LOX is a secreted, copper- and lysine-tyrosylquinone-dependent protein-lysine 6-oxidase synthesized as a preproprotein. Extracellular proteolysis produces a mature C-terminal enzyme that oxidatively deaminates selected peptidyl lysine and hydroxylysine residues in collagen and elastin, generating aldehydes that initiate covalent cross-links and stabilize collagen fibrils and elastic fibers. Collagen targeting is regulated by precursor processing and tyrosine sulfation, while the propeptide participates in recruitment to tropoelastin before being released as the noncatalytic LOX propeptide (LOX-PP). Loss-of-function variants impair LOX activity and cause familial thoracic aortic aneurysm and dissection, consistent with an essential role in aortic-wall extracellular-matrix integrity.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004720 protein-lysine 6-oxidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: LOX is a copper-dependent protein-lysine 6-oxidase; this is the core catalytic activity of the mature extracellular enzyme. Reason: The specific reaction matches the experimentally supported oxidative deamination of lysine and hydroxylysine residues in collagen and elastin (PMID:26838787; PMID:31152061). 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 Supporting Evidence: file:human/LOX/LOX-uniprot.txt Responsible for the post-translational oxidative deamination |
| GO:0005576 extracellular region | IBA GO_REF:0000033 | ACCEPT | Summary: LOX is secreted and its catalytic forms act in the extracellular region. Reason: Secretion and extracellular activation are intrinsic to LOX biology; the precursor is secreted before BMP1 or ADAMTS processing (PMID:31152061). 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 Supporting Evidence: file:human/LOX/LOX-uniprot.txt Secreted, extracellular space. |
| GO:0031012 extracellular matrix | IBA GO_REF:0000033 | ACCEPT | Summary: LOX acts in the extracellular matrix on collagen and elastin precursors. Reason: Matrix localization is integral to its core cross-link initiation function and is supported by collagen-binding and elastic-fiber assembly evidence. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:106096 MGI:MGI:96817 PANTHER:PTN008698711 RGD:1308435 RGD:1308752 RGD:3015 Supporting Evidence: PMID:31152061 post-translationally modified by tyrosine O-sulfation and contribute to binding to collagen |
| GO:0035791 platelet-derived growth factor receptor-beta signaling pathway | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: LOX activity modulates PDGFR-beta-dependent signaling and chemotactic sensitivity in rat aortic smooth muscle cells, with a concordant phenotype in LOX-null mouse fibroblasts. Reason: Direct primary evidence supports this pathway connection in rat and mouse cells (PMID:18586678), but it remains a context-dependent signaling consequence of extracellular LOX activity rather than the defining matrix-cross-linking function, and direct human-cell validation is not shown. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: MGI:MGI:96817 PANTHER:PTN002910759 RGD:3015 Supporting Evidence: PMID:18586678 Phosphorylated members of the PDGFR-beta-dependent signal transduction pathway, including PDGFR-beta, SHP2, AKT1, and ERK1/ERK2 (p44/42 MAPK), turned over faster in BAPN-treated than in control SMCs. |
| GO:0030199 collagen fibril organization | IBA GO_REF:0000033 | ACCEPT | Summary: LOX initiates collagen cross-linking required for stable collagen fibrils. Reason: Oxidation of collagen lysines and LOX collagen binding directly support a core role in collagen fibril organization (PMID:31152061). Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:96817 PANTHER:PTN008698711 RGD:3015 UniProtKB:Q9Y4K0 Supporting Evidence: PMID:31152061 the initial step in the formation of covalent collagen cross-links, an essential process for fibril stabilization |
| GO:0004720 protein-lysine 6-oxidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: The automated Rhea/EC and ortholog mapping correctly assigns the core protein-lysine 6-oxidase activity. Reason: Human LOX has direct experimental support for EC 1.4.3.13 activity (PMID:26838787; PMID:31152061). Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P16636 ensembl:ENSRNOP00000019844 UniProtKB:P28301 ensembl:ENSMUSP00000025409 RHEA:24544 EC:1.4.3.13 |
| GO:0005507 copper ion binding | IEA GO_REF:0000120 | ACCEPT | Summary: Copper is a required cofactor of the mature LOX catalytic domain. Reason: The family domains and conserved copper-coordinating residues support this core cofactor-binding function; human biochemical descriptions identify LOX as copper dependent (PMID:1352776). Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P16636 ensembl:ENSRNOP00000019844 InterPro:IPR001695 InterPro:IPR019828 Supporting Evidence: PMID:1352776 Lysyl oxidase (EC 1.4.3.13) is a copper-dependent enzyme |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | ACCEPT | Summary: Automated ortholog and subcellular-location mappings correctly place LOX extracellularly. Reason: The precursor is secreted and processed in the extracellular space, where the mature enzyme acts. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P28301 ensembl:ENSMUSP00000025409 UniProtKB-SubCell:SL-0112 UniProtKB-SubCell:SL-0243 Supporting Evidence: file:human/LOX/LOX-uniprot.txt Secreted, extracellular space. |
| GO:0016641 oxidoreductase activity, acting on the CH-NH2 group of donors, oxygen as acceptor | IEA GO_REF:0000002 | MODIFY | Summary: This InterPro-derived oxidoreductase term is true but less informative than LOX's specific protein-lysine 6-oxidase activity. Reason: Replace the broad donor-class activity with the experimentally established specific reaction term. 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: LOX is recruited to elastic fibers during elastogenesis. Reason: The localization is consistent with direct evidence that the LOX propeptide promotes assembly of LOX onto tropoelastin and with LOX-dependent elastin cross-linking (PMID:19855011). Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00084594 Supporting Evidence: PMID:19855011 FBLN4 is essential for tethering LOX to tropoelastin to facilitate cross-linking. |
| GO:0005515 protein binding | IPI PMID:19570982 Differential regulation of elastic fiber formation by fibuli... | MODIFY | Summary: Recombinant full-length LOX binds several elastic-fiber extracellular matrix proteins; generic protein binding obscures that context. Reason: The study tested full-length precursor LOX and supports binding to EFEMP2/fibulin-4, elastin, fibrillin-1, and fibulin-5 in an elastic-fiber assembly system. Replace generic protein binding with extracellular matrix protein binding; this is not evidence that the isolated mature catalytic chain binds every partner. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:O95967 UniProtKB:P15502 UniProtKB:P35555 UniProtKB:Q9UBX5 Proposed replacements: extracellular matrix protein binding Supporting Evidence: PMID:19570982 We have determined how they interact with tropoelastin, lysyl oxidase, and fibrillin-1 |
| GO:0005515 protein binding | IPI PMID:19855011 Fibulin-4 conducts proper elastogenesis via interaction with... | MODIFY | Summary: EFEMP2/fibulin-4 binds specifically to the LOX propeptide and recruits proLOX to tropoelastin. Reason: Replace uninformative protein binding with extracellular matrix protein binding, explicitly scoped to the propeptide region of the secreted precursor rather than the mature catalytic chain. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:O95967 Proposed replacements: extracellular matrix protein binding Supporting Evidence: PMID:19855011 We also found a specific interaction between FBLN4 and the propeptide of LOX |
| GO:0005515 protein binding | IPI PMID:21690299 The lysyl oxidase propeptide interacts with the receptor-typ... | MODIFY | Summary: The released LOX propeptide binds the intracellular phosphatase domains of PTPRK; this is a propeptide function, not an activity of mature extracellular LOX. Reason: The experiment supports the more informative protein phosphatase binding term and specifically concerns LOX-PP residues 22-168. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q15262 Proposed replacements: protein phosphatase binding Supporting Evidence: PMID:21690299 a yeast two-hybrid assay of LOX-PP-interacting proteins identified a clone encoding the intracellular phosphatase domains of receptor-type protein tyrosine phosphatase kappa (RPTP-ΞΊ), and the interaction of the two proteins in mammalian cells was confirmed. |
| GO:0005515 protein binding | IPI PMID:25118846 Nuclear translocation of lysyl oxidase is promoted by intera... | UNDECIDED | Summary: The abstract reports binding between the LOX catalytic domain and transcriptional corepressor p66beta, but the GOA WITH entity is FBLN5 and the full text is unavailable. Reason: Curator deference is required for this experimental annotation because the cached article is abstract-only, while the explicit interactor in the abstract does not match the supporting entity recorded in GOA. Propagation Review Root cause: UNRESOLVED Failure modes: SOURCE MISCITATION Sources checked: UniProtKB:Q9UBX5 Supporting Evidence: PMID:25118846 the LOX catalytic domain interacts with the transcription repressor p66Ξ² |
| GO:0005581 collagen trimer | IEA GO_REF:0000107 | REMOVE | Summary: LOX modifies collagen trimers but is not a structural subunit of the collagen triple-helical complex. Reason: The part_of qualifier conflates an enzyme acting on collagen with membership in the collagen trimer; direct evidence instead supports collagen binding and peptidyl-lysine oxidation. Propagation Review Root cause: PROPAGATION BAD Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P28301 ensembl:ENSMUSP00000025409 |
| GO:0009410 response to xenobiotic stimulus | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: This rat-ortholog transfer captures a toxicological expression-response context rather than LOX's biochemical role. Reason: A xenobiotic-responsive change in a donor organism is too contextual to define human LOX function and has no direct support in the human record. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:P16636 ensembl:ENSRNOP00000019844 |
| GO:0009725 response to hormone | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: This broad hormone-response term was transferred from rat and is peripheral to human LOX function. Reason: Donor expression or physiological response evidence does not establish that human LOX is core response machinery. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:P16636 ensembl:ENSRNOP00000019844 |
| GO:0030199 collagen fibril organization | IEA GO_REF:0000107 | ACCEPT | Summary: Orthology transfer correctly captures LOX's core role in collagen fibril stabilization. Reason: Direct human evidence shows collagen binding and initiation of covalent collagen cross-links, independently supporting the transferred process term (PMID:31152061). Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P16636 ensembl:ENSRNOP00000019844 Supporting Evidence: PMID:31152061 the initial step in the formation of covalent collagen cross-links, an essential process for fibril stabilization |
| GO:0031012 extracellular matrix | IEA GO_REF:0000120 | ACCEPT | Summary: Automated ortholog mapping correctly places secreted LOX in the extracellular matrix. Reason: Both precursor targeting and mature enzyme substrate chemistry are extracellular, and collagen-binding evidence directly supports matrix association. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P16636 ensembl:ENSRNOP00000019844 UniProtKB:P28301 ensembl:ENSMUSP00000025409 |
| GO:0048251 elastic fiber assembly | IEA GO_REF:0000107 | ACCEPT | Summary: LOX initiates elastin cross-linking and is recruited to tropoelastin during elastic fiber assembly. Reason: This is a core extracellular role supported by direct fibulin-4/proLOX/tropoelastin assembly evidence and the established LOX reaction. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P16636 ensembl:ENSRNOP00000019844 Supporting Evidence: PMID:19855011 FBLN4 is essential for tethering LOX to tropoelastin to facilitate cross-linking. |
| GO:0048514 blood vessel morphogenesis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: LOX-dependent collagen and elastin cross-linking contributes to vascular structure, but blood vessel morphogenesis is an organismal consequence rather than the enzyme's core molecular function. Reason: Ortholog phenotypes and human aortic disease support vascular relevance while remaining downstream of the core matrix-cross-linking activity (PMID:26838787). Propagation Review Root cause: NO FAILURE NON CORE Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:P28301 ensembl:ENSMUSP00000025409 Supporting Evidence: PMID:26838787 rare genetic variants in LOX predispose to thoracic aortic disease |
| GO:0048545 response to steroid hormone | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: This rat-derived steroid-hormone response is contextual and does not describe the core function of human LOX. Reason: A transferred expression-response association is too indirect to establish LOX as response machinery in humans. Propagation Review Root cause: PROPAGATION BAD Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:P16636 ensembl:ENSRNOP00000019844 |
| GO:0071953 elastic fiber | TAS PMID:16893474 Elastic fibres in health and disease. | ACCEPT | Summary: LOX is associated with elastic fibers, where it initiates cross-link formation in tropoelastin. Reason: Although the cited review cache is abstract-only, the localization is independently supported by direct LOX-fibulin-tropoelastin studies and Reactome elastin cross-linking. Supporting Evidence: Reactome:R-HSA-2129375 Soluble monomers of tropoelastin are cross-linked by the oxidative deamination of lysine residues, catalyzed by lysyl oxidase (LOX). |
| GO:0004720 protein-lysine 6-oxidase activity | EXP PMID:26838787 LOX Mutations Predispose to Thoracic Aortic Aneurysms and Di... | ACCEPT | Summary: Disease-associated LOX variants reduce lysyl oxidase activity relative to wild type, directly supporting the core catalytic term. Reason: The full-text human study experimentally compared enzyme activity of wild-type and mutant LOX proteins. Supporting Evidence: PMID:26838787 resulted in significantly lower lysyl oxidase activity when compared with the wild-type protein |
| GO:0060090 molecular adaptor activity | IPI PMID:30082873 Insights into the structure and dynamics of lysyl oxidase pr... | REMOVE | Summary: The released LOX propeptide binds many molecules, but the study does not demonstrate that it bridges two or more partners as a molecular adaptor. Reason: Pairwise binding and an interaction network do not satisfy the GO definition of adaptor activity; the evidence concerns LOX-PP, not mature catalytic LOX. Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION Sources checked: ChEBI:16336 ChEBI:18376 ChEBI:37397 ChEBI:28304 ChEBI:28815 Supporting Evidence: PMID:30082873 we have identified 17 new binding partners of the propeptide by label-free assays |
| GO:0005515 protein binding | IPI PMID:30082873 Insights into the structure and dynamics of lysyl oxidase pr... | MODIFY | Summary: Human LOX-PP binds numerous extracellular, cell-surface, and enzyme partners, but generic protein binding is uninformative and applies to the released propeptide. Reason: The assayed protein partners are dominated by extracellular-matrix proteins and matrix-associated enzymes, so extracellular matrix protein binding is more informative than generic protein binding. This replacement applies specifically to released LOX-PP residues 22-168, not the mature catalytic chain, and does not imply one stable complex containing all partners. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P00747 UniProtKB:P01133 UniProtKB:P02452 UniProtKB:P02751 UniProtKB:P08123 UniProtKB:P08253 UniProtKB:P12109 UniProtKB:P13605 UniProtKB:P15502 UniProtKB:P21980 UniProtKB:Q07507 UniProtKB:Q14766 UniProtKB:Q9H6X2-2 UniProtKB:Q9Y4K0 Proposed replacements: extracellular matrix protein binding Supporting Evidence: PMID:30082873 We have identified 17 new partners of LOX-PP including four GAGs (chondroitin sulfate, dermatan sulfate, heparan sulfate, hyaluronan), collagen I, cross-linking and proteolytic enzymes (lysyl oxidase-like 2, transglutaminase-2, and MMP-2), one proteoglycan (fibromodulin), one matricryptin (anastellin), |
| GO:0036094 small molecule binding | IPI PMID:30082873 Insights into the structure and dynamics of lysyl oxidase pr... | MODIFY | Summary: LOX-PP binds glycosaminoglycan polymers, not small molecules as defined by GO. Reason: Hyaluronan, chondroitin sulfate, dermatan sulfate, heparan sulfate, and heparin are glycans; glycosaminoglycan binding is the correctly scoped function of the released propeptide. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: ChEBI:16336 ChEBI:18376 ChEBI:28304 ChEBI:28815 ChEBI:37397 Proposed replacements: glycosaminoglycan binding Supporting Evidence: PMID:30082873 They include four glycosaminoglycans (hyaluronan, chondroitin, dermatan and heparan sulfate) |
| GO:0005515 protein binding | IPI PMID:27339457 Functional consequence of fibulin-4 missense mutations assoc... | MODIFY | Summary: EFEMP2/fibulin-4 binds the LOX propeptide; generic protein binding is less informative than extracellular matrix protein binding. Reason: The abstract-only study directly identifies LOX-propeptide binding, so the interaction is retained with curator deference and explicitly scoped away from mature LOX. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:O95967 Proposed replacements: extracellular matrix protein binding Supporting Evidence: PMID:27339457 the binding of fibulin-4 to the LOX propeptide was strongly reduced by the mutation E57K |
| GO:0005515 protein binding | IPI PMID:22919265 Yeast two-hybrid analysis of a human trabecular meshwork cDN... | REMOVE | Summary: This citation studies EFEMP2 binding to PITX2 and contains no LOX experiment despite the GOA WITH entity being EFEMP2. Reason: Full text is available and contains no LOX or lysyl-oxidase mention; the LOX-EFEMP2 interaction is supported by other papers, but PMID:22919265 is a genuine source miscitation for this row. Propagation Review Root cause: SOURCE BAD Failure modes: SOURCE MISCITATION Sources checked: UniProtKB:O95967 Supporting Evidence: PMID:22919265 We discovered EFEMP2 as a novel PITX2-interacting protein. |
| GO:0004720 protein-lysine 6-oxidase activity | IDA PMID:31152061 Differential cleavage of lysyl oxidase by the metalloprotein... | ACCEPT | Summary: Enzymatic assays directly support protein-lysine 6-oxidase activity of secreted LOX forms. Reason: BMP1 and ADAMTS cleavage change collagen binding but retain enzyme activity; this catalytic activity belongs to the C-terminal mature enzyme rather than the released propeptide. Supporting Evidence: PMID:31152061 the enzyme catalyzing the initial step in the formation of covalent collagen cross-links |
| GO:0005518 collagen binding | IDA PMID:31152061 Differential cleavage of lysyl oxidase by the metalloprotein... | ACCEPT | Summary: LOX directly binds collagen through a sulfated tyrosine-rich region retained in the BMP1-generated long mature form. Reason: Solid-phase binding assays and differential cleavage establish collagen binding; additional ADAMTS2/14 cleavage removes the sulfated region and reduces binding. Supporting Evidence: PMID:31152061 some are post-translationally modified by tyrosine O-sulfation and contribute to binding to collagen |
| GO:0005576 extracellular region | IDA PMID:31152061 Differential cleavage of lysyl oxidase by the metalloprotein... | ACCEPT | Summary: The LOX precursor is secreted and both analyzed processed enzyme forms are extracellular. Reason: This directly supports extracellular-region localization while distinguishing secretion of proLOX from extracellular proteolytic maturation. Supporting Evidence: file:human/LOX/LOX-uniprot.txt Secreted, extracellular space. |
| GO:0018057 peptidyl-lysine oxidation | IDA PMID:31152061 Differential cleavage of lysyl oxidase by the metalloprotein... | ACCEPT | Summary: Mature LOX oxidizes peptidyl lysine and hydroxylysine to initiate covalent collagen cross-link formation. Reason: This process term accurately captures the direct biochemical transformation catalyzed by the mature extracellular enzyme. Supporting Evidence: PMID:31152061 LOX precursor, the enzyme catalyzing the initial step in the formation of covalent collagen cross-links |
| GO:0004720 protein-lysine 6-oxidase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Curator-reviewed similarity transfer from mouse LOX correctly assigns the conserved core catalytic activity. Reason: Direct human enzyme assays independently confirm the transferred protein-lysine 6-oxidase activity. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P28301 Supporting Evidence: PMID:26838787 resulted in significantly lower lysyl oxidase activity when compared with the wild-type protein |
| GO:0005576 extracellular region | ISS GO_REF:0000024 | ACCEPT | Summary: Curator-reviewed transfer from mouse LOX correctly assigns extracellular localization. Reason: Human LOX is directly shown to be secreted and extracellularly processed. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P28301 Supporting Evidence: file:human/LOX/LOX-uniprot.txt Secreted, extracellular space. |
| GO:0048514 blood vessel morphogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Mouse-ortholog evidence for blood vessel morphogenesis is consistent with LOX-dependent vascular matrix integrity but is downstream of the core enzyme function. Reason: Human pathogenic variants establish aortic relevance, while morphogenesis is an organismal phenotype rather than direct catalysis. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: CONTEXT OR TISSUE MISMATCH Sources checked: UniProtKB:P28301 Supporting Evidence: PMID:26838787 rare genetic variants in LOX predispose to thoracic aortic disease |
| GO:0005515 protein binding | IPI PMID:26601954 Characterization of Microfibrillar-associated Protein 4 (MFA... | UNDECIDED | Summary: The cached abstract concerns MFAP4 interactions, but the full text needed to verify the curated LOX-MFAP4 interaction is unavailable. Reason: Curator deference is required for this experimental IPI annotation because absence of LOX from an abstract does not establish absence from the full study; the interaction cannot be independently verified from the accessible evidence. Propagation Review Root cause: UNRESOLVED Failure modes: SOURCE EVIDENCE WEAK Sources checked: UniProtKB:P55083 |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-2022141 | ACCEPT | Summary: Reactome places proLOX activation in the extracellular space. Reason: The precursor is secreted extracellularly before cleavage to the mature enzyme. Supporting Evidence: Reactome:R-HSA-2022141 Lysyl oxidase (LOX) is secreted to the extracellular space in an inactive, proenzyme form (proLOX). |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-2002466 | ACCEPT | Summary: Reactome correctly places LOX-catalyzed collagen lysine oxidation extracellularly. Reason: Collagen substrate modification occurs in the extracellular matrix and is a core LOX role. Supporting Evidence: Reactome:R-HSA-2002466 Lysine residues can be converted to allysine by lysyl oxidase. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-2129375 | ACCEPT | Summary: Reactome correctly places LOX-catalyzed tropoelastin oxidation and cross-link initiation extracellularly. Reason: Elastin cross-linking is a core action of extracellular mature LOX. Supporting Evidence: Reactome:R-HSA-2129375 Soluble monomers of tropoelastin are cross-linked by the oxidative deamination of lysine residues, catalyzed by lysyl oxidase (LOX). |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-2395340 | ACCEPT | Summary: Reactome correctly places hydroxylysine-to-hydroxyallysine conversion by LOX in extracellular collagen. Reason: The representative collagen reaction is consistent with mature LOX substrate chemistry. Supporting Evidence: Reactome:R-HSA-2395340 Hydroxylysines residues can be converted to hydroxyallysines by lysyl oxidase. |
| GO:0004720 protein-lysine 6-oxidase activity | TAS PMID:1352776 Characterization of the human lysyl oxidase gene locus. | ACCEPT | Summary: The human locus paper explicitly identifies LOX as EC 1.4.3.13 and describes its aldehyde-generating collagen and elastin cross-linking activity. Reason: Although the enzyme statement is background in an abstract-only gene-locus paper, it is correct and corroborated by later direct human experiments. Supporting Evidence: PMID:1352776 Lysyl oxidase (EC 1.4.3.13) is a copper-dependent enzyme acting principally on collagen and elastin catalyzing the formation of aldehyde cross-links. |
| GO:0005507 copper ion binding | TAS PMID:1357535 The complete derived amino acid sequence of human lysyl oxid... | ACCEPT | Summary: Human LOX contains a conserved C-terminal copper-binding catalytic domain. Reason: The sequence paper provides human-specific domain evidence and the copper-dependent chemistry is independently established; copper binding belongs to the mature catalytic chain, not LOX-PP. Supporting Evidence: PMID:1357535 contains the putative copper binding sites and is likely to be the catalytically active domain |
| GO:0036211 protein modification process | TAS PMID:1685472 Molecular cloning of human lysyl oxidase and assignment of t... | MODIFY | Summary: Protein modification process is correct but far broader than the specific LOX-catalyzed oxidation of collagen and elastin lysines. Reason: Replace the generic process with peptidyl-lysine oxidation, which captures the direct covalent modification initiated by mature extracellular LOX. Proposed replacements: peptidyl-lysine oxidation Supporting Evidence: PMID:1685472 initiates the crosslinking of collagens and elastin by catalyzing oxidative deamination of the epsilon-amino group in certain lysine and hydroxylysine residues |
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Download this section (compressed HTML)Q: Which collagen and elastin lysine or hydroxylysine sites are modified specifically by LOX, rather than LOXL paralogs, in the normal and aneurysmal human aortic wall?
Q: How do BMP1 and ADAMTS2/14 cleavage, tyrosine sulfation, and fibulin-4-dependent recruitment control the distribution of LOX activity between collagen fibrils and elastic fibers in vivo?
Q: Does released endogenous LOX-PP have a reproducible physiological signaling function, and is any endogenous nuclear LOX pool catalytically active in normal human cells?
Experiment: Engineer selective LOX knockout or acute degradation in primary human aortic smooth-muscle cells and matrix-producing vascular organoids, then quantify site-resolved allysine, hydroxyallysine, and mature cross-links by mass spectrometry. Compare wild-type, catalytic-dead, and disease-variant rescue while measuring LOXL expression and activity as paralog controls.
Hypothesis: LOX modifies a defined subset of collagen and elastin sites in human aortic matrix that is not redundantly oxidized by LOXL paralogs.
Type: genome editing and matrix cross-link proteomics
Experiment: Introduce endogenous cleavage-site and sulfotyrosine-site substitutions in human fibroblasts or vascular organoids, perturb EFEMP2, and use pulse-chase labeling, form-specific immunoprecipitation, proximity labeling, and collagen/elastin cross-link measurements to distinguish transient substrate targeting from stable complex formation.
Hypothesis: Proteolytic processing and tyrosine sulfation direct LOX toward collagen, whereas the intact propeptide and fibulin-4 favor tropoelastin targeting.
Type: endogenous protein processing and substrate-targeting analysis
Experiment: Tag the endogenous precursor on each side of the BMP1 cleavage site to track the mature enzyme and LOX-PP separately, quantify their extracellular and intracellular pools, and compare endogenous perturbation with matched overexpression in normal and tumor-derived cells. Test nuclear oxidase activity, Ξ²-catenin output, and rescue with secretion-defective, cleavage-resistant, and catalytic-dead alleles.
Hypothesis: Reported LOX-PP signaling and nuclear LOX phenotypes require nonphysiological overexpression and are absent at endogenous abundance in normal human cells.
Type: form-specific endogenous localization and functional analysis
What is not known β curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The quantitative substrate partitioning of endogenous human LOX among collagen types, elastin, and the corresponding LOXL-family enzymes in the aortic wall is unresolved.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Human sequence and biochemical evidence establish oxidation of collagen and elastin substrates, and human loss-of-function variants establish aortic-disease relevance. They do not identify which native matrix sites are modified by LOX rather than another lysyl oxidase, or quantify the relative contribution of each substrate class in human aortic tissue.
Significance: Resolving enzyme-specific substrates is necessary to connect reduced LOX activity to the collagen and elastic-lamella defects that weaken the human aortic wall.
What would resolve it: Map LOX-dependent allysine, hydroxyallysine, and mature cross-links in primary human aortic matrix after selective LOX perturbation, with orthogonal control of LOXL paralog activity and rescue by wild-type or catalytic-dead LOX.
Provenance (the field's own admissions):
Gap: How BMP1 cleavage, downstream ADAMTS2/14 cleavage, tyrosine sulfation, and propeptide-mediated recruitment are coordinated to partition LOX between collagen and elastin substrates in native human tissues is not known.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Expressed-LOX experiments in murine skin fibroblasts and HEK293 cells show that ADAMTS2/14 processing and sulfated tyrosines affect collagen binding. Recombinant interaction studies support fibulin-4/tropoelastin targeting through the propeptide, but do not establish the timing, stoichiometry, or tissue-specific balance of these events in vivo.
Significance: Form-specific targeting may determine which extracellular-matrix substrate is cross-linked and could explain why defects in LOX processing or recruitment preferentially disrupt particular connective tissues.
What would resolve it: Quantify endogenous long and short mature LOX forms, sulfation states, and transient substrate associations in human matrix-producing cells and organoids while perturbing BMP1, ADAMTS2/14, and EFEMP2 independently.
Provenance (the field's own admissions):
Gap: The physiological functions of released LOX-PP, and whether endogenous mature LOX has any normal intracellular or nuclear activity, remain unresolved.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Recombinant LOX-PP binds numerous molecules in vitro and ectopic LOX-PP alters signaling in lung-cancer cells. Nuclear accumulation of the LOX catalytic domain was observed after co-expression with p66Ξ² in tumor cells, but these experiments do not demonstrate a native nuclear pool or physiological nuclear catalysis.
Significance: Separating precursor, mature-enzyme, and released-propeptide effects is essential to prevent extracellular catalytic activity from being conflated with proposed intracellular signaling roles.
What would resolve it: Use form-specific endogenous tags and cleavage-resistant alleles to track proLOX, mature LOX, and LOX-PP in normal human cells, then test whether any nuclear pool is catalytically active and required for a reproducible phenotype at endogenous levels.
Provenance (the field's own admissions):
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