protein binding is defensible. Non-core; the informative core MF is calcium-dependent carbohydrate
binding.
action: KEEP_AS_NON_CORE
- term:
id: GO:0048306
label: calcium-dependent protein binding
evidence_type: IPI
original_reference_id: PMID:18596036
qualifier: enables
review:
summary: Calcium-dependent association within the MBL/ficolin-MASP system (binding to the MASP proteases).
The Ca2+ dependence reflects MBL C-type-lectin biology, but the partner here is a protein, so calcium-dependent
protein binding is defensible. Non-core; the informative core MF is calcium-dependent carbohydrate
binding.
action: KEEP_AS_NON_CORE
- term:
id: GO:0005537
label: D-mannose binding
evidence_type: TAS
original_reference_id: PMID:2477488
qualifier: enables
review:
summary: D-mannose binding is the defining core molecular function of MBL and is well supported by
the IDA annotations (PMID:6643429). The function is correct; the issue is solely that this specific
reference (PMID:2477488) is the LBP paper and is a miscitation (see reference_review on PMID:2477488).
The annotation is accepted on the basis of the function, not the citation.
action: ACCEPT
reason: Mannose binding is the core MBL MF (PMID:6643429); only the cited reference is miscited (LBP
paper).
- term:
id: GO:0006953
label: acute-phase response
evidence_type: TAS
original_reference_id: PMID:2477488
qualifier: involved_in
review:
summary: MBL is a (modest) acute-phase reactant (its founding cDNA paper titled it an acute-phase
reactant). The function is plausibly correct and kept as a non-core process; only this specific reference
(PMID:2477488) is a miscitation (an LBP paper - see reference_review on PMID:2477488).
action: KEEP_AS_NON_CORE
reason: Acute-phase behavior of MBL is real but modest; only the cited reference is miscited (LBP paper).
- term:
id: GO:0008228
label: opsonization
evidence_type: TAS
original_reference_id: PMID:2477488
qualifier: involved_in
review:
summary: MBL is an opsonin (its deficiency causes a common opsonic defect, PMID:2573758). The process
is correct though downstream and kept as non-core; only this specific reference (PMID:2477488) is
a miscitation (an LBP paper - see reference_review on PMID:2477488).
action: KEEP_AS_NON_CORE
reason: Opsonization role well established (PMID:2573758) but a downstream effector consequence; only
the cited reference is miscited (LBP paper).
- term:
id: GO:0001867
label: complement activation, lectin pathway
evidence_type: IPI
original_reference_id: PMID:11549596
qualifier: involved_in
review:
summary: MBL binding to oxidative-stress-induced endothelial cytokeratin-1 activates the lectin pathway
(altered-self recognition). Supports the lectin-pathway process. Core process role.
action: ACCEPT
- term:
id: GO:0005102
label: signaling receptor binding
evidence_type: IPI
original_reference_id: PMID:11549596
qualifier: enables
review:
summary: This annotation derives from MBL binding endothelial cytokeratin-1 (CK1) after oxidative
stress. CK1 is not a canonical signaling receptor, and the interaction is recognition of an altered-self
surface ligand by the lectin. Signaling receptor binding misclassifies this; the informative MF
remains carbohydrate/altered-self ligand binding via the CRD.
action: MARK_AS_OVER_ANNOTATED
reason: The CK1 interaction is altered-self ligand recognition by the lectin, not binding of a bona
fide signaling receptor; the term is a poor fit.
- term:
id: GO:0005537
label: D-mannose binding
evidence_type: NAS
original_reference_id: PMID:11549596
qualifier: enables
review:
summary: D-mannose binding is the core MF of MBL and is correct; supported far more directly by the
IDA annotations (PMID:6643429). This NAS entry is redundant but accurate.
action: ACCEPT
- term:
id: GO:0006979
label: response to oxidative stress
evidence_type: NAS
original_reference_id: PMID:11549596
qualifier: involved_in
review:
summary: MBL does not respond to oxidative stress; rather, oxidative stress on endothelium exposes
a ligand (cytokeratin-1) that MBL then binds. Annotating MBL with response to oxidative stress misattributes
the host cell stress response to MBL.
action: REMOVE
reason: The oxidative stress is experienced by the endothelial cell (inducing CK1); MBL merely recognizes
the resulting altered-self ligand. MBL itself has no role in the oxidative-stress response.
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: PMID:1304173
qualifier: located_in
review:
summary: Correct secreted location (MBL2 population-genetics paper noting low serum MBP).
action: ACCEPT
references:
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000044
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping,
accompanied by conservative changes to GO terms applied by UniProt
findings: []
- id: GO_REF:0000117
title: Electronic Gene Ontology annotations created by ARBA machine learning models
findings: []
- id: GO_REF:0000120
title: Combined Automated Annotation using Multiple IEA Methods
findings: []
- id: file:human/MBL2/MBL2-goa.tsv
title: GOA annotation export for MBL2
publication_type: DATABASE
findings:
- statement: GOA records the phylogenetic IBA source for the MBL2 GO:0043129 annotation.
supporting_text: "UniProtKB\tP11226\tMBL2\tinvolved_in\tGO:0043129\tsurfactant homeostasis\tbiological_process\tECO:0000318\tIBA\tGO_REF:0000033\tPANTHER:PTN001523874|RGD:3667|UniProtKB:P35247\t9606\tHomo sapiens\tGO_Central\tMannose-binding protein C\t20170613"
- id: file:human/MBL2/MBL2-hypotheses/function-hypothesis-go-0043129/openscientist.md
title: OpenScientist hypothesis report for MBL2 GO:0043129
publication_type: DEEP_RESEARCH
findings:
- statement: OpenScientist refutes surfactant homeostasis as a direct MBL2 function.
supporting_text: The seed hypothesis that **MBL2 has surfactant homeostasis (GO:0043129)** is **over-annotated / refuted as a direct function.**
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: Focused OpenScientist report supports removing GO:0043129 as
collectin-family surfactant-homeostasis over-propagation from pulmonary
surfactant collectins to serum MBL2.
- id: PMID:11290788
title: Interaction properties of human mannan-binding lectin (MBL)-associated serine proteases-1 and
-2, MBL-associated protein 19, and MBL.
findings: []
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: Characterizes the MBL-MASP1/MASP2/MAp19 interactions that constitute the lectin-protease
initiating complex. Supports MBL as a scaffold for the MASP proteases (basis of the GO:0005515 IPI),
but protein binding is uninformative as an MF.
- id: PMID:11485744
title: MASP-3 and its association with distinct complexes of the mannan-binding lectin complement activation
pathway.
findings: []
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: Documents MASP-3 association with MBL complexes; supports MBL-MASP complex membership
rather than an informative independent MF.
- id: PMID:11549596
title: 'Endothelial oxidative stress activates the lectin complement pathway: role of cytokeratin 1.'
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: Shows oxidative-stress-induced cytokeratin-1 on endothelium binds MBL and activates
the lectin pathway (altered-self recognition). The response-to-oxidative-stress link is indirect
and context-specific; not a core MBL function.
- id: PMID:12421953
title: Characterization of the interaction between L-ficolin/p35 and mannan-binding lectin-associated
serine proteases-1 and -2.
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: Primarily about L-ficolin-MASP interactions; informs the shared MASP system and grounds
a calcium-dependent protein binding IPI for the MBL/ficolin-MASP complex.
- id: PMID:1304173
title: High frequencies in African and non-African populations of independent mutations in the mannose
binding protein gene.
findings: []
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: Population genetics of MBL2 structural variants (codon 54/57) causing MBL deficiency.
Background for the secreted-protein/disease context; used here only for an extracellular-region
location annotation.
- id: PMID:15117939
title: The X-ray structure of human mannan-binding lectin-associated protein 19 (MAp19) and its interaction
site with mannan-binding lectin and L-ficolin.
findings: []
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: Structure of MAp19 and its MBL/ficolin interaction site; supports the MBL-MASP/MAp complex
assembly (basis of an IPI protein-binding annotation).
- id: PMID:15148336
title: Mannose-binding lectin-deficient mice are susceptible to infection with Staphylococcus aureus.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: In vivo MBL-null mouse (Mbl1/Mbl2 double KO) shows 100% mortality after i.v. S. aureus
vs 45% in WT; full text frames MBL as a prototypic pattern-recognition molecule and opsonin. Strong
functional support for innate defense / lectin pathway via the rodent orthologs (cross-species transfer
to human MBL2).
- id: PMID:18177377
title: The chaperone and potential mannan-binding lectin (MBL) co-receptor calreticulin interacts with
MBL through the binding site for MBL-associated serine proteases.
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: Calreticulin interacts with MBL via the MASP-binding site (possible co-receptor). A
specific partner interaction; protein binding remains uninformative as MF.
- id: PMID:18596036
title: Crystal structure of the CUB1-EGF-CUB2 domain of human MASP-1/3 and identification of its interaction
sites with mannan-binding lectin and ficolins.
findings: []
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: Structural mapping of the MASP-1/3 sites that bind MBL/ficolins; supports the calcium-dependent
MBL-MASP interaction underlying complex assembly.
- id: PMID:19939495
title: MBL-associated serine protease-3 circulates in high serum concentrations predominantly in complex
with Ficolin-3 and regulates Ficolin-3 mediated complement activation.
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: Mainly about MASP-3/Ficolin-3; touches the shared MASP system. Weak direct support for
MBL function.
- id: PMID:20956340
title: Collectin 11 (CL-11, CL-K1) is a MASP-1/3-associated plasma collectin with microbial-binding
activity.
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: About collectin-11; a comparator collectin in the MASP system. Background only.
- id: PMID:21035894
title: Serum concentration and interaction properties of MBL/ficolin associated protein-1.
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: MAP-1/MAp44 interaction properties within MBL/ficolin complexes; supports complex membership,
uninformative as MF.
- id: PMID:21054788
title: CD91 interacts with mannan-binding lectin (MBL) through the MBL-associated serine protease-binding
site.
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: CD91/LRP1 binds MBL via the MASP-binding site (possible clearance receptor). Specific
interaction; not a core MF.
- id: PMID:21106539
title: Heterocomplexes of mannose-binding lectin and the pentraxins PTX3 or serum amyloid P component
trigger cross-activation of the complement system.
findings: []
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: MBL-pentraxin heterocomplexes cross-activate complement; supports MBL self/identical-protein
and pentraxin interactions modulating the lectin pathway.
- id: PMID:21203938
title: Specific interaction of hepatitis C virus glycoproteins with mannan binding lectin inhibits virus
entry.
findings: []
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: MBL binds HCV glycoproteins and inhibits entry; an example of antiviral carbohydrate
recognition. Supports the lectin/antiviral role rather than generic binding.
- id: PMID:21268013
title: 'Serglycin inhibits the classical and lectin pathways of complement via its glycosaminoglycan
chains: implications for multiple myeloma.'
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: Serglycin GAGs inhibit the lectin pathway; MBL is a target. Regulatory context.
- id: PMID:21383675
title: Mannan-binding lectin directly interacts with Toll-like receptor 4 and suppresses lipopolysaccharide-induced
inflammatory cytokine secretion from THP-1 cells.
findings: []
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: MBL binds the TLR4 ectodomain and dampens LPS-induced TNF-alpha/IL-12 and NF-kB in THP-1
cells - an immunomodulatory interaction. Supports a regulatory partner interaction; protein binding
still uninformative as MF.
- id: PMID:22607836
title: MASP interactions with plasma-derived MBL.
findings: []
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: Quantitative MASP-MBL interaction study; supports MBL-MASP complex assembly.
- id: PMID:22691502
title: Revised mechanism of complement lectin-pathway activation revealing the role of serine protease
MASP-1 as the exclusive activator of MASP-2.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: Establishes that in normal human serum MASP-1 is the exclusive activator of MASP-2 within
the MBL/ficolin-MASP complex, and MASP-1 generates ~60% of C2a. Strong mechanistic support for the
lectin-pathway-initiation core process and the proteolysis that MBL nucleates (MBL itself is not
the protease).
- id: PMID:22811680
title: The salivary scavenger and agglutinin binds MBL and regulates the lectin pathway of complement
in solution and on surfaces.
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: DMBT1/SALSA binds MBL and regulates the lectin pathway; a specific regulatory interaction.
- id: PMID:22854970
title: Crystal structure and functional characterization of the complement regulator mannose-binding
lectin (MBL)/ficolin-associated protein-1 (MAP-1).
findings: []
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: Structure of MAP-1, a competitive regulator of the MBL/ficolin-MASP complex; supports
complex membership/regulation.
- id: PMID:22966085
title: Mannan-binding lectin-associated serine protease (MASP)-1 is crucial for lectin pathway activation
in human serum, whereas neither MASP-1 nor MASP-3 is required for alternative pathway function.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: Patient-based functional study; MASP-1 is crucial for lectin-pathway activation and
co-complexes with MASP-2 on MBL. Strong support for the MBL-MASP initiating complex and lectin-pathway
/ PRR-signaling annotations.
- id: PMID:23460739
title: Deciphering complement receptor type 1 interactions with recognition proteins of the lectin complement
pathway.
findings: []
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: Maps MBL (and C1q/ficolin) interactions with CR1; supports a specific receptor interaction,
not an informative independent MF.
- id: PMID:23544079
title: Serum amyloid P is a sialylated glycoprotein inhibitor of influenza A viruses.
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: Paper primary subject is serum amyloid P (SAP), but the full text genuinely discusses
MBL as a beta-type C-type-lectin inhibitor of influenza A and uses purified human MBL as a comparator/reagent.
The paper therefore does support the MBL annotations grounded on it (mannose binding, antiviral/negative
regulation of viral process, extracellular location, innate immune response), albeit weakly/comparatively
- so it is correctly cited (not MISCITED), with LOW relevance. The antiviral role itself is real
and better supported elsewhere (PMID:21203938, PMID:35102342).
- id: PMID:2477488
title: Lipopolysaccharide (LPS) binding protein opsonizes LPS-bearing particles for recognition by a
novel receptor on macrophages.
findings: []
reference_review:
relevance: LOW
correctness: MISCITED
review_notes: This paper is about lipopolysaccharide-binding protein (LBP), an acute-phase opsonin
- NOT MBL2, and it does not assay MBL. The functions it is used to ground for MBL2 (opsonization,
acute-phase response, defense response to bacterium, cell surface) are independently true of MBL
but are correctly supported by other references; the D-mannose binding TAS attributed to this paper
is not supported by it at all. Treat as a likely wrong-paper / over-broad TAS citation.
- id: PMID:25579818
title: Structural insights into the initiating complex of the lectin pathway of complement activation.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: Architecture of the ~450 kDa MBL/MASP-1 initiating complex by SAXS/EM; strong support
for MBL membership in the serine-type endopeptidase (MBL-MASP) complex and for the intercomplex
activation model.
- id: PMID:2573758
title: Association of low levels of mannan-binding protein with a common defect of opsonisation.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: Classic study linking low serum MBP (a Ca2+-dependent serum lectin) to a common opsonic
defect that purified MBP corrects dose-dependently. Supports MBL as a Ca2+-dependent lectin acting
at the pathogen surface and in opsonization/innate defense.
- id: PMID:27104295
title: Oligomerization of Mannan-binding Lectin Dictates Binding Properties and Complement Activation.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: Higher oligomers (tetramers) of the MBL homotrimer bind microbes and MASPs more strongly
and activate complement better than trimers/dimers - establishing oligomerization as central to
MBL function. Supports identical-protein (self) association and the complement-activation role.
- id: PMID:29563915
title: C1q and Mannose-Binding Lectin Interact with CR1 in the Same Region on CCP24-25 Modules.
findings: []
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: Localizes the MBL (and C1q) binding site on CR1 to CCP24-25; supports a specific receptor
interaction.
- id: PMID:32041782
title: C1q/TNF-Related Protein 6 Is a Pattern Recognition Molecule That Recruits Collectin-11 from the
Complement System to Ligands.
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: Primarily about CTRP6/collectin-11; MBL appears as part of the broader collectin system.
Background relevance.
- id: PMID:32296183
title: A reference map of the human binary protein interactome.
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: High-throughput Y2H interactome (HuRI). Generic, low-specificity source of the GO:0005515
protein-binding IPI; not informative about MBL molecular function.
- id: PMID:32759297
title: Complement Activation and Thrombin Generation by MBL Bound to β2-Glycoprotein I.
findings: []
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: MBL binds beta2-glycoprotein I and can trigger complement/thrombin generation; a specific
ligand interaction linking MBL to coagulation crosstalk.
- id: PMID:33961781
title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: High-throughput AP-MS interactome (BioPlex). Generic source of the protein-binding IPI;
not informative about MBL molecular function.
- id: PMID:35102342
title: Recognition and inhibition of SARS-CoV-2 by humoral innate immunity pattern recognition molecules.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: MBL binds SARS-CoV-2 trimeric spike (including VoC) in a glycan- and calcium-dependent
manner, activates the lectin pathway after binding, and inhibits the virus in vitro; MBL2 polymorphisms
associate with COVID-19 severity. Strong support for calcium-dependent carbohydrate/glycoprotein
recognition, PRR activity, antiviral innate immunity and lectin-pathway activation.
- id: PMID:6643429
title: Isolation and characterization of a mannan-binding protein from human serum.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: Original isolation of human serum MBP; defines it as a Ca2+-dependent serum lectin specific
for mannose and N-acetylglucosamine with high-affinity, saturable, reversible mannan binding (Kd
~2.3e-9 M). Foundational support for the core D-mannose/carbohydrate binding MF.
- id: PMID:7982896
title: Structure and function of mannan-binding proteins isolated from human liver and serum.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: Purifies liver and serum MBP; shows both are liver-synthesized, secreted, differ in
oligomer number (L-MBP ~9, S-MBP ~18 subunits), and that complement activation requires higher oligomerization
and the collagen-like-domain N-terminus. Supports secreted location and oligomer-dependent complement
activation.
- id: PMID:8082295
title: Binding of mannan-binding protein to various bacterial pathogens of meningitis.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: MBP (a Ca2+-dependent plasma lectin) binds bacterial surfaces; binding inhibited by
mannose and N-acetyl-D-glucosamine. Supports Ca2+-dependent carbohydrate recognition at the microbial
cell surface and defense against bacteria.
- id: PMID:9087411
title: A second serine protease associated with mannan-binding lectin that activates complement.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: Identifies MASP-2 and establishes that MBL binds microbial carbohydrates and activates
complement through associated serine proteases (analogous to C1r/C1s), with MBL structurally related
to C1q. Foundational support for PRR activity and lectin-pathway initiation.
- id: Reactome:R-HSA-166721
title: MBL binds to repetitive carbohydrate structures on the surfaces of viruses, bacteria, fungi,
and protozoa
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: Reactome reaction capturing the core MBL recognition event - binding repetitive microbial
surface carbohydrate. Supports the carbohydrate-binding MF and extracellular location.
- id: Reactome:R-HSA-166726
title: Activation of MASPs
findings: []
- id: Reactome:R-HSA-166753
title: Conversion of C4 into C4a and C4b
findings: []
- id: Reactome:R-HSA-166792
title: Conversion of C2 into C2a and C2b
findings: []
- id: Reactome:R-HSA-9758529
title: SARS-CoV-2 N binds MASP2
findings: []
- id: Reactome:R-HSA-9921544
title: NS1 binds MBL
findings: []
- id: Reactome:R-HSA-9957161
title: MBL2 binds SARS-CoV-2 S
findings: []
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: Reactome reaction for MBL2 binding SARS-CoV-2 spike; consistent with PMID:35102342.
- id: file:human/MBL2/MBL2-notes.md
title: MBL2 curator research notes (this review)
findings: []
- id: file:human/MBL2/MBL2-deep-research-falcon.md
title: FutureHouse Falcon deep-research report for MBL2 (P11226)
findings: []
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: AI deep-research synthesis used as a starting point. Its core conclusions (Ca2+-dependent
carbohydrate binding, lectin-pathway complement activation, innate defense/opsonization as core;
cytoplasm/cytosol/nucleus/synapse/apoptosis-execution/pyroptosis/neuronal roles as high-risk and
unsupported) agree with the primary literature reviewed here, and all its cited sources resolve
to real published papers (no preprint-only/unresolvable PMIDs). Used to corroborate, not as primary
evidence.
core_functions:
- description: Calcium-dependent recognition of terminal mannose, N-acetylglucosamine and fucose residues
arranged in the repetitive geometric patterns of microbial surfaces, by the C-type carbohydrate-recognition
domain (CRD). This Ca2+-dependent carbohydrate binding is the defining, evolutionarily conserved molecular
function of MBL and the basis of all its downstream biology.
molecular_function:
id: GO:0120153
label: calcium-dependent carbohydrate binding
directly_involved_in:
- id: GO:0045087
label: innate immune response
locations:
- id: GO:0005576
label: extracellular region
- id: GO:0106139
label: symbiont cell surface
supported_by:
- reference_id: PMID:6643429
supporting_text: A serum lectin specific for mannose and N-acetylglucosamine residues was
- reference_id: PMID:6643429
supporting_text: mannan was dependent upon the presence of Ca2+
- reference_id: PMID:8082295
supporting_text: The binding was inhibited by unlabelled MBP, by mannose and by N-acetyl-D-glucosamine
- reference_id: file:human/MBL2/MBL2-deep-research-falcon.md
supporting_text: binds carbohydrates in a **calcium-dependent** manner
- description: D-mannose / mannan binding - the specific monosaccharide specificity of the MBL CRD, the
molecular basis of microbial surface recognition.
molecular_function:
id: GO:0005537
label: D-mannose binding
locations:
- id: GO:0106139
label: symbiont cell surface
supported_by:
- reference_id: PMID:6643429
supporting_text: A serum lectin specific for mannose and N-acetylglucosamine residues was
- description: Pattern-recognition-receptor activity - MBL acts as a soluble pattern-recognition molecule
that distinguishes microbial (and altered-self) carbohydrate patterns from host glycans and, upon
binding, triggers the associated MASP serine proteases to initiate the complement lectin pathway.
This is the effector molecular function that converts carbohydrate recognition into innate immune
activation.
molecular_function:
id: GO:0038187
label: pattern recognition receptor activity
directly_involved_in:
- id: GO:0001867
label: complement activation, lectin pathway
- id: GO:0042742
label: defense response to bacterium
locations:
- id: GO:0005576
label: extracellular region
- id: GO:0106139
label: symbiont cell surface
in_complex:
id: GO:1905370
label: serine-type endopeptidase complex
supported_by:
- reference_id: PMID:9087411
supporting_text: found on the surface of a range of microorganisms, including bacteria, yeasts,
- reference_id: PMID:9087411
supporting_text: complement activation through MBL, like the classical pathway,
- reference_id: PMID:22966085
supporting_text: MASP-1 and MASP-2 can associate in the same
- reference_id: PMID:25579818
supporting_text: initiates the pathway by activating a second protease, MASP-2.
proposed_new_terms:
- proposed_name: collectin oligomer carbohydrate-pattern recognition
proposed_definition: Recognition of a spatially repetitive, geometrically defined array of terminal
monosaccharides (e.g. mannose, N-acetylglucosamine, fucose) on a microbial or altered-self surface
by a multivalent oligomeric collectin, in which avidity arises from the simultaneous engagement of
multiple low-affinity C-type lectin carbohydrate-recognition domains presented by the oligomer, thereby
discriminating microbial macropatterns from host glycoproteins.
justification: MBL specificity for non-self arises from the geometric spacing of multiple CRDs across
a higher-order oligomer (the macropattern concept). Existing MF terms (carbohydrate binding, calcium-dependent
carbohydrate binding, pattern recognition receptor activity) capture facets but none captures the
multivalent, oligomer-dependent macropattern discrimination that distinguishes collectins/ficolins
and that experimentally governs microbial binding and complement activation.
supported_by:
- reference_id: PMID:27104295
supporting_text: oligomeric state of MBL is crucial both for the binding properties and the
- reference_id: file:human/MBL2/MBL2-deep-research-falcon.md
supporting_text: Recognizes microbial or exposed glycans containing
suggested_questions:
- question: Beyond binding, does MBL contribute any conformational/allosteric signal that activates the
bound MASP zymogens, or is its role purely to cluster and co-localize MASPs on the target surface?
experts: []
- question: How quantitatively important is the antibody-independent MBL lectin pathway in healthy human
adults (most MBL-deficient adults are healthy), versus in specific windows such as infancy, neutropenia,
or immunosuppression?
experts: []
suggested_experiments:
- hypothesis: The calcium-dependent carbohydrate-recognition activity of the CRD is strictly required
for all MBL effector functions (complement activation, opsonization, antiviral inhibition).
description: Compare wild-type recombinant MBL with CRD point mutants that abolish Ca2+/sugar binding
(mutations of the Ca2+/glycosyl-coordinating residues around 212-233) for binding to mannan, S. aureus,
influenza A and SARS-CoV-2 spike, and for MASP-dependent C4/C2 cleavage and opsonophagocytosis, using
EDTA and competing mannose/GlcNAc as controls.
experiment_type: structure-function / CRD mutagenesis with binding and complement-activation assays
- hypothesis: MBL oligomerization state (trimer vs tetramer-and-higher) sets the threshold for microbial
discrimination and complement activation in a physiologically meaningful way.
description: Produce defined recombinant MBL oligomers, quantify avidity for panels of microbial vs
host glycans (SPR / glycan arrays) and MASP recruitment, correlate with C4 deposition and bacterial
opsonophagocytosis, and relate to oligomer distributions produced by common MBL2 structural variants.
experiment_type: biophysical oligomer fractionation with glycan-array and complement assays