LOXL1 is a secreted copper- and lysine-tyrosylquinone-dependent protein-lysine oxidase of the extracellular matrix. Proteolytic processing of the precursor produces extracellular LOXL1 forms whose C-terminal catalytic region oxidatively deaminates lysine and hydroxylysine side chains in matrix proteins, initiating covalent cross-link formation. LOXL1 is especially important for elastin deposition and adult elastic-fiber homeostasis: recruitment to elastogenic sites through fibulin-5 helps spatially target its activity, while collagen is an additional substrate supported most directly by orthologous biochemical evidence. Loss of Loxl1 in mice disrupts elastic tissues, and human LOXL1 variants confer susceptibility to exfoliation syndrome.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004720 protein-lysine 6-oxidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference assigns LOXL1 protein-lysine 6-oxidase activity. Reason: This is the defining catalytic activity of the conserved copper-dependent lysyl-oxidase domain and is central to mature extracellular LOXL1. Propagation Review Root cause: NO FAILURE CORE Sources checked: FB:FBgn0034660 FB:FBgn0039848 MGI:MGI:106096 MGI:MGI:1337004 MGI:MGI:1914823 MGI:MGI:96817 PANTHER:PTN002550804 RGD:3015 UniProtKB:P28300 UniProtKB:P58215 UniProtKB:Q05063 UniProtKB:Q95L39 UniProtKB:Q96JB6 UniProtKB:Q9Y4K0 |
| GO:0005576 extracellular region | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference places active LOXL1 in the extracellular region. Reason: LOXL1 is a signal-peptide-containing secreted precursor whose catalytically active processed forms act extracellularly; this broad compartment is correct and core. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:106096 MGI:MGI:1337004 MGI:MGI:1914823 MGI:MGI:96817 PANTHER:PTN002550804 RGD:1308435 RGD:1308752 RGD:3015 UniProtKB:P28300 UniProtKB:P33072 UniProtKB:P58215 UniProtKB:Q08397 UniProtKB:Q9Y4K0 |
| GO:0031012 extracellular matrix | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference places active LOXL1 in the extracellular matrix. Reason: Matrix localization is integral to LOXL1-mediated collagen and elastin cross-linking and is independently supported by human ECM proteomics. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:106096 MGI:MGI:96817 PANTHER:PTN008698711 RGD:1308435 RGD:1308752 RGD:3015 |
| GO:0030199 collagen fibril organization | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic inference assigns LOXL1 a role in collagen fibril organization. Reason: Processed bovine LOXL1 can act on collagen, and the phylogenetic transfer is biologically plausible, but direct human LOXL1-specific evidence for collagen fibril organization is weaker than the evidence for elastic-fiber assembly. Retain this as a secondary, non-core matrix role. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: MGI:MGI:96817 PANTHER:PTN008698711 RGD:3015 UniProtKB:Q9Y4K0 |
| GO:0004720 protein-lysine 6-oxidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated reaction and EC mappings assign protein-lysine 6-oxidase activity. Reason: RHEA:24544 and EC 1.4.3.13 describe the LOXL1 reaction on protein lysine residues and match its conserved catalytic domain. Propagation Review Root cause: NO FAILURE CORE Sources checked: RHEA:24544 EC:1.4.3.13 |
| GO:0005507 copper ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro domain mappings assign copper ion binding. Reason: Copper is an obligatory lysyl-oxidase cofactor, and LOXL1 retains the conserved catalytic copper-binding residues. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR001695 InterPro:IPR019828 |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | ACCEPT | Summary: The UniProt subcellular-location mapping assigns LOXL1 to the extracellular region. Reason: The precursor has a signal peptide and is secreted to extracellular space and matrix; this broad electronic localization is correct. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0112 |
| GO:0016641 oxidoreductase activity, acting on the CH-NH2 group of donors, oxygen as acceptor | IEA GO_REF:0000002 | MODIFY | Summary: InterPro assigns the broad parent oxidoreductase activity acting on CH-NH2 donors. Reason: The parent is true but needlessly generic because LOXL1 has a defined protein-lysine 6-oxidase reaction. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: InterPro:IPR001695 InterPro:IPR019828 Proposed replacements: protein-lysine 6-oxidase activity |
| GO:0071953 elastic fiber | IEA GO_REF:0000117 | ACCEPT | Summary: An ARBA model places LOXL1 at elastic fibers. Reason: Elastic-fiber association is consistent with fibulin binding and LOXL1's important role in elastin cross-linking and elastic-fiber maintenance. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00084594 |
| GO:0001669 acrosomal vesicle | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl orthology transfer places LOXL1 in the acrosomal vesicle from rat LOXL1. Reason: This is plausible for a conserved ortholog but is a specialized germ-cell localization rather than the general matrix site of LOXL1 catalysis. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q5FWS5 ensembl:ENSRNOP00000032184 |
| GO:0005604 basement membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl orthology transfer places LOXL1 in basement membrane from rat LOXL1. Reason: Basement membrane is a plausible specialized matrix niche, but is contextual and not required to define LOXL1's core activity. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q5FWS5 ensembl:ENSRNOP00000032184 |
| GO:0031012 extracellular matrix | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl orthology transfer places LOXL1 in extracellular matrix from rat LOXL1. Reason: The transfer agrees with secretion, conserved matrix-remodeling function, and multiple direct human ECM proteomics annotations. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q5FWS5 ensembl:ENSRNOP00000032184 |
| GO:0032496 response to lipopolysaccharide | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl orthology transfer assigns response to lipopolysaccharide from rat LOXL1. Reason: This likely reflects context-dependent expression or phenotype during LPS challenge, not LOXL1 acting as response machinery; it is downstream and contextual. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH ROLE CONFLATION Sources checked: UniProtKB:Q5FWS5 ensembl:ENSRNOP00000032184 |
| GO:0035904 aorta development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl orthology transfer assigns aorta development from rat LOXL1. Reason: Aortic development is compatible with matrix and elastic-fiber maturation but is an organismal outcome downstream of extracellular catalysis. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q5FWS5 ensembl:ENSRNOP00000032184 |
| GO:0071953 elastic fiber | TAS PMID:16893474 Elastic fibres in health and disease. | ACCEPT | Summary: A curator statement associates LOXL1 with elastic fibers using an elastic-fiber review. Reason: The cached record is abstract-only and lacks the LOXL1 passage, but the term is fully consistent with established LOXL1 biology; curator judgment is retained. Supporting Evidence: PMID:16893474 Elastic fibres are a major class of extracellular matrix fibres that are abundant in dynamic connective tissues such as arteries, lungs, skin and ligaments. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-2022141 | ACCEPT | Summary: A Reactome-derived TAS row assigns LOXL1 to the extracellular region during prolysyl-oxidase activation. Reason: The cached event summary describes canonical LOX and cannot verify an LOXL1-specific participant or processing boundary. Retain the curator's broad extracellular-location assertion because LOXL1 secretion is independently well established, while treating this event only as contextual background. |
| GO:0004720 protein-lysine 6-oxidase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Curator-reviewed similarity to mouse Loxl1 assigns protein-lysine 6-oxidase activity. Reason: The orthologous transfer is specific and agrees with LOXL1's conserved catalytic domain, reaction mapping, and phylogenetic annotation. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P97873 |
| GO:0005576 extracellular region | IDA PMID:37602378 HELZ2: a new, interferon-regulated, human 3'-5' exoribonucle... | UNDECIDED | Summary: An IDA annotation cites a HELZ2 exoribonuclease paper for LOXL1 localization. Reason: The complete cached article concerns HELZ2 RNA metabolism and contains no LOXL1 evidence, so it cannot verify this experimental annotation. Extracellular localization is independently correct for LOXL1, but the provenance of this IDA row cannot be reconstructed; defer to the curator rather than remove it. Supporting Evidence: PMID:37602378 Database searches identified a new RNB domain-containing protein in human: HELZ2. |
| GO:0005515 protein binding | IPI PMID:27339457 Functional consequence of fibulin-4 missense mutations assoc... | MODIFY | Summary: IPI reports LOXL1 binding to the matrix glycoprotein fibulin-4/EFEMP2. Reason: The interaction is real, but generic protein binding is uninformative. Extracellular matrix protein binding captures it without conflating binding with catalysis or a stable complex. Proposed replacements: extracellular matrix protein binding Supporting Evidence: PMID:27339457 We show that fibulin-4 binds stronger than fibulin-3 and -5 to LTBP1s, 3, and 4s, and to the lysyl oxidases LOX and LOXL1 |
| GO:0031012 extracellular matrix | HDA PMID:28327460 Comprehensive proteomic characterization of stem cell-derive... | ACCEPT | Summary: A curator-reviewed bone-marrow mesenchymal-stem-cell matrisome dataset assigns LOXL1 to extracellular matrix. Reason: The LOXL1-specific peptide table is not exposed in the cached narrative, so the HDA call is retained with curator deference. It is biologically concordant with independently supported LOXL1 matrix residence and preserves the bone-marrow MSC extension without claiming narrative-level verification. |
| GO:0031012 extracellular matrix | HDA PMID:28675934 Characterization of the Extracellular Matrix of Normal and D... | ACCEPT | Summary: A curator-reviewed human omentum matrisome dataset assigns LOXL1 to extracellular matrix. Reason: The LOXL1-specific peptide table is not exposed in the cached narrative, so the HDA call is retained with curator deference. It is concordant with independently supported LOXL1 matrix residence and does not generalize the omentum extension to all tissues. |
| GO:0031012 extracellular matrix | HDA PMID:27068509 Extracellular matrix remodelling in response to venous hyper... | ACCEPT | Summary: A curator-reviewed human saphenous-vein matrisome dataset assigns LOXL1 to extracellular matrix. Reason: The LOXL1-specific peptide table is not exposed in the cached narrative, so the HDA call is retained with curator deference. It is concordant with independently supported LOXL1 matrix residence and preserves the saphenous-vein context. |
| GO:0031012 extracellular matrix | HDA PMID:20551380 Proteomics characterization of extracellular space component... | ACCEPT | Summary: Human ascending-aorta proteomics detected LOXL1 in an ECM-enriched fraction. Reason: The study identifies LOXL1 among proteins of the vascular extracellular environment, directly supporting tissue-qualified ECM colocalization. Supporting Evidence: PMID:20551380 Lysyl oxidase homolog 1bLOXL1_HUMAN6312127.323 |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-2002466 | ACCEPT | Summary: A Reactome-derived TAS row assigns LOXL1 to the extracellular region during collagen lysine oxidation. Reason: The cached event summary describes canonical LOX and cannot verify an LOXL1-specific participant. Retain the curator's broad extracellular-location assertion because LOXL1 secretion is independently well established, while treating this event only as contextual lysyl-oxidase pathway background. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-2129375 | ACCEPT | Summary: A Reactome-derived TAS row assigns LOXL1 to the extracellular region during elastin cross-linking. Reason: The cached event summary describes canonical LOX and cannot verify an LOXL1-specific participant. Retain the curator's broad extracellular-location assertion because LOXL1 secretion is independently well established, while treating this event only as contextual lysyl-oxidase pathway background. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-2395340 | ACCEPT | Summary: A Reactome-derived TAS row assigns LOXL1 to the extracellular region during collagen hydroxylysine oxidation. Reason: The cached event summary describes canonical LOX and cannot verify an LOXL1-specific participant. Retain the curator's broad extracellular-location assertion because LOXL1 secretion is independently well established, while treating this event only as contextual lysyl-oxidase pathway background. |
| GO:0005576 extracellular region | TAS PMID:7689553 A novel human cDNA with a predicted protein similar to lysyl... | ACCEPT | Summary: The original human LOXL1 cDNA report supports an extracellular lysyl-oxidase-family protein. Reason: The abstract mainly establishes homology, but extracellular localization is correct and independently established; this old curator statement is retained. Supporting Evidence: PMID:7689553 A novel human cDNA with a predicted protein homologous to the carboxyl end of lysyl oxidase, an extracellular enzyme involved in the maturation of collagen and elastin, has been isolated. |
| GO:0018277 protein deamination | TAS PMID:7689553 A novel human cDNA with a predicted protein similar to lysyl... | MODIFY | Summary: A curator statement assigns the broad process protein deamination. Reason: LOXL1 does not perform generic protein deamination; it oxidatively deaminates peptidyl lysine and hydroxylysine to initiate matrix cross-linking. Proposed replacements: peptidyl-lysine oxidation Supporting Evidence: PMID:7689553 A novel human cDNA with a predicted protein homologous to the carboxyl end of lysyl oxidase |
| GO:0048251 elastic fiber assembly | ISO PMID:14745449 Elastic fiber homeostasis requires lysyl oxidase-like 1 prot... | NEW | Summary: Proposed new annotation by orthology. Loxl1-null mice fail to deposit normal postpartum uterine elastic fibers and accumulate tropoelastin, while LOXL1 localizes to elastogenic sites and interacts with fibulin-5. Reason: Elastic-fiber assembly captures LOXL1's best-supported specialized biological process more directly than collagen fibril organization or broad extracellular matrix terms. The evidence is explicitly transferred from mouse rather than presented as a direct human perturbation result; human recombinant fibulin-5 binding independently supports the conserved elastogenic-targeting mechanism. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P97873 SUPPORTS TRANSFER Mouse Loxl1 loss-of-function and elastogenic-site evidence support transfer of elastic-fiber assembly to the human ortholog. Supporting Evidence: PMID:14745449 Here we show that mice lacking the protein lysyl oxidase-like 1 (LOXL1) do not deposit normal elastic fibers in the uterine tract post partum and develop pelvic organ prolapse, enlarged airspaces of the lung, loose skin and vascular abnormalities with concomitant tropoelastin accumulation. PMID:14745449 Distinct from the prototypic lysyl oxidase (LOX), LOXL1 localizes specifically to sites of elastogenesis and interacts with fibulin-5. PMID:17371835 As shown in Fig. 7 B, we detected the specific interaction of LOXL1, 2, and 4 proteins with fibulin-5 protein (top, lanes 1, 7, and 13). |
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Download this section (compressed HTML)Q: Which lysine and hydroxylysine sites in native human elastin and collagen are oxidized specifically by LOXL1 rather than LOX or another LOXL paralog?
Q: Which human LOXL1 cleavage products acquire a mature copper/LTQ catalytic center, and how do BMP1- and ADAMTS14-dependent cleavages alter their stability, matrix retention, and substrate preference?
Q: Does fibulin-5 recruit a particular precursor or processed LOXL1 form at endogenous abundance, and is that transient targeting interaction required for elastic-fiber assembly without constituting a stable complex?
Q: How do exfoliation-syndrome-associated LOXL1 variants alter expression, secretion, processing, elastogenic targeting, or catalysis in relevant human ocular tissues?
Experiment: Use inducible LOXL1 degradation in primary human fibroblasts and elastogenic organoids, with matched single and combinatorial LOX-family perturbations. Quantify site-resolved aldehydes and mature elastin/collagen cross-links by mass spectrometry, then rescue with wild-type or catalytic-dead LOXL1 and compare purified human enzyme kinetics on matched matrix substrates.
Hypothesis: Human LOXL1 preferentially oxidizes a defined subset of elastin sites that is not redundantly modified by other lysyl oxidases.
Type: endogenous perturbation and matrix cross-link proteomics
Experiment: Engineer endogenous cleavage-site substitutions in human matrix-producing cells, quantify each extracellular LOXL1 form and LTQ maturation, and measure activity, matrix retention, elastin deposition, and collagen cross-links. Include protease perturbation and rescue with purified, cleavage-matched LOXL1 forms.
Hypothesis: Distinct BMP1- and ADAMTS14-generated LOXL1 forms differ in catalytic competence and matrix-substrate targeting.
Type: endogenous processing and form-specific activity analysis
Experiment: Endogenously tag LOXL1 on both sides of mapped cleavage sites, perturb FBLN5, and use pulse-chase super-resolution imaging, proximity labeling, and form-specific immunoprecipitation alongside elastin cross-link measurements. Test rescue with fibulin-5 variants defective in LOXL1 binding and distinguish transient colocalization from stable complex formation by quantitative residence-time measurements.
Hypothesis: Fibulin-5 transiently recruits a processing-defined LOXL1 form to elastogenic sites and is required for spatially restricted elastin cross-linking.
Type: endogenous interaction and elastogenic-targeting analysis
Experiment: Create isogenic human ocular fibroblast or anterior-segment organoid lines carrying common LOXL1 risk and protective haplotypes. Quantify transcription, secretion, cleavage forms, fibulin-5 recruitment, oxidase activity, matrix cross-links, and exfoliation-material phenotypes under matched stress conditions.
Hypothesis: Exfoliation-syndrome risk variants perturb a specific LOXL1 biogenesis or targeting step rather than creating a new catalytic activity.
Type: isogenic variant-to-function analysis
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The catalytic efficiency and native substrate-site spectrum of purified human LOXL1 have not been established directly, including how its contribution to elastin cross-linking differs from its contribution to collagen cross-linking and from those of other lysyl oxidases.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Human sequence, reaction mappings, and orthology support protein-lysine 6-oxidase activity, while processed bovine LOXL1 is directly active on elastin and collagen and mouse Loxl1 loss causes pronounced elastic-fiber defects. These data do not identify endogenous human LOXL1-specific oxidation sites or quantify paralog redundancy.
Significance: Direct human substrate maps are needed to define why LOXL1 is especially important for elastic fibers and to separate conserved catalytic capacity from paralog-specific matrix deployment.
What would resolve it: Purify correctly cofactor-loaded human LOXL1 forms and combine kinetic assays with site-resolved allysine, hydroxyallysine, and mature-cross-link proteomics in LOXL1-depleted human elastogenic cell cultures, using selective LOX/LOXL paralog perturbations and wild-type versus catalytic-dead rescue.
Provenance (the field's own admissions):
Gap: Which extracellular human LOXL1 cleavage products are catalytically active, and how BMP1 and ADAMTS14 processing regulates activity, stability, and substrate targeting, remains unresolved.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Human-cell proteomics maps one BMP1 site and three ADAMTS14 sites, including sites beyond the annotated propeptide boundary, but does not assay the activity of every resulting species. Older activation evidence and cleavage assignments come from bovine LOXL1 and cannot define human form-specific activity.
Significance: Resolving form-specific activity is necessary to distinguish precursor processing from catalytic activation and to avoid assigning one fixed functional boundary to heterogeneous extracellular LOXL1 species.
What would resolve it: Introduce endogenous human LOXL1 cleavage-site substitutions individually and in combination, quantify secreted forms by targeted proteomics, and measure cofactor formation, catalytic activity, matrix retention, and elastin/collagen cross-links with rescue by purified matched forms.
Provenance (the field's own admissions):
Gap: The in-vivo mechanism and specificity by which fibulin-5 and other matrix partners target human LOXL1 to elastogenic sites are not known, nor is it clear which LOXL1 precursor or processed form mediates each interaction.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Human recombinant proteins demonstrate fibulin-5 binding, and mouse genetics links LOXL1 localization at elastogenic sites to spatially defined elastin deposition. These observations do not establish interaction stoichiometry, form specificity, or stable complex membership, and fibulin-5 also binds LOXL2 and LOXL4 in the assay.
Significance: Targeting could explain LOXL1's elastic-fiber specialization despite a catalytic domain shared with other lysyl oxidases and could reveal how disease-associated changes perturb matrix assembly without abolishing catalysis.
What would resolve it: Tag endogenous LOXL1 on both sides of its principal processing sites in human elastogenic cells, perturb FBLN5 and EFEMP2 separately, and combine pulse-chase imaging, proximity labeling, form-specific co-immunoprecipitation, and cross-link measurements to distinguish transient targeting from stable complexes.
Provenance (the field's own admissions):
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