Existing Annotations Review

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-κ), 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 p66β
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

Core Functions

After secretion and extracellular processing of proLOX, the mature C-terminal copper/LTQ enzyme oxidatively deaminates selected lysine and hydroxylysine side chains in collagen and elastin to allysine and hydroxyallysine. These aldehydes initiate covalent cross-link formation, thereby stabilizing collagen fibrils and elastic fibers. Substrate delivery is form- and processing-dependent: sulfated tyrosines retained in the long mature form promote collagen binding, whereas the propeptide can recruit proLOX to fibulin-4/tropoelastin assemblies before it is released. These targeting interactions are not treated as stable complex membership. The released LOX-PP is a distinct noncatalytic product, and reported tumor-cell or nuclear effects are not assigned to this extracellular catalytic activity. Human catalytic-domain variants with reduced enzyme activity predispose to thoracic aortic disease, supporting the physiological importance of this reaction for aortic-wall matrix integrity without making disease or blood-vessel morphogenesis a second molecular function.

Molecular Function:

protein-lysine 6-oxidase activity

Directly Involved In:

peptidyl-lysine oxidation collagen fibril organization elastic fiber assembly

Cellular Locations:

extracellular matrix

Supporting Evidence:

PMID:1685472
Lysyl oxidase (EC 1.4.3.13) initiates the crosslinking of collagens and elastin by catalyzing oxidative deamination of the epsilon-amino group in certain lysine and hydroxylysine residues.
PMID:1357535
This is the first step in the covalent cross-linking of collagen and tropoelastin and results in the formation of insoluble collagen and elastic fibers in the extracellular matrix.
PMID:31152061
the initial step in the formation of covalent collagen cross-links, an essential process for fibril stabilization
PMID:26838787
Expression of the LOX variants p.Ser280Arg and p.Ser348Arg resulted in significantly lower lysyl oxidase activity when compared with the wild-type protein.

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

file:human/LOX/LOX-uniprot.txt

UniProtKB reviewed entry P28300 (LYOX_HUMAN), protein-lysine 6-oxidase

Curated human LOX function is oxidative deamination of peptidyl lysines in collagen and elastin precursors.

"Responsible for the post-translational oxidative deamination of peptidyl lysine residues in precursors to fibrous collagen and elastin"
Curated human LOX localization is secreted extracellular space.

"Secreted, extracellular space."
BMP1 removes the LOX propeptide, while ADAMTS2 and ADAMTS14 make an additional downstream cleavage.

"Proteolytically cleaved by BMP1 which removes the propeptide (PubMed:31152061). Also proteolytically cleaved by ADAMTS2 and ADAMTS14, but not by ADAMTS3, at an additional cleavage site downstream of the BMP1 cleavage site (PubMed:31152061)."
Differential LOX processing regulates collagen binding.

"Cleavage by BMP1 to remove the propeptide does not increase enzymatic activity but increases binding to collagen (PubMed:31152061). Cleavage by ADAMTS2 produces a form with reduced collagen-binding activity (PubMed:31152061)."

PMID:1352776

Characterization of the human lysyl oxidase gene locus.

Human LOX is a copper-dependent collagen- and elastin-cross-linking enzyme; the locus produces multiple alternatively spliced transcripts.

"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."

PMID:1357535

The complete derived amino acid sequence of human lysyl oxidase and assignment of the gene to chromosome 5 (extensive sequence homology with the murine ras recision gene).

Human LOX oxidizes lysine to an aldehyde that initiates covalent collagen and tropoelastin cross-linking in the extracellular matrix.

"Lysyl oxidase catalyzes the oxidation of lysine residues to alpha-aminoadipic-delta-semialdehyde. This is the first step in the covalent cross-linking of collagen and tropoelastin and results in the formation of insoluble collagen and elastic fibers in the extracellular matrix."

PMID:1685472

Molecular cloning of human lysyl oxidase and assignment of the gene to chromosome 5q23.3-31.2.

Human LOX initiates collagen and elastin cross-linking by oxidative deamination of selected lysine and hydroxylysine epsilon-amino groups.

"Lysyl oxidase (EC 1.4.3.13) initiates the crosslinking of collagens and elastin by catalyzing oxidative deamination of the epsilon-amino group in certain lysine and hydroxylysine residues."
The cloned 417-residue human precursor includes a 21-residue signal peptide.

"This cDNA encodes a polypeptide of 417 amino acid residues, including a signal peptide of 21 amino acids."

PMID:16893474

Elastic fibres in health and disease.

Elastic fibers provide elastic recoil and resilience to dynamic connective tissues.

"Their structural role is to endow tissues with elastic recoil and resilience."

PMID:18586678

Lysyl oxidase oxidizes cell membrane proteins and enhances the chemotactic response of vascular smooth muscle cells.

In cultured rat aortic smooth-muscle cells, inhibiting LOX reduced chemotaxis toward LOX and PDGF-BB, while sub-chemotactic LOX enhanced the PDGF-BB response.

"Here we demonstrate that inhibition of LOX activity by beta-aminopropionitrile (BAPN) in cultured rat aortic smooth muscle cells (SMCs) reduced the chemotactic response and sensitivity of these cells toward LOX and toward PDGF-BB. The chemotactic activity of PDGF-BB was significantly enhanced in the presence of a non-chemotactic concentration of LOX."
LOX-dependent oxidation of cell-surface PDGFR-beta altered ligand binding and downstream signaling kinetics in rat SMCs, with LOX-knockout mouse embryonic fibroblasts providing orthogonal support.

"These novel findings suggest that LOX activity is essential to generate optimal chemotactic sensitivity of cells to chemoattractants by oxidizing specific cell surface proteins, such as PDGFR-beta."

PMID:19570982

Differential regulation of elastic fiber formation by fibulin-4 and -5.

Human fibulin-4 directly binds LOX and promotes a ternary complex with tropoelastin that can target elastin cross-linking.

"Novel findings are that fibulin-4 directly binds LOX, and this interaction enhances fibulin-4 binding to tropoelastin, thus forming a ternary complex that may be critical for elastin cross-linking."

PMID:19855011

Fibulin-4 conducts proper elastogenesis via interaction with cross-linking enzyme lysyl oxidase.

Fibulin-4 binds the LOX propeptide and promotes assembly of LOX onto tropoelastin.

"We also found a specific interaction between FBLN4 and the propeptide of LOX, which efficiently promotes assembly of LOX onto tropoelastin."

PMID:21690299

The lysyl oxidase propeptide interacts with the receptor-type protein tyrosine phosphatase kappa and inhibits β-catenin transcriptional activity in lung cancer cells.

LOX propeptide directly interacts with the intracellular phosphatase domains of receptor-type protein tyrosine phosphatase kappa in mammalian cells.

"Here, 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-κ), and the interaction of the two proteins in mammalian cells was confirmed."

PMID:22919265

Yeast two-hybrid analysis of a human trabecular meshwork cDNA library identified EFEMP2 as a novel PITX2 interacting protein.

PMID:25118846

Nuclear translocation of lysyl oxidase is promoted by interaction with transcription repressor p66β.

Co-expression with p66β drives nuclear accumulation of LOX in tumor cells, after direct interaction with the LOX catalytic domain.

"Moreover, co-expression of p66β and LOX in living tumor cells leads to the nuclear accumulation of LOX."

PMID:26601954

Characterization of Microfibrillar-associated Protein 4 (MFAP4) as a Tropoelastin- and Fibrillin-binding Protein Involved in Elastic Fiber Formation.

PMID:26838787

LOX Mutations Predispose to Thoracic Aortic Aneurysms and Dissections.

Human disease-associated catalytic-domain LOX variants have significantly reduced lysyl oxidase activity.

"Expression of the LOX variants p.Ser280Arg and p.Ser348Arg resulted in significantly lower lysyl oxidase activity when compared with the wild-type protein."
Rare LOX variants predispose to thoracic aortic disease, supporting a physiological requirement for LOX in aortic-wall integrity.

"These data, along with previous studies showing that the deficiency of LOX in mice or inhibition of lysyl oxidases in turkeys and rats causes aortic dissections, support the conclusion that rare genetic variants in LOX predispose to thoracic aortic disease."

PMID:27339457

Functional consequence of fibulin-4 missense mutations associated with vascular and skeletal abnormalities and cutis laxa.

Fibulin-4 binds LOX and LOXL1, and the E57K fibulin-4 mutation strongly reduces binding to the LOX propeptide.

"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; the binding of fibulin-4 to the LOX propeptide was strongly reduced by the mutation E57K."

PMID:30082873

Insights into the structure and dynamics of lysyl oxidase propeptide, a flexible protein with numerous partners.

Recombinant human LOX propeptide is elongated, monomeric, intrinsically disordered, and flexible.

"We characterized the recombinant human propeptide by circular dichroism, dynamic light scattering, and small-angle X-ray scattering (SAXS), and showed that it is elongated, monomeric, disordered and flexible (Dmax: 11.7 nm, Rg: 3.7 nm)."
Human LOX propeptide directly binds multiple extracellular-matrix proteins and matrix-associated enzymes in vitro.

"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),"

PMID:31152061

Differential cleavage of lysyl oxidase by the metalloproteinases BMP1 and ADAMTS2/14 regulates collagen binding through a tyrosine sulfate domain.

BMP1 activates proLOX, whereas ADAMTS2/14 make a second downstream cleavage in expressed LOX.

"In this study, using murine skin fibroblasts and HEK293 cells, along with immunoprecipitation, LOX enzymatic activity, solid-phase binding assays, and proteomics analyses, we report that the LOX precursor is proteolytically processed by the procollagen N-proteinases ADAMTS2 and ADAMTS14 between Asp-218 and Tyr-219, 50 amino acids downstream of the BMP1 cleavage site."
Sulfated tyrosines in the segment between the BMP1 and ADAMTS cleavage sites contribute to LOX collagen binding.

"We noted that the LOX sequence between the BMP1- and ADAMTS-processing sites contains several conserved tyrosine residues, of which some are post-translationally modified by tyrosine O-sulfation and contribute to binding to collagen."

PMID:27432961

Loss of function mutation in LOX causes thoracic aortic aneurysm and dissection in humans.

A human LOX missense allele segregates with thoracic aortic disease, and the homologous engineered mouse allele disrupts elastic lamellae and causes severe aortic disease when homozygous.

"Mutant mice that were heterozygous for the human allele displayed disorganized ultrastructural properties of the aortic wall characterized by fragmented elastic lamellae, whereas mice homozygous for the human allele died shortly after parturition from ascending aortic aneurysm and spontaneous hemorrhage."
The authors infer that insufficient collagen and elastin cross-linking explains LOX-associated aortic-wall weakness.

"These data suggest that a missense mutation in LOX is associated with aortic disease in humans, likely through insufficient cross-linking of elastin and collagen in the aortic wall."

Reactome:R-HSA-2002466

Formation of allysine by LOX

Reactome:R-HSA-2022141

Prolysyl oxidase activation

Reactome:R-HSA-2129375

Elastin cross-linking by lysyl oxidase

Reactome:R-HSA-2395340

Formation of hydroxyallysine by LOX

Suggested Experiments

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, β-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

Knowledge Gaps

What is not known — 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):

"These data, along with previous studies showing that the deficiency of LOX in mice or inhibition of lysyl oxidases in turkeys and rats causes aortic dissections, support the conclusion that rare genetic variants in LOX predispose to thoracic aortic disease." — PMID:26838787

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):

"We noted that the LOX sequence between the BMP1- and ADAMTS-processing sites contains several conserved tyrosine residues, of which some are post-translationally modified by tyrosine O-sulfation and contribute to binding to collagen." — PMID:31152061
"We also found a specific interaction between FBLN4 and the propeptide of LOX, which efficiently promotes assembly of LOX onto tropoelastin." — PMID:19855011

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 p66β 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):

"In H1299 lung cancer cells, ectopic LOX-PP expression reduced the nuclear levels of PIC by increasing its turnover in the lysosome, thereby decreasing the nuclear levels and transcriptional activity of β-catenin while increasing β-catenin membrane localization." — PMID:21690299
"Moreover, co-expression of p66β and LOX in living tumor cells leads to the nuclear accumulation of LOX." — PMID:25118846

📚 Additional Documentation

Notes

(LOX-notes.md)

LOX literature notes

Evidence access and scope

The seeded references were checked against the local publication cache. Full text is
available for PMID:19570982, PMID:21690299, PMID:22919265, PMID:26838787, and
PMID:30082873. The remaining seeded papers are abstract-only in the cache, so claims
from those papers are limited to what the abstract explicitly states. The added
PMID:27432961 is also abstract-only; it provides an independent human genetic and
engineered-mouse test of LOX loss of function.

LOX is synthesized as a preproprotein. Functional claims must distinguish the
secreted precursor, the mature C-terminal catalytic enzyme, and the released
N-terminal propeptide (LOX-PP); activity or interactions of one form should not be
silently assigned to another.

Core catalytic function and extracellular-matrix role

Human LOX initiates collagen and elastin cross-linking by oxidative deamination of
selected lysine/hydroxylysine residues. The foundational human cDNA paper states:
[PMID:1685472, ABSTRACT, "Lysyl oxidase (EC 1.4.3.13) initiates the crosslinking of collagens and elastin by catalyzing oxidative deamination of the epsilon-amino group in certain lysine and hydroxylysine residues."]
The reaction creates the aldehyde precursor used for covalent matrix cross-links:
[PMID:1357535, ABSTRACT, "Lysyl oxidase catalyzes the oxidation of lysine residues to alpha-aminoadipic-delta-semialdehyde. This is the first step in the covalent cross-linking of collagen and tropoelastin and results in the formation of insoluble collagen and elastic fibers in the extracellular matrix."]
The same human sequence study places the conserved putative copper-binding and
catalytic region at the C terminus, but this is sequence-based localization rather
than a direct human structural determination:
[PMID:1357535, ABSTRACT, "The carboxy terminus of the protein, which contains the putative copper binding sites and is likely to be the catalytically active domain, was more highly conserved than the amino terminus."]
Direct human variant assays connect the conserved catalytic domain to enzymatic
function and aortic-wall integrity:
[PMID:26838787, ABSTRACT, "Expression of the LOX variants p.Ser280Arg and p.Ser348Arg resulted in significantly lower lysyl oxidase activity when compared with the wild-type protein."]
A second human family plus knock-in mouse model links the disease mechanism to
deficient matrix cross-linking, but the mechanistic wording is explicitly an
inference ("likely") rather than a direct measurement in human aortic tissue:
[PMID:27432961, ABSTRACT, "These data suggest that a missense mutation in LOX is associated with aortic disease in humans, likely through insufficient cross-linking of elastin and collagen in the aortic wall."]

Processing, localization, and collagen targeting

Human LOX contains a classical signal peptide: [PMID:1685472, ABSTRACT, "This cDNA encodes a polypeptide of 417 amino acid residues, including a signal peptide of 21 amino acids."]
BMP1 activates the precursor for matrix cross-linking, while ADAMTS2/14 can make a
downstream cut. The experiments in this paper used murine skin fibroblasts and
HEK293 cells, so they establish conserved processing of expressed LOX rather than
an exclusively human-tissue observation:
[PMID:31152061, ABSTRACT, "BMP1 also cleaves and activates the lysyl oxidase (LOX) precursor, the enzyme catalyzing the initial step in the formation of covalent collagen cross-links, an essential process for fibril stabilization."]
[PMID:31152061, ABSTRACT, "In this study, using murine skin fibroblasts and HEK293 cells, along with immunoprecipitation, LOX enzymatic activity, solid-phase binding assays, and proteomics analyses, we report that the LOX precursor is proteolytically processed by the procollagen N-proteinases ADAMTS2 and ADAMTS14 between Asp-218 and Tyr-219, 50 amino acids downstream of the BMP1 cleavage site."]
Conserved tyrosine sulfation between the processing sites contributes to collagen
binding; cleavage therefore regulates substrate targeting as well as precursor
maturation:
[PMID:31152061, ABSTRACT, "We noted that the LOX sequence between the BMP1- and ADAMTS-processing sites contains several conserved tyrosine residues, of which some are post-translationally modified by tyrosine O-sulfation and contribute to binding to collagen."]

Elastic-fiber assembly partners

Full-text experiments with recombinant human proteins show that fibulin-4 directly
binds LOX and promotes a ternary complex with tropoelastin:
[PMID:19570982, INTRODUCTION, "Novel findings are that fibulin-4 directly binds LOX, and this interaction enhances fibulin-4 binding to tropoelastin, thus forming a ternary complex that may be critical for elastin cross-linking."]
An independent mouse-centered study localizes that interaction to the LOX
propeptide and proposes that fibulin-4 recruits LOX to tropoelastin:
[PMID:19855011, ABSTRACT, "We also found a specific interaction between FBLN4 and the propeptide of LOX, which efficiently promotes assembly of LOX onto tropoelastin."]
The fibulin-4 mutation study further supports propeptide binding, but is primarily
about EFEMP2 disease alleles and is corroborative rather than foundational for LOX:
[PMID:27339457, ABSTRACT, "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; the binding of fibulin-4 to the LOX propeptide was strongly reduced by the mutation E57K."]
PMID:26601954 does not report a direct LOX-MFAP4 interaction in its cached abstract;
it reports MFAP4 binding to tropoelastin, fibrillins, desmosine, collagen, and
elastin. Because the full text is unavailable, the curated LOX-MFAP4 IPI cannot be
verified here and must not be rejected on the abstract alone.

LOX propeptide and intracellular claims

The mature catalytic enzyme and released LOX-PP are distinct products. Recombinant
human LOX-PP is an elongated, monomeric, intrinsically disordered protein, and the
study identified many extracellular binding partners:
[PMID:30082873, ABSTRACT, "We characterized the recombinant human propeptide by circular dichroism, dynamic light scattering, and small-angle X-ray scattering (SAXS), and showed that it is elongated, monomeric, disordered and flexible (Dmax: 11.7 nm, Rg: 3.7 nm)."]
[PMID:30082873, RESULTS, "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), and the ectodomain of one membrane protein (Tumor Endothelial Marker-8 also known as anthrax receptor-1)."]
LOX-PP/RPTP-kappa and β-catenin results come from ectopic LOX-PP in lung-cancer
cells. They describe a context-specific propeptide effect, not the catalytic
enzyme's core extracellular function:
[PMID:21690299, ABSTRACT, "In H1299 lung cancer cells, ectopic LOX-PP expression reduced the nuclear levels of PIC by increasing its turnover in the lysosome, thereby decreasing the nuclear levels and transcriptional activity of β-catenin while increasing β-catenin membrane localization."]
Nuclear accumulation was reported for the LOX catalytic domain when co-expressed
with p66β in tumor cells. This does not establish constitutive nuclear
localization or a physiological nuclear catalytic role in normal tissue:
[PMID:25118846, ABSTRACT, "Moreover, co-expression of p66β and LOX in living tumor cells leads to the nuclear accumulation of LOX."]
PMID:22919265 is a PITX2-EFEMP2 interaction paper. Its cached text does not assay
LOX, so it is not valid evidence for a LOX physical interaction.

PDGFR-beta signaling boundary

A direct primary study supports LOX involvement in PDGFR-beta-dependent signaling,
but its experiments were in cultured rat aortic smooth-muscle cells and LOX-knockout
mouse embryonic fibroblasts, not human cells:
[PMID:18586678, ABSTRACT, "Here we demonstrate that inhibition of LOX activity by beta-aminopropionitrile (BAPN) in cultured rat aortic smooth muscle cells (SMCs) reduced the chemotactic response and sensitivity of these cells toward LOX and toward PDGF-BB."]
The proposed mechanism is extracellular LOX-dependent oxidation of surface proteins,
including PDGFR-beta, which changes ligand binding and downstream signal turnover:
[PMID:18586678, ABSTRACT, "These novel findings suggest that LOX activity is essential to generate optimal chemotactic sensitivity of cells to chemoattractants by oxidizing specific cell surface proteins, such as PDGFR-beta."]
This evidence supports retaining PDGFR-beta signaling as a non-core biological-process
role. It does not establish a human-specific signaling function, and the cached paper
is abstract-only.

Curation implications

The evidence-supported core is secreted copper-dependent protein-lysine
6-oxidase activity acting on collagen and elastin, producing aldehydes that initiate
covalent cross-link formation and stabilize collagen fibrils and elastic fibers.
Collagen binding, fibulin-4-assisted elastic-fiber targeting, and extracellular-matrix
localization directly support that core. Released-propeptide signaling and
overexpression-dependent nuclear localization should remain non-core and retain their
tested-fragment and cellular-context qualifiers. Human thoracic-aortic disease supports
physiological importance but is not itself a molecular function.

📄 View Raw YAML

id: P28300
gene_symbol: LOX
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  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.
existing_annotations:
- term:
    id: GO:0004720
    label: protein-lysine 6-oxidase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  supporting_entities:
  - 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
  review:
    summary: LOX is a copper-dependent protein-lysine 6-oxidase; this is the core catalytic activity of the mature extracellular enzyme.
    action: ACCEPT
    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
      source_entities:
      - source_id: FB:FBgn0034660
      - source_id: FB:FBgn0039848
      - source_id: MGI:MGI:106096
      - source_id: MGI:MGI:1337004
      - source_id: MGI:MGI:1914823
      - source_id: MGI:MGI:96817
      - source_id: PANTHER:PTN002550804
      - source_id: RGD:3015
      - source_id: UniProtKB:P28300
      - source_id: UniProtKB:P58215
      - source_id: UniProtKB:Q05063
      - source_id: UniProtKB:Q95L39
      - source_id: UniProtKB:Q96JB6
      - source_id: UniProtKB:Q9Y4K0
    supported_by:
    - reference_id: file:human/LOX/LOX-uniprot.txt
      supporting_text: Responsible for the post-translational oxidative deamination
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  supporting_entities:
  - 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
  review:
    summary: LOX is secreted and its catalytic forms act in the extracellular region.
    action: ACCEPT
    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
      source_entities:
      - source_id: MGI:MGI:106096
      - source_id: MGI:MGI:1337004
      - source_id: MGI:MGI:1914823
      - source_id: MGI:MGI:96817
      - source_id: PANTHER:PTN002550804
      - source_id: RGD:1308435
      - source_id: RGD:1308752
      - source_id: RGD:3015
      - source_id: UniProtKB:P28300
      - source_id: UniProtKB:P33072
      - source_id: UniProtKB:P58215
      - source_id: UniProtKB:Q08397
      - source_id: UniProtKB:Q9Y4K0
    supported_by:
    - reference_id: file:human/LOX/LOX-uniprot.txt
      supporting_text: Secreted, extracellular space.
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  supporting_entities:
  - MGI:MGI:106096
  - MGI:MGI:96817
  - PANTHER:PTN008698711
  - RGD:1308435
  - RGD:1308752
  - RGD:3015
  review:
    summary: LOX acts in the extracellular matrix on collagen and elastin precursors.
    action: ACCEPT
    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
      source_entities:
      - source_id: MGI:MGI:106096
      - source_id: MGI:MGI:96817
      - source_id: PANTHER:PTN008698711
      - source_id: RGD:1308435
      - source_id: RGD:1308752
      - source_id: RGD:3015
    supported_by:
    - reference_id: PMID:31152061
      supporting_text: post-translationally modified by tyrosine O-sulfation and contribute to binding to collagen
- term:
    id: GO:0035791
    label: platelet-derived growth factor receptor-beta signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  supporting_entities:
  - MGI:MGI:96817
  - PANTHER:PTN002910759
  - RGD:3015
  review:
    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.
    action: KEEP_AS_NON_CORE
    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
      source_entities:
      - source_id: MGI:MGI:96817
      - source_id: PANTHER:PTN002910759
      - source_id: RGD:3015
    supported_by:
    - reference_id: PMID:18586678
      supporting_text: 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.
- term:
    id: GO:0030199
    label: collagen fibril organization
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  supporting_entities:
  - MGI:MGI:96817
  - PANTHER:PTN008698711
  - RGD:3015
  - UniProtKB:Q9Y4K0
  review:
    summary: LOX initiates collagen cross-linking required for stable collagen fibrils.
    action: ACCEPT
    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
      source_entities:
      - source_id: MGI:MGI:96817
      - source_id: PANTHER:PTN008698711
      - source_id: RGD:3015
      - source_id: UniProtKB:Q9Y4K0
    supported_by:
    - reference_id: PMID:31152061
      supporting_text: the initial step in the formation of covalent collagen cross-links, an essential process for fibril stabilization
- term:
    id: GO:0004720
    label: protein-lysine 6-oxidase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  supporting_entities:
  - UniProtKB:P16636
  - ensembl:ENSRNOP00000019844
  - UniProtKB:P28301
  - ensembl:ENSMUSP00000025409
  - RHEA:24544
  - EC:1.4.3.13
  review:
    summary: The automated Rhea/EC and ortholog mapping correctly assigns the core protein-lysine 6-oxidase activity.
    action: ACCEPT
    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
      source_entities:
      - source_id: UniProtKB:P16636
      - source_id: ensembl:ENSRNOP00000019844
      - source_id: UniProtKB:P28301
      - source_id: ensembl:ENSMUSP00000025409
      - source_id: RHEA:24544
      - source_id: EC:1.4.3.13
- term:
    id: GO:0005507
    label: copper ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  supporting_entities:
  - UniProtKB:P16636
  - ensembl:ENSRNOP00000019844
  - InterPro:IPR001695
  - InterPro:IPR019828
  review:
    summary: Copper is a required cofactor of the mature LOX catalytic domain.
    action: ACCEPT
    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
      source_entities:
      - source_id: UniProtKB:P16636
      - source_id: ensembl:ENSRNOP00000019844
      - source_id: InterPro:IPR001695
      - source_id: InterPro:IPR019828
    supported_by:
    - reference_id: PMID:1352776
      supporting_text: Lysyl oxidase (EC 1.4.3.13) is a copper-dependent enzyme
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  supporting_entities:
  - UniProtKB:P28301
  - ensembl:ENSMUSP00000025409
  - UniProtKB-SubCell:SL-0112
  - UniProtKB-SubCell:SL-0243
  review:
    summary: Automated ortholog and subcellular-location mappings correctly place LOX extracellularly.
    action: ACCEPT
    reason: The precursor is secreted and processed in the extracellular space, where the mature enzyme acts.
    propagation_review:
      root_cause: NO_FAILURE_CORE
      source_entities:
      - source_id: UniProtKB:P28301
      - source_id: ensembl:ENSMUSP00000025409
      - source_id: UniProtKB-SubCell:SL-0112
      - source_id: UniProtKB-SubCell:SL-0243
    supported_by:
    - reference_id: file:human/LOX/LOX-uniprot.txt
      supporting_text: Secreted, extracellular space.
- term:
    id: GO:0016641
    label: oxidoreductase activity, acting on the CH-NH2 group of donors, oxygen as
      acceptor
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  supporting_entities:
  - InterPro:IPR001695
  - InterPro:IPR019828
  review:
    summary: This InterPro-derived oxidoreductase term is true but less informative than LOX's specific protein-lysine 6-oxidase activity.
    action: MODIFY
    reason: Replace the broad donor-class activity with the experimentally established specific reaction term.
    proposed_replacement_terms:
    - id: GO:0004720
      label: protein-lysine 6-oxidase activity
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - GRANULARITY_MISMATCH
      source_entities:
      - source_id: InterPro:IPR001695
      - source_id: InterPro:IPR019828
- term:
    id: GO:0071953
    label: elastic fiber
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  supporting_entities:
  - ARBA:ARBA00084594
  review:
    summary: LOX is recruited to elastic fibers during elastogenesis.
    action: ACCEPT
    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
      source_entities:
      - source_id: ARBA:ARBA00084594
    supported_by:
    - reference_id: PMID:19855011
      supporting_text: FBLN4 is essential for tethering LOX to tropoelastin to facilitate cross-linking.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19570982
  qualifier: enables
  supporting_entities:
  - UniProtKB:O95967
  - UniProtKB:P15502
  - UniProtKB:P35555
  - UniProtKB:Q9UBX5
  review:
    summary: Recombinant full-length LOX binds several elastic-fiber extracellular matrix proteins; generic protein binding obscures that context.
    action: MODIFY
    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.
    proposed_replacement_terms:
    - id: GO:1990430
      label: extracellular matrix protein binding
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - GRANULARITY_MISMATCH
      source_entities:
      - source_id: UniProtKB:O95967
      - source_id: UniProtKB:P15502
      - source_id: UniProtKB:P35555
      - source_id: UniProtKB:Q9UBX5
    supported_by:
    - reference_id: PMID:19570982
      supporting_text: We have determined how they interact with tropoelastin, lysyl oxidase, and fibrillin-1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19855011
  qualifier: enables
  supporting_entities:
  - UniProtKB:O95967
  review:
    summary: EFEMP2/fibulin-4 binds specifically to the LOX propeptide and recruits proLOX to tropoelastin.
    action: MODIFY
    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.
    proposed_replacement_terms:
    - id: GO:1990430
      label: extracellular matrix protein binding
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - GRANULARITY_MISMATCH
      source_entities:
      - source_id: UniProtKB:O95967
    supported_by:
    - reference_id: PMID:19855011
      supporting_text: We also found a specific interaction between FBLN4 and the propeptide of LOX
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21690299
  qualifier: enables
  supporting_entities:
  - UniProtKB:Q15262
  review:
    summary: The released LOX propeptide binds the intracellular phosphatase domains of PTPRK; this is a propeptide function, not an activity of mature extracellular LOX.
    action: MODIFY
    reason: The experiment supports the more informative protein phosphatase binding term and specifically concerns LOX-PP residues 22-168.
    proposed_replacement_terms:
    - id: GO:0019903
      label: protein phosphatase binding
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - GRANULARITY_MISMATCH
      source_entities:
      - source_id: UniProtKB:Q15262
    supported_by:
    - reference_id: PMID:21690299
      supporting_text: 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-κ), and the interaction of the two proteins in mammalian cells was confirmed.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25118846
  qualifier: enables
  supporting_entities:
  - UniProtKB:Q9UBX5
  review:
    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.
    action: UNDECIDED
    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
      source_entities:
      - source_id: UniProtKB:Q9UBX5
    supported_by:
    - reference_id: PMID:25118846
      supporting_text: the LOX catalytic domain interacts with the transcription repressor p66β
- term:
    id: GO:0005581
    label: collagen trimer
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: part_of
  supporting_entities:
  - UniProtKB:P28301
  - ensembl:ENSMUSP00000025409
  review:
    summary: LOX modifies collagen trimers but is not a structural subunit of the collagen triple-helical complex.
    action: REMOVE
    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
      source_entities:
      - source_id: UniProtKB:P28301
      - source_id: ensembl:ENSMUSP00000025409
- term:
    id: GO:0009410
    label: response to xenobiotic stimulus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  supporting_entities:
  - UniProtKB:P16636
  - ensembl:ENSRNOP00000019844
  review:
    summary: This rat-ortholog transfer captures a toxicological expression-response context rather than LOX's biochemical role.
    action: MARK_AS_OVER_ANNOTATED
    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
      source_entities:
      - source_id: UniProtKB:P16636
      - source_id: ensembl:ENSRNOP00000019844
- term:
    id: GO:0009725
    label: response to hormone
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  supporting_entities:
  - UniProtKB:P16636
  - ensembl:ENSRNOP00000019844
  review:
    summary: This broad hormone-response term was transferred from rat and is peripheral to human LOX function.
    action: MARK_AS_OVER_ANNOTATED
    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
      source_entities:
      - source_id: UniProtKB:P16636
      - source_id: ensembl:ENSRNOP00000019844
- term:
    id: GO:0030199
    label: collagen fibril organization
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  supporting_entities:
  - UniProtKB:P16636
  - ensembl:ENSRNOP00000019844
  review:
    summary: Orthology transfer correctly captures LOX's core role in collagen fibril stabilization.
    action: ACCEPT
    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
      source_entities:
      - source_id: UniProtKB:P16636
      - source_id: ensembl:ENSRNOP00000019844
    supported_by:
    - reference_id: PMID:31152061
      supporting_text: the initial step in the formation of covalent collagen cross-links, an essential process for fibril stabilization
- term:
    id: GO:0031012
    label: extracellular matrix
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  supporting_entities:
  - UniProtKB:P16636
  - ensembl:ENSRNOP00000019844
  - UniProtKB:P28301
  - ensembl:ENSMUSP00000025409
  review:
    summary: Automated ortholog mapping correctly places secreted LOX in the extracellular matrix.
    action: ACCEPT
    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
      source_entities:
      - source_id: UniProtKB:P16636
      - source_id: ensembl:ENSRNOP00000019844
      - source_id: UniProtKB:P28301
      - source_id: ensembl:ENSMUSP00000025409
- term:
    id: GO:0048251
    label: elastic fiber assembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  supporting_entities:
  - UniProtKB:P16636
  - ensembl:ENSRNOP00000019844
  review:
    summary: LOX initiates elastin cross-linking and is recruited to tropoelastin during elastic fiber assembly.
    action: ACCEPT
    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
      source_entities:
      - source_id: UniProtKB:P16636
      - source_id: ensembl:ENSRNOP00000019844
    supported_by:
    - reference_id: PMID:19855011
      supporting_text: FBLN4 is essential for tethering LOX to tropoelastin to facilitate cross-linking.
- term:
    id: GO:0048514
    label: blood vessel morphogenesis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  supporting_entities:
  - UniProtKB:P28301
  - ensembl:ENSMUSP00000025409
  review:
    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.
    action: KEEP_AS_NON_CORE
    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
      source_entities:
      - source_id: UniProtKB:P28301
      - source_id: ensembl:ENSMUSP00000025409
    supported_by:
    - reference_id: PMID:26838787
      supporting_text: rare genetic variants in LOX predispose to thoracic aortic disease
- term:
    id: GO:0048545
    label: response to steroid hormone
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  supporting_entities:
  - UniProtKB:P16636
  - ensembl:ENSRNOP00000019844
  review:
    summary: This rat-derived steroid-hormone response is contextual and does not describe the core function of human LOX.
    action: MARK_AS_OVER_ANNOTATED
    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
      source_entities:
      - source_id: UniProtKB:P16636
      - source_id: ensembl:ENSRNOP00000019844
- term:
    id: GO:0071953
    label: elastic fiber
  evidence_type: TAS
  original_reference_id: PMID:16893474
  qualifier: located_in
  review:
    summary: LOX is associated with elastic fibers, where it initiates cross-link formation in tropoelastin.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: Reactome:R-HSA-2129375
      supporting_text: Soluble monomers of tropoelastin are cross-linked by the oxidative deamination of lysine residues, catalyzed by lysyl oxidase (LOX).
- term:
    id: GO:0004720
    label: protein-lysine 6-oxidase activity
  evidence_type: EXP
  original_reference_id: PMID:26838787
  qualifier: enables
  review:
    summary: Disease-associated LOX variants reduce lysyl oxidase activity relative to wild type, directly supporting the core catalytic term.
    action: ACCEPT
    reason: The full-text human study experimentally compared enzyme activity of wild-type and mutant LOX proteins.
    supported_by:
    - reference_id: PMID:26838787
      supporting_text: resulted in significantly lower lysyl oxidase activity when compared with the wild-type protein
- term:
    id: GO:0060090
    label: molecular adaptor activity
  evidence_type: IPI
  original_reference_id: PMID:30082873
  qualifier: enables
  supporting_entities:
  - ChEBI:16336
  - ChEBI:18376
  - ChEBI:37397
  - ChEBI:28304
  - ChEBI:28815
  review:
    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.
    action: REMOVE
    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
      source_entities:
      - source_id: ChEBI:16336
      - source_id: ChEBI:18376
      - source_id: ChEBI:37397
      - source_id: ChEBI:28304
      - source_id: ChEBI:28815
    supported_by:
    - reference_id: PMID:30082873
      supporting_text: we have identified 17 new binding partners of the propeptide by label-free assays
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:30082873
  qualifier: enables
  supporting_entities:
  - 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
  review:
    summary: Human LOX-PP binds numerous extracellular, cell-surface, and enzyme partners, but generic protein binding is uninformative and applies to the released propeptide.
    action: MODIFY
    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.
    proposed_replacement_terms:
    - id: GO:1990430
      label: extracellular matrix protein binding
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - GRANULARITY_MISMATCH
      source_entities:
      - source_id: UniProtKB:P00747
      - source_id: UniProtKB:P01133
      - source_id: UniProtKB:P02452
      - source_id: UniProtKB:P02751
      - source_id: UniProtKB:P08123
      - source_id: UniProtKB:P08253
      - source_id: UniProtKB:P12109
      - source_id: UniProtKB:P13605
      - source_id: UniProtKB:P15502
      - source_id: UniProtKB:P21980
      - source_id: UniProtKB:Q07507
      - source_id: UniProtKB:Q14766
      - source_id: UniProtKB:Q9H6X2-2
      - source_id: UniProtKB:Q9Y4K0
    supported_by:
    - reference_id: PMID:30082873
      supporting_text: >-
        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),
- term:
    id: GO:0036094
    label: small molecule binding
  evidence_type: IPI
  original_reference_id: PMID:30082873
  qualifier: enables
  supporting_entities:
  - ChEBI:16336
  - ChEBI:18376
  - ChEBI:28304
  - ChEBI:28815
  - ChEBI:37397
  review:
    summary: LOX-PP binds glycosaminoglycan polymers, not small molecules as defined by GO.
    action: MODIFY
    reason: Hyaluronan, chondroitin sulfate, dermatan sulfate, heparan sulfate, and heparin are glycans; glycosaminoglycan binding is the correctly scoped function of the released propeptide.
    proposed_replacement_terms:
    - id: GO:0005539
      label: glycosaminoglycan binding
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - ROLE_CONFLATION
      source_entities:
      - source_id: ChEBI:16336
      - source_id: ChEBI:18376
      - source_id: ChEBI:28304
      - source_id: ChEBI:28815
      - source_id: ChEBI:37397
    supported_by:
    - reference_id: PMID:30082873
      supporting_text: They include four glycosaminoglycans (hyaluronan, chondroitin, dermatan and heparan sulfate)
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:27339457
  qualifier: enables
  supporting_entities:
  - UniProtKB:O95967
  review:
    summary: EFEMP2/fibulin-4 binds the LOX propeptide; generic protein binding is less informative than extracellular matrix protein binding.
    action: MODIFY
    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.
    proposed_replacement_terms:
    - id: GO:1990430
      label: extracellular matrix protein binding
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - GRANULARITY_MISMATCH
      source_entities:
      - source_id: UniProtKB:O95967
    supported_by:
    - reference_id: PMID:27339457
      supporting_text: the binding of fibulin-4 to the LOX propeptide was strongly reduced by the mutation E57K
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22919265
  qualifier: enables
  supporting_entities:
  - UniProtKB:O95967
  review:
    summary: This citation studies EFEMP2 binding to PITX2 and contains no LOX experiment despite the GOA WITH entity being EFEMP2.
    action: REMOVE
    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
      source_entities:
      - source_id: UniProtKB:O95967
    supported_by:
    - reference_id: PMID:22919265
      supporting_text: We discovered EFEMP2 as a novel PITX2-interacting protein.
- term:
    id: GO:0004720
    label: protein-lysine 6-oxidase activity
  evidence_type: IDA
  original_reference_id: PMID:31152061
  qualifier: enables
  review:
    summary: Enzymatic assays directly support protein-lysine 6-oxidase activity of secreted LOX forms.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:31152061
      supporting_text: the enzyme catalyzing the initial step in the formation of covalent collagen cross-links
- term:
    id: GO:0005518
    label: collagen binding
  evidence_type: IDA
  original_reference_id: PMID:31152061
  qualifier: enables
  review:
    summary: LOX directly binds collagen through a sulfated tyrosine-rich region retained in the BMP1-generated long mature form.
    action: ACCEPT
    reason: Solid-phase binding assays and differential cleavage establish collagen binding; additional ADAMTS2/14 cleavage removes the sulfated region and reduces binding.
    supported_by:
    - reference_id: PMID:31152061
      supporting_text: some are post-translationally modified by tyrosine O-sulfation and contribute to binding to collagen
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: IDA
  original_reference_id: PMID:31152061
  qualifier: located_in
  review:
    summary: The LOX precursor is secreted and both analyzed processed enzyme forms are extracellular.
    action: ACCEPT
    reason: This directly supports extracellular-region localization while distinguishing secretion of proLOX from extracellular proteolytic maturation.
    supported_by:
    - reference_id: file:human/LOX/LOX-uniprot.txt
      supporting_text: Secreted, extracellular space.
- term:
    id: GO:0018057
    label: peptidyl-lysine oxidation
  evidence_type: IDA
  original_reference_id: PMID:31152061
  qualifier: involved_in
  review:
    summary: Mature LOX oxidizes peptidyl lysine and hydroxylysine to initiate covalent collagen cross-link formation.
    action: ACCEPT
    reason: This process term accurately captures the direct biochemical transformation catalyzed by the mature extracellular enzyme.
    supported_by:
    - reference_id: PMID:31152061
      supporting_text: LOX precursor, the enzyme catalyzing the initial step in the formation of covalent collagen cross-links
- term:
    id: GO:0004720
    label: protein-lysine 6-oxidase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  supporting_entities:
  - UniProtKB:P28301
  review:
    summary: Curator-reviewed similarity transfer from mouse LOX correctly assigns the conserved core catalytic activity.
    action: ACCEPT
    reason: Direct human enzyme assays independently confirm the transferred protein-lysine 6-oxidase activity.
    propagation_review:
      root_cause: NO_FAILURE_CORE
      source_entities:
      - source_id: UniProtKB:P28301
    supported_by:
    - reference_id: PMID:26838787
      supporting_text: resulted in significantly lower lysyl oxidase activity when compared with the wild-type protein
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  supporting_entities:
  - UniProtKB:P28301
  review:
    summary: Curator-reviewed transfer from mouse LOX correctly assigns extracellular localization.
    action: ACCEPT
    reason: Human LOX is directly shown to be secreted and extracellularly processed.
    propagation_review:
      root_cause: NO_FAILURE_CORE
      source_entities:
      - source_id: UniProtKB:P28301
    supported_by:
    - reference_id: file:human/LOX/LOX-uniprot.txt
      supporting_text: Secreted, extracellular space.
- term:
    id: GO:0048514
    label: blood vessel morphogenesis
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  supporting_entities:
  - UniProtKB:P28301
  review:
    summary: Mouse-ortholog evidence for blood vessel morphogenesis is consistent with LOX-dependent vascular matrix integrity but is downstream of the core enzyme function.
    action: KEEP_AS_NON_CORE
    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
      source_entities:
      - source_id: UniProtKB:P28301
    supported_by:
    - reference_id: PMID:26838787
      supporting_text: rare genetic variants in LOX predispose to thoracic aortic disease
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26601954
  qualifier: enables
  supporting_entities:
  - UniProtKB:P55083
  review:
    summary: The cached abstract concerns MFAP4 interactions, but the full text needed to verify the curated LOX-MFAP4 interaction is unavailable.
    action: UNDECIDED
    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
      source_entities:
      - source_id: UniProtKB:P55083
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2022141
  qualifier: located_in
  review:
    summary: Reactome places proLOX activation in the extracellular space.
    action: ACCEPT
    reason: The precursor is secreted extracellularly before cleavage to the mature enzyme.
    supported_by:
    - reference_id: Reactome:R-HSA-2022141
      supporting_text: Lysyl oxidase (LOX) is secreted to the extracellular space in an inactive, proenzyme form (proLOX).
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2002466
  qualifier: located_in
  review:
    summary: Reactome correctly places LOX-catalyzed collagen lysine oxidation extracellularly.
    action: ACCEPT
    reason: Collagen substrate modification occurs in the extracellular matrix and is a core LOX role.
    supported_by:
    - reference_id: Reactome:R-HSA-2002466
      supporting_text: Lysine residues can be converted to allysine by lysyl oxidase.
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2129375
  qualifier: located_in
  review:
    summary: Reactome correctly places LOX-catalyzed tropoelastin oxidation and cross-link initiation extracellularly.
    action: ACCEPT
    reason: Elastin cross-linking is a core action of extracellular mature LOX.
    supported_by:
    - reference_id: Reactome:R-HSA-2129375
      supporting_text: Soluble monomers of tropoelastin are cross-linked by the oxidative deamination of lysine residues, catalyzed by lysyl oxidase (LOX).
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-2395340
  qualifier: located_in
  review:
    summary: Reactome correctly places hydroxylysine-to-hydroxyallysine conversion by LOX in extracellular collagen.
    action: ACCEPT
    reason: The representative collagen reaction is consistent with mature LOX substrate chemistry.
    supported_by:
    - reference_id: Reactome:R-HSA-2395340
      supporting_text: Hydroxylysines residues can be converted to hydroxyallysines by lysyl oxidase.
- term:
    id: GO:0004720
    label: protein-lysine 6-oxidase activity
  evidence_type: TAS
  original_reference_id: PMID:1352776
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: Although the enzyme statement is background in an abstract-only gene-locus paper, it is correct and corroborated by later direct human experiments.
    supported_by:
    - reference_id: PMID:1352776
      supporting_text: 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.
- term:
    id: GO:0005507
    label: copper ion binding
  evidence_type: TAS
  original_reference_id: PMID:1357535
  qualifier: enables
  review:
    summary: Human LOX contains a conserved C-terminal copper-binding catalytic domain.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:1357535
      supporting_text: contains the putative copper binding sites and is likely to be the catalytically active domain
- term:
    id: GO:0036211
    label: protein modification process
  evidence_type: TAS
  original_reference_id: PMID:1685472
  qualifier: involved_in
  review:
    summary: Protein modification process is correct but far broader than the specific LOX-catalyzed oxidation of collagen and elastin lysines.
    action: MODIFY
    reason: Replace the generic process with peptidyl-lysine oxidation, which captures the direct covalent modification initiated by mature extracellular LOX.
    proposed_replacement_terms:
    - id: GO:0018057
      label: peptidyl-lysine oxidation
    supported_by:
    - reference_id: PMID:1685472
      supporting_text: initiates the crosslinking of collagens and elastin by catalyzing oxidative deamination of the epsilon-amino group in certain lysine and hydroxylysine residues
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  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/LOX/LOX-uniprot.txt
  title: UniProtKB reviewed entry P28300 (LYOX_HUMAN), protein-lysine 6-oxidase
  findings:
  - statement: Curated human LOX function is oxidative deamination of peptidyl lysines
      in collagen and elastin precursors.
    supporting_text: Responsible for the post-translational oxidative deamination of
      peptidyl lysine residues in precursors to fibrous collagen and elastin
    reference_section_type: DATABASE_ENTRY
  - statement: Curated human LOX localization is secreted extracellular space.
    supporting_text: Secreted, extracellular space.
    reference_section_type: DATABASE_ENTRY
  - statement: BMP1 removes the LOX propeptide, while ADAMTS2 and ADAMTS14 make an
      additional downstream cleavage.
    supporting_text: Proteolytically cleaved by BMP1 which removes the propeptide
      (PubMed:31152061). Also proteolytically cleaved by ADAMTS2 and ADAMTS14, but
      not by ADAMTS3, at an additional cleavage site downstream of the BMP1 cleavage
      site (PubMed:31152061).
    reference_section_type: DATABASE_ENTRY
  - statement: Differential LOX processing regulates collagen binding.
    supporting_text: Cleavage by BMP1 to remove the propeptide does not increase enzymatic
      activity but increases binding to collagen (PubMed:31152061). Cleavage by ADAMTS2
      produces a form with reduced collagen-binding activity (PubMed:31152061).
    reference_section_type: DATABASE_ENTRY
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Reviewed UniProtKB record for human LOX; exact source for the function,
      extracellular-localization, and proteolytic-processing statements cited by annotation
      evidence items in this review.
- id: PMID:1352776
  title: Characterization of the human lysyl oxidase gene locus.
  findings:
  - statement: Human LOX is a copper-dependent collagen- and elastin-cross-linking enzyme;
      the locus produces multiple alternatively spliced transcripts.
    supporting_text: 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.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Human gene-locus paper; the enzyme statement is background and the
      direct experimental contribution is gene organization/transcript analysis. Abstract
      only in cache; title and quote verified.
- id: PMID:1357535
  title: The complete derived amino acid sequence of human lysyl oxidase and assignment
    of the gene to chromosome 5 (extensive sequence homology with the murine ras recision
    gene).
  findings:
  - statement: Human LOX oxidizes lysine to an aldehyde that initiates covalent collagen
      and tropoelastin cross-linking in the extracellular matrix.
    supporting_text: Lysyl oxidase catalyzes the oxidation of lysine residues to alpha-aminoadipic-delta-semialdehyde.
      This is the first step in the covalent cross-linking of collagen and tropoelastin
      and results in the formation of insoluble collagen and elastic fibers in the extracellular
      matrix.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Foundational human sequence paper with a concise catalytic and ECM-cross-linking
      account; catalytic-domain localization is sequence-based. Abstract only in cache;
      title and quote verified.
- id: PMID:1685472
  title: Molecular cloning of human lysyl oxidase and assignment of the gene to chromosome
    5q23.3-31.2.
  findings:
  - statement: Human LOX initiates collagen and elastin cross-linking by oxidative
      deamination of selected lysine and hydroxylysine epsilon-amino groups.
    supporting_text: Lysyl oxidase (EC 1.4.3.13) initiates the crosslinking of collagens
      and elastin by catalyzing oxidative deamination of the epsilon-amino group in certain
      lysine and hydroxylysine residues.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  - statement: The cloned 417-residue human precursor includes a 21-residue signal
      peptide.
    supporting_text: This cDNA encodes a polypeptide of 417 amino acid residues, including
      a signal peptide of 21 amino acids.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Human cDNA paper supporting catalytic substrate class and secretory
      targeting. Abstract only in cache; title and quotes verified.
- id: PMID:16893474
  title: Elastic fibres in health and disease.
  findings:
  - statement: Elastic fibers provide elastic recoil and resilience to dynamic connective
      tissues.
    supporting_text: Their structural role is to endow tissues with elastic recoil and
      resilience.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: General elastic-fiber review providing physiological context, not direct
      LOX experimentation. Abstract only in cache; title and quote verified.
- id: PMID:18586678
  title: Lysyl oxidase oxidizes cell membrane proteins and enhances the chemotactic
    response of vascular smooth muscle cells.
  findings:
  - statement: In cultured rat aortic smooth-muscle cells, inhibiting LOX reduced
      chemotaxis toward LOX and PDGF-BB, while sub-chemotactic LOX enhanced the PDGF-BB
      response.
    supporting_text: Here we demonstrate that inhibition of LOX activity by beta-aminopropionitrile
      (BAPN) in cultured rat aortic smooth muscle cells (SMCs) reduced the chemotactic
      response and sensitivity of these cells toward LOX and toward PDGF-BB. The chemotactic
      activity of PDGF-BB was significantly enhanced in the presence of a non-chemotactic
      concentration of LOX.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  - statement: LOX-dependent oxidation of cell-surface PDGFR-beta altered ligand binding
      and downstream signaling kinetics in rat SMCs, with LOX-knockout mouse embryonic
      fibroblasts providing orthogonal support.
    supporting_text: These novel findings suggest that LOX activity is essential to
      generate optimal chemotactic sensitivity of cells to chemoattractants by oxidizing
      specific cell surface proteins, such as PDGFR-beta.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Primary mechanistic evidence for LOX involvement in PDGFR-beta-dependent
      signaling and chemotaxis. Experiments in the cached abstract are cultured rat aortic
      SMCs and LOX-knockout mouse embryonic fibroblasts, not human cells; only the abstract
      is available locally.
- id: PMID:19570982
  title: Differential regulation of elastic fiber formation by fibulin-4 and -5.
  findings:
  - statement: Human fibulin-4 directly binds LOX and promotes a ternary complex with
      tropoelastin that can target elastin cross-linking.
    supporting_text: Novel findings are that fibulin-4 directly binds LOX, and this
      interaction enhances fibulin-4 binding to tropoelastin, thus forming a ternary
      complex that may be critical for elastin cross-linking.
    reference_section_type: INTRODUCTION
    full_text_unavailable: false
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full-text biochemical interaction study using recombinant human elastic-fiber
      proteins; directly supports LOX-fibulin-4 binding and elastic-fiber targeting.
- id: PMID:19855011
  title: Fibulin-4 conducts proper elastogenesis via interaction with cross-linking
    enzyme lysyl oxidase.
  findings:
  - statement: Fibulin-4 binds the LOX propeptide and promotes assembly of LOX onto
      tropoelastin.
    supporting_text: We also found a specific interaction between FBLN4 and the propeptide
      of LOX, which efficiently promotes assembly of LOX onto tropoelastin.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Supports a propeptide-specific fibulin-4 interaction and an extracellular
      targeting mechanism; much of the physiological work is in mouse. Abstract only
      in cache; title and quote verified.
- id: PMID:21690299
  title: The lysyl oxidase propeptide interacts with the receptor-type protein tyrosine
    phosphatase kappa and inhibits β-catenin transcriptional activity in lung cancer
    cells.
  findings:
  - statement: LOX propeptide directly interacts with the intracellular phosphatase
      domains of receptor-type protein tyrosine phosphatase kappa in mammalian cells.
    supporting_text: Here, 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-κ), and the interaction of the two proteins in
      mammalian cells was confirmed.
    reference_section_type: ABSTRACT
    full_text_unavailable: false
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Full text verifies a context-specific effect of the released propeptide
      under ectopic expression in lung-cancer cells; it is not evidence for the mature
      enzyme's core extracellular catalytic function.
- id: PMID:22919265
  title: Yeast two-hybrid analysis of a human trabecular meshwork cDNA library identified
    EFEMP2 as a novel PITX2 interacting protein.
  findings: []
  reference_review:
    relevance: NONE
    correctness: MISCITED
    review_notes: The cached full text identifies EFEMP2 as a PITX2-interacting protein
      in trabecular-meshwork experiments and does not assay or mention LOX. It cannot
      support a LOX protein-binding annotation.
- id: PMID:25118846
  title: Nuclear translocation of lysyl oxidase is promoted by interaction with transcription
    repressor p66β.
  findings:
  - statement: Co-expression with p66β drives nuclear accumulation of LOX in tumor
      cells, after direct interaction with the LOX catalytic domain.
    supporting_text: Moreover, co-expression of p66β and LOX in living tumor cells
      leads to the nuclear accumulation of LOX.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Supports a tumor-cell/co-expression-dependent nuclear observation;
      it does not establish constitutive nuclear localization or a normal nuclear function.
      Abstract only in cache; title and quote verified.
- id: PMID:26601954
  title: Characterization of Microfibrillar-associated Protein 4 (MFAP4) as a Tropoelastin-
    and Fibrillin-binding Protein Involved in Elastic Fiber Formation.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: UNVERIFIED
    review_notes: The cached abstract characterizes MFAP4 interactions with several
      elastic-fiber components but does not mention the curated LOX-MFAP4 IPI. Because
      the full text is unavailable, that interaction cannot be verified here and must
      not be rejected based on the abstract alone.
- id: PMID:26838787
  title: LOX Mutations Predispose to Thoracic Aortic Aneurysms and Dissections.
  findings:
  - statement: Human disease-associated catalytic-domain LOX variants have significantly
      reduced lysyl oxidase activity.
    supporting_text: Expression of the LOX variants p.Ser280Arg and p.Ser348Arg resulted
      in significantly lower lysyl oxidase activity when compared with the wild-type
      protein.
    reference_section_type: ABSTRACT
    full_text_unavailable: false
  - statement: Rare LOX variants predispose to thoracic aortic disease, supporting
      a physiological requirement for LOX in aortic-wall integrity.
    supporting_text: These data, along with previous studies showing that the deficiency
      of LOX in mice or inhibition of lysyl oxidases in turkeys and rats causes aortic
      dissections, support the conclusion that rare genetic variants in LOX predispose
      to thoracic aortic disease.
    reference_section_type: ABSTRACT
    full_text_unavailable: false
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Direct human genetics plus biochemical assays of expressed LOX variants;
      full text available and quotes verified. Disease establishes physiological importance
      but is not itself a molecular function.
- id: PMID:27339457
  title: Functional consequence of fibulin-4 missense mutations associated with vascular
    and skeletal abnormalities and cutis laxa.
  findings:
  - statement: Fibulin-4 binds LOX and LOXL1, and the E57K fibulin-4 mutation strongly
      reduces binding to the LOX propeptide.
    supporting_text: 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; the binding of fibulin-4
      to the LOX propeptide was strongly reduced by the mutation E57K.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Corroborates propeptide-specific fibulin-4 binding but primarily studies
      disease-causing EFEMP2 variants. Abstract only in cache; title and quote verified.
- id: PMID:30082873
  title: Insights into the structure and dynamics of lysyl oxidase propeptide, a flexible
    protein with numerous partners.
  findings:
  - statement: Recombinant human LOX propeptide is elongated, monomeric, intrinsically
      disordered, and flexible.
    supporting_text: >-
      We characterized the recombinant human propeptide by circular dichroism, dynamic
      light scattering, and small-angle X-ray scattering (SAXS), and showed that it
      is elongated, monomeric, disordered and flexible (Dmax: 11.7 nm, Rg: 3.7 nm).
    reference_section_type: ABSTRACT
    full_text_unavailable: false
  - statement: Human LOX propeptide directly binds multiple extracellular-matrix
      proteins and matrix-associated enzymes in vitro.
    supporting_text: 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),
    reference_section_type: RESULTS
    full_text_unavailable: false
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full-text structural/interaction characterization of recombinant human
      LOX-PP. Findings belong specifically to the released propeptide and should not
      be transferred to the mature catalytic enzyme.
- id: PMID:31152061
  title: Differential cleavage of lysyl oxidase by the metalloproteinases BMP1 and
    ADAMTS2/14 regulates collagen binding through a tyrosine sulfate domain.
  findings:
  - statement: BMP1 activates proLOX, whereas ADAMTS2/14 make a second downstream
      cleavage in expressed LOX.
    supporting_text: In this study, using murine skin fibroblasts and HEK293 cells,
      along with immunoprecipitation, LOX enzymatic activity, solid-phase binding assays,
      and proteomics analyses, we report that the LOX precursor is proteolytically
      processed by the procollagen N-proteinases ADAMTS2 and ADAMTS14 between Asp-218
      and Tyr-219, 50 amino acids downstream of the BMP1 cleavage site.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  - statement: Sulfated tyrosines in the segment between the BMP1 and ADAMTS cleavage
      sites contribute to LOX collagen binding.
    supporting_text: We noted that the LOX sequence between the BMP1- and ADAMTS-processing
      sites contains several conserved tyrosine residues, of which some are post-translationally
      modified by tyrosine O-sulfation and contribute to binding to collagen.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Direct processing, activity, binding, and proteomics study in murine
      skin fibroblasts and HEK293 cells. Abstract only in the local cache despite a
      PMCID; title and quotes verified.
- id: PMID:27432961
  title: Loss of function mutation in LOX causes thoracic aortic aneurysm and dissection
    in humans.
  findings:
  - statement: A human LOX missense allele segregates with thoracic aortic disease,
      and the homologous engineered mouse allele disrupts elastic lamellae and causes
      severe aortic disease when homozygous.
    supporting_text: Mutant mice that were heterozygous for the human allele displayed
      disorganized ultrastructural properties of the aortic wall characterized by fragmented
      elastic lamellae, whereas mice homozygous for the human allele died shortly after
      parturition from ascending aortic aneurysm and spontaneous hemorrhage.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  - statement: The authors infer that insufficient collagen and elastin cross-linking
      explains LOX-associated aortic-wall weakness.
    supporting_text: These data suggest that a missense mutation in LOX is associated
      with aortic disease in humans, likely through insufficient cross-linking of elastin
      and collagen in the aortic wall.
    reference_section_type: ABSTRACT
    full_text_unavailable: true
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Independent human segregation plus knock-in mouse model. The cache
      contains only the abstract; its title and quotes were verified. The cross-linking
      mechanism is explicitly presented as a likely inference, so it supports physiological
      relevance without replacing direct biochemical evidence.
- id: Reactome:R-HSA-2002466
  title: Formation of allysine by LOX
  findings: []
- id: Reactome:R-HSA-2022141
  title: Prolysyl oxidase activation
  findings: []
- id: Reactome:R-HSA-2129375
  title: Elastin cross-linking by lysyl oxidase
  findings: []
- id: Reactome:R-HSA-2395340
  title: Formation of hydroxyallysine by LOX
  findings: []
core_functions:
- description: >-
    After secretion and extracellular processing of proLOX, the mature C-terminal
    copper/LTQ enzyme oxidatively deaminates selected lysine and hydroxylysine side
    chains in collagen and elastin to allysine and hydroxyallysine. These aldehydes
    initiate covalent cross-link formation, thereby stabilizing collagen fibrils and
    elastic fibers. Substrate delivery is form- and processing-dependent: sulfated
    tyrosines retained in the long mature form promote collagen binding, whereas the
    propeptide can recruit proLOX to fibulin-4/tropoelastin assemblies before it is
    released. These targeting interactions are not treated as stable complex
    membership. The released LOX-PP is a distinct noncatalytic product, and reported
    tumor-cell or nuclear effects are not assigned to this extracellular catalytic
    activity. Human catalytic-domain variants with reduced enzyme activity predispose
    to thoracic aortic disease, supporting the physiological importance of this
    reaction for aortic-wall matrix integrity without making disease or blood-vessel
    morphogenesis a second molecular function.
  molecular_function:
    id: GO:0004720
    label: protein-lysine 6-oxidase activity
  directly_involved_in:
  - id: GO:0018057
    label: peptidyl-lysine oxidation
  - id: GO:0030199
    label: collagen fibril organization
  - id: GO:0048251
    label: elastic fiber assembly
  locations:
  - id: GO:0031012
    label: extracellular matrix
  supported_by:
  - reference_id: PMID:1685472
    supporting_text: Lysyl oxidase (EC 1.4.3.13) initiates the crosslinking of collagens
      and elastin by catalyzing oxidative deamination of the epsilon-amino group in
      certain lysine and hydroxylysine residues.
  - reference_id: PMID:1357535
    supporting_text: This is the first step in the covalent cross-linking of collagen
      and tropoelastin and results in the formation of insoluble collagen and elastic
      fibers in the extracellular matrix.
  - reference_id: PMID:31152061
    supporting_text: the initial step in the formation of covalent collagen cross-links,
      an essential process for fibril stabilization
  - reference_id: PMID:26838787
    supporting_text: Expression of the LOX variants p.Ser280Arg and p.Ser348Arg resulted
      in significantly lower lysyl oxidase activity when compared with the wild-type
      protein.
knowledge_gaps:
- gap_statement: >-
    The quantitative substrate partitioning of endogenous human LOX among collagen
    types, elastin, and the corresponding LOXL-family enzymes in the aortic wall is
    unresolved.
  boundary: >-
    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.
  gap_kind:
  - BIOLOGY
  dark_aspect: RESIDUAL_SUBGAP
  status: OPEN
  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.
  resolution: >-
    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:
  - reference_id: PMID:26838787
    supporting_text: These data, along with previous studies showing that the deficiency
      of LOX in mice or inhibition of lysyl oxidases in turkeys and rats causes aortic
      dissections, support the conclusion that rare genetic variants in LOX predispose
      to thoracic aortic disease.
- gap_statement: >-
    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.
  boundary: >-
    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.
  gap_kind:
  - BIOLOGY
  dark_aspect: RESIDUAL_SUBGAP
  status: OPEN
  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.
  resolution: >-
    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:
  - reference_id: PMID:31152061
    supporting_text: We noted that the LOX sequence between the BMP1- and ADAMTS-processing
      sites contains several conserved tyrosine residues, of which some are post-translationally
      modified by tyrosine O-sulfation and contribute to binding to collagen.
  - reference_id: PMID:19855011
    supporting_text: We also found a specific interaction between FBLN4 and the propeptide
      of LOX, which efficiently promotes assembly of LOX onto tropoelastin.
- gap_statement: >-
    The physiological functions of released LOX-PP, and whether endogenous mature LOX
    has any normal intracellular or nuclear activity, remain unresolved.
  boundary: >-
    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 p66β in tumor cells, but these experiments
    do not demonstrate a native nuclear pool or physiological nuclear catalysis.
  gap_kind:
  - BIOLOGY
  dark_aspect: RESIDUAL_SUBGAP
  status: OPEN
  significance: >-
    Separating precursor, mature-enzyme, and released-propeptide effects is essential
    to prevent extracellular catalytic activity from being conflated with proposed
    intracellular signaling roles.
  resolution: >-
    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:
  - reference_id: PMID:21690299
    supporting_text: In H1299 lung cancer cells, ectopic LOX-PP expression reduced the
      nuclear levels of PIC by increasing its turnover in the lysosome, thereby decreasing
      the nuclear levels and transcriptional activity of β-catenin while increasing
      β-catenin membrane localization.
  - reference_id: PMID:25118846
    supporting_text: Moreover, co-expression of p66β and LOX in living tumor cells leads
      to the nuclear accumulation of LOX.
proposed_new_terms: []
suggested_questions:
- question: >-
    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?
- question: >-
    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?
- question: >-
    Does released endogenous LOX-PP have a reproducible physiological signaling
    function, and is any endogenous nuclear LOX pool catalytically active in normal
    human cells?
suggested_experiments:
- hypothesis: >-
    LOX modifies a defined subset of collagen and elastin sites in human aortic matrix
    that is not redundantly oxidized by LOXL paralogs.
  description: >-
    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.
  experiment_type: genome editing and matrix cross-link proteomics
- hypothesis: >-
    Proteolytic processing and tyrosine sulfation direct LOX toward collagen, whereas
    the intact propeptide and fibulin-4 favor tropoelastin targeting.
  description: >-
    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.
  experiment_type: endogenous protein processing and substrate-targeting analysis
- hypothesis: >-
    Reported LOX-PP signaling and nuclear LOX phenotypes require nonphysiological
    overexpression and are absent at endogenous abundance in normal human cells.
  description: >-
    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, β-catenin output, and rescue with
    secretion-defective, cleavage-resistant, and catalytic-dead alleles.
  experiment_type: form-specific endogenous localization and functional analysis

LOX

Gene Description

Existing Annotations Review

Core Functions

References

Suggested Questions for Experts

Suggested Experiments

Knowledge Gaps

📚 Additional Documentation

Notes

LOX literature notes

Evidence access and scope

Core catalytic function and extracellular-matrix role

Processing, localization, and collagen targeting

Elastic-fiber assembly partners

LOX propeptide and intracellular claims

PDGFR-beta signaling boundary

Curation implications

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