Malectin is an ER-resident type I membrane lectin that specifically recognizes di-glucosylated high-mannose N-glycans (Glc2Man9GlcNAc2, G2M9) on nascent glycoproteins. It functions in the early steps of ER glycoprotein quality control, acting upstream of the calnexin/calreticulin cycle. Malectin forms a stable complex with ribophorin I (RPN1), an oligosaccharyltransferase subunit, which enhances its association with misfolded glycoproteins and promotes their retention for ERAD. The protein contains a lumenal carbohydrate-binding malectin domain with specificity for the Glc-alpha-1,3-Glc (nigerose) disaccharide motif, with binding affinity Ka of approximately 1.97 x 10^5 M^-1 for G2M9.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0016020 membrane | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for membrane localization. Malectin is a type I membrane protein with a single transmembrane helix (UniProt feature TRANSMEM 270-290), consistent with membrane association. Reason: The annotation is correct. Malectin is a single-pass type I membrane protein with a characterized transmembrane domain. The IBA evidence from phylogenetic inference is consistent with the protein's membrane topology as determined by structural and biochemical studies (MLEC-deep-research-falcon.md). Supporting Evidence: file:human/MLEC/MLEC-deep-research-falcon.md Human MLEC (Malectin), UniProt Q14165 -- type I membrane protein with a lumenal carbohydrate-binding (malectin) domain, single transmembrane helix and short cytosolic tail. |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000117 | ACCEPT | Summary: IEA annotation based on ARBA machine learning for ER localization. The protein is well-established as an ER-resident lectin. Reason: Malectin is definitively localized to the ER. Multiple experimental studies confirm ER localization. The deep research review notes malectin is an ER-resident lectin that localizes in ER subdomains with RPN1-dependent ER retention. Supporting Evidence: file:human/MLEC/MLEC-deep-research-falcon.md Malectin is a type I ER membrane lectin with a lumenal glycan-binding domain. It resides predominantly in the ER, often concentrated in ER subdomains. PMID:22988243 Malectin is an endoplasmic reticulum-resident lectin |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation based on UniProtKB subcellular location vocabulary mapping. Consistent with the protein being a type I ER membrane protein. Reason: Correct and well-supported. Malectin is a type I membrane protein anchored in the ER membrane with its malectin domain facing the ER lumen and a short cytoplasmic tail. This is consistent with UniProt topology annotations and structural studies. Supporting Evidence: PMID:31831667 In OST-A, interactions with TMEM258 and STT3A allow ribophorin-I to form a four-helix bundle file:human/MLEC/MLEC-deep-research-falcon.md type I membrane protein with a lumenal carbohydrate-binding (malectin) domain, single transmembrane helix and short cytosolic tail |
| GO:0030246 carbohydrate binding | IEA GO_REF:0000002 | ACCEPT | Summary: IEA annotation from InterPro mapping. Malectin is a well-characterized carbohydrate-binding lectin with specificity for di-glucosylated N-glycans. Reason: This general term is appropriate as malectin has demonstrated carbohydrate binding activity. Malectin binds specifically to Glc2Man9GlcNAc2 (G2M9) N-glycans with Ka approximately 1.97 x 10^5 M^-1, recognizing the Glc-alpha-1,3-Glc (nigerose) disaccharide epitope. Supporting Evidence: PMID:22988243 Malectin is an endoplasmic reticulum-resident lectin, which recognizes di-glucosylated Glc(2)Man(9)GlcNAc(2) (G2M9) N-glycans on newly synthesized glycoproteins file:human/MLEC/MLEC-deep-research-falcon.md Strong, selective recognition of di-glucosylated high-mannose N-glycans (Glc2Man9GlcNAc2, G2M9); epitope centers on a Glc-alpha-1,3-Glc disaccharide |
| GO:0005515 protein binding | IPI PMID:30021884 Histone Interaction Landscapes Visualized by Crosslinking Ma... | REMOVE | Summary: IPI annotation from histone crosslinking mass spectrometry study with P04843 (RPN1). The interaction with RPN1 is real but protein binding is uninformative. Reason: While malectin does interact with RPN1 (ribophorin I), the term "protein binding" (GO:0005515) is uninformative per GO curation guidelines. The interaction with RPN1 is functionally significant for ER retention and association with misfolded glycoproteins (PMID:22988243), but should be captured with more specific terms. The cited publication (PMID:30021884) is about histone interaction landscapes and is not directly relevant to malectin's core function. Supporting Evidence: PMID:30021884 Epub 2018 Jul 18. Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei. |
| GO:0005515 protein binding | IPI PMID:31831667 Cryo-electron microscopy structures of human oligosaccharylt... | REMOVE | Summary: IPI annotation from cryo-EM structural study showing malectin interaction with OST complex components including RPN1 (P04843). Reason: The term "protein binding" (GO:0005515) is too vague and uninformative. The interaction documented in PMID:31831667 is specific to the oligosaccharyltransferase (OST) complex. A more appropriate annotation would be GO:0062062 (oligosaccharyltransferase complex binding) or GO:0008250 (oligosaccharyltransferase complex) as a cellular component. Proposed replacements: oligosaccharyltransferase complex binding Supporting Evidence: PMID:31831667 Cryo-electron microscopy structures of human oligosaccharyltransferase complexes OST-A and OST-B. |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | REMOVE | Summary: IPI annotation from OpenCell high-throughput endogenous tagging study showing interactions with RPN1 (P04843) and STT3B (Q8TCJ2). Reason: The term "protein binding" (GO:0005515) is too general per GO guidelines. The cited study (OpenCell) is high-throughput proteomics for cellular organization mapping. While the interactions detected are consistent with malectin's association with the OST complex, a more specific term should be used. The interaction is better captured by oligosaccharyltransferase complex binding (GO:0062062). Supporting Evidence: PMID:35271311 2022 Mar 11. OpenCell: Endogenous tagging for the cartography of human cellular organization. |
| GO:0051087 protein-folding chaperone binding | IDA PMID:22988243 Malectin forms a complex with ribophorin I for enhanced asso... | MODIFY | Summary: IDA annotation indicating malectin binds to protein-folding chaperones. This annotation requires careful evaluation of the publication. Reason: PMID:22988243 (Qin et al. 2012) demonstrates that malectin forms a stable complex with ribophorin I (RPN1), not a classical protein-folding chaperone. The study shows RPN1 may function as a chaperone that recognizes misfolded proteins, but RPN1 is primarily an OST subunit. Malectin itself functions more as a lectin recognizing glycan intermediates on misfolded proteins rather than binding to classical chaperones. A more accurate annotation would be misfolded protein binding (GO:0051787) or oligosaccharyltransferase complex binding (GO:0062062). Proposed replacements: misfolded protein binding oligosaccharyltransferase complex binding Supporting Evidence: PMID:22988243 we found that malectin formed a stable complex with an endoplasmic reticulum-resident transmembrane protein, ribophorin I PMID:22988243 ribophorin I preferentially interacted with misfolded ribonuclease A but not with the native form, suggesting that ribophorin I may function as a chaperone that recognizes misfolded proteins inside cells |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-6799350 | KEEP AS NON CORE | Summary: TAS annotation from Reactome pathway for exocytosis of specific granule membrane proteins. This annotation suggests malectin is found at the plasma membrane. Reason: Malectin's primary localization is the ER membrane, not the plasma membrane. The Reactome pathway R-HSA-6799350 relates to neutrophil degranulation where specific granule contents are released. While malectin may transiently appear at the plasma membrane during exocytosis of granule contents, this is not its primary functional location. The ER is the core location where malectin performs its glycoprotein quality control function. |
| GO:0035579 specific granule membrane | TAS Reactome:R-HSA-6799350 | KEEP AS NON CORE | Summary: TAS annotation from Reactome indicating malectin is found in neutrophil-specific granule membranes. Reason: This annotation reflects malectin detection in neutrophil-specific granules. While this may be accurate in the context of neutrophil biology, it does not represent the core functional location of malectin. The primary role of malectin is in ER glycoprotein quality control. Presence in granules may reflect trafficking through the secretory pathway rather than a primary functional location. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | ACCEPT | Summary: HDA annotation from high-throughput proteomics study of NK cell membrane proteome. Reason: The annotation is correct but generic. PMID:19946888 is a large-scale membrane proteomics study that identified malectin as a membrane protein. This is consistent with malectin being a type I membrane protein. The HDA evidence appropriately reflects the high-throughput nature of the detection. Supporting Evidence: PMID:19946888 Mass spectrometric analysis identified 1843 proteins with high confidence scores |
| GO:0019899 enzyme binding | IPI PMID:22988243 Malectin forms a complex with ribophorin I for enhanced asso... | MODIFY | Summary: IPI annotation indicating malectin binds to an enzyme, specifically RPN1 (P04843) which is a subunit of the OST complex. Reason: RPN1 (ribophorin I) is a subunit of the oligosaccharyltransferase (OST) complex. While OST has enzymatic activity (N-glycosyltransferase), RPN1 itself is a non-catalytic subunit. The annotation "enzyme binding" is technically not wrong since malectin associates with the OST complex, but a more specific term would be oligosaccharyltransferase complex binding (GO:0062062). This better captures the functional relationship. Proposed replacements: oligosaccharyltransferase complex binding Supporting Evidence: PMID:22988243 we found that malectin formed a stable complex with an endoplasmic reticulum-resident transmembrane protein, ribophorin I PMID:31831667 Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-532667 | ACCEPT | Summary: TAS annotation from Reactome pathway for N-glycan trimming/removal of second glucose by glucosidase II. Reason: This annotation is correct. The Reactome pathway R-HSA-532667 describes N-glycan trimming in the ER where malectin functions. Malectin recognizes the G2 (di-glucosylated) N-glycan intermediate that exists after glucosidase I action and before complete glucosidase II trimming. Supporting Evidence: file:human/MLEC/MLEC-deep-research-falcon.md Malectin recognizes G2 immediately after glucosidase I action and before complete glucosidase II trimming |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-901006 | ACCEPT | Summary: TAS annotation from Reactome pathway specifically about malectin binding in the ER. Reason: Correct annotation. Reactome pathway R-HSA-901006 (Binding of Malectin) directly describes malectin's function in the ER membrane where it binds to di-glucosylated N-glycans on nascent glycoproteins as part of the quality control machinery. |
| GO:0005783 endoplasmic reticulum | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation based on sequence similarity to mouse malectin (Q6INX3) for ER localization. Reason: The annotation is correct and supported by experimental evidence in human cells. ER localization is well-established for human malectin through multiple experimental studies. |
| GO:0030246 carbohydrate binding | ISS GO_REF:0000024 | ACCEPT | Summary: ISS annotation based on sequence similarity to mouse malectin for carbohydrate binding function. Reason: Carbohydrate binding is the core molecular function of malectin. This is well-established experimentally in human cells. Malectin specifically binds Glc2Man9GlcNAc2 (G2M9) N-glycans with strong affinity (Ka approximately 1.97 x 10^5 M^-1). The malectin domain is highly conserved across species. Supporting Evidence: PMID:22988243 Malectin is an endoplasmic reticulum-resident lectin, which recognizes di-glucosylated Glc(2)Man(9)GlcNAc(2) (G2M9) N-glycans on newly synthesized glycoproteins |
| GO:0051787 misfolded protein binding | IDA PMID:22988243 Malectin forms a complex with ribophorin I for enhanced asso... | NEW | Summary: Proposed new annotation. Malectin preferentially associates with misfolded glycoproteins bearing G2M9 N-glycans. Reason: PMID:22988243 demonstrates that malectin preferentially associates with misfolded glycoproteins. The study showed malectin binds to folding-defective alpha1-antitrypsin (null Hong Kong variant) and showed enhanced association with misfolded glycoproteins via the malectin-RPN1 complex. Supporting Evidence: PMID:22988243 Co-expression of malectin and ribophorin I significantly enhanced the association between malectin and a folding-defective alpha1-antitrypsin variant (null Hong Kong) and reduced its secretion PMID:22988243 malectin preferentially associates with misfolded glycoproteins and inhibits their secretion |
| GO:0062062 oligosaccharyltransferase complex binding | IDA PMID:31831667 Cryo-electron microscopy structures of human oligosaccharylt... | NEW | Summary: Proposed new annotation. Malectin interacts with the OST complex as shown by cryo-EM structural studies. Reason: PMID:31831667 (Ramirez et al. 2019) determined the cryo-EM structure of human OST complexes. Additionally, PMID:22988243 showed malectin forms a stable complex with ribophorin I, a key OST subunit. This is more informative than the generic "protein binding" term and captures the specific interaction with the OST complex that is functionally important for malectin's role in glycoprotein quality control. Supporting Evidence: PMID:31831667 Oligosaccharyltransferase (OST) catalyzes the transfer of a high-mannose glycan onto secretory proteins in the endoplasmic reticulum PMID:22988243 we found that malectin formed a stable complex with an endoplasmic reticulum-resident transmembrane protein, ribophorin I |
| GO:0036503 ERAD pathway | IDA PMID:22988243 Malectin forms a complex with ribophorin I for enhanced asso... | NEW | Summary: Proposed new annotation. Malectin functions in promoting ERAD of misfolded glycoproteins. Reason: Malectin overexpression enhances ERAD of misfolded alpha1-antitrypsin (ATNHK) and reduces its secretion, while wild-type AT is not similarly affected. This positions malectin as an early recognition/retention factor for ERAD substrates. Supporting Evidence: PMID:22988243 malectin preferentially associates with misfolded glycoproteins and inhibits their secretion file:human/MLEC/MLEC-deep-research-falcon.md In human cells, malectin stably associates with misfolded alpha1-antitrypsin (ATNHK) via G2M9; malectin overexpression enhances ER-associated degradation (ERAD) of ATNHK and reduces its secretion |
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