LOXL4 is a secreted lysyl-oxidase-family amine oxidase with an N-terminal signal peptide, four scavenger-receptor cysteine-rich domains, and a conserved copper- and lysine-tyrosylquinone-containing catalytic region. Purified recombinant human LOXL4 has beta-aminopropionitrile-sensitive amine-oxidase activity. As a lysyl-oxidase-family protein it is predicted to initiate covalent extracellular- matrix cross-links by oxidizing protein lysine residues; collagen-I and collagen-II oxidation has been demonstrated for the mouse ortholog. Human LOXL4 is widely expressed, with the highest reported levels in skeletal muscle, testis, and pancreas, and is also expressed in cartilage. Recombinant human LOXL4 is secreted without evident proteolytic processing.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004720 protein-lysine 6-oxidase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference assigns LOXL4 protein-lysine 6-oxidase activity. Reason: This is the defining activity of the conserved copper-dependent lysyl-oxidase domain and agrees with direct biochemical evidence that recombinant human LOXL4 is an active beta-aminopropionitrile-sensitive amine oxidase. Propagation Review Root cause: NO FAILURE CORE Sources checked: FB:FBgn0034660 FB:FBgn0039848 MGI:MGI:106096 MGI:MGI:1337004 MGI:MGI:1914823 MGI:MGI:96817 PANTHER:PTN002550804 RGD:3015 UniProtKB:P28300 UniProtKB:P58215 UniProtKB:Q05063 UniProtKB:Q95L39 UniProtKB:Q96JB6 UniProtKB:Q9Y4K0 |
| GO:0005576 extracellular region | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference places active LOXL4 in the extracellular region. Reason: LOXL4 has an N-terminal signal peptide and is a secreted lysyl-oxidase-family enzyme, so this broad active compartment is biologically coherent and core. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:106096 MGI:MGI:1337004 MGI:MGI:1914823 MGI:MGI:96817 PANTHER:PTN002550804 RGD:1308435 RGD:1308752 RGD:3015 UniProtKB:P28300 UniProtKB:P33072 UniProtKB:P58215 UniProtKB:Q08397 UniProtKB:Q9Y4K0 |
| GO:0031012 extracellular matrix | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference places active LOXL4 in extracellular matrix. Reason: Matrix residence is consistent with secretion and the conserved role of lysyl oxidases in oxidative cross-link initiation, while remaining broader than any single substrate claim. Propagation Review Root cause: NO FAILURE CORE Sources checked: MGI:MGI:106096 MGI:MGI:96817 PANTHER:PTN008698711 RGD:1308435 RGD:1308752 RGD:3015 |
| GO:0030199 collagen fibril organization | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic inference assigns LOXL4 a role in collagen fibril organization. Reason: LOXL4 retains the conserved lysyl-oxidase catalytic chemistry, and the mouse ortholog directly oxidizes collagen I and II. However, substrate and pathway assignments diverge among LOX paralogs and direct human LOXL4 evidence for collagen-fibril organization is lacking, so this conserved downstream role remains non-core. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: MGI:MGI:96817 PANTHER:PTN008698711 RGD:3015 UniProtKB:Q9Y4K0 |
| GO:0004720 protein-lysine 6-oxidase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated orthology, reaction, and EC mappings assign protein-lysine 6-oxidase activity. Reason: The specific reaction and EC mapping agree with LOXL4's conserved catalytic domain and experimentally demonstrated amine-oxidase activity. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00088088 UniProtKB:Q924C6 ensembl:ENSMUSP00000026190 RHEA:24544 EC:1.4.3.13 |
| GO:0005507 copper ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro domain mappings assign copper ion binding. Reason: Copper is an obligatory lysyl-oxidase cofactor, and LOXL4 retains the conserved copper-binding catalytic region. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR001695 InterPro:IPR019828 |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | ACCEPT | Summary: Orthology and UniProt subcellular-location mappings assign LOXL4 to the extracellular region. Reason: LOXL4 contains a signal peptide and is secreted, so the broad electronic localization agrees with its conserved extracellular enzyme biology. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q924C6 ensembl:ENSMUSP00000026190 UniProtKB-SubCell:SL-0112 |
| GO:0016020 membrane | IEA GO_REF:0000002 | REMOVE | Summary: InterPro scavenger-receptor cysteine-rich domain mappings assign membrane localization. Reason: This is a domain-to-compartment over-transfer. LOXL4 is a soluble secreted protein with a signal peptide but no annotated transmembrane segment or membrane anchor; an SRCR domain does not by itself make the protein membrane-bound. Propagation Review Root cause: PROPAGATION BAD Failure modes: ROLE CONFLATION Sources checked: InterPro:IPR001190 InterPro:IPR036772 |
| GO:0016641 oxidoreductase activity, acting on the CH-NH2 group of donors, oxygen as acceptor | IEA GO_REF:0000002 | MODIFY | Summary: InterPro assigns the broad parent oxidoreductase activity acting on CH-NH2 donors. Reason: The parent is true but needlessly generic because LOXL4 has the more informative protein-lysine 6-oxidase annotation. 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 | KEEP AS NON CORE | Summary: An ARBA model places LOXL4 at elastic fibers. Reason: Elastic-fiber association is plausible for a secreted lysyl-oxidase-family protein, but direct LOXL4-specific localization evidence is not available in the accessible record. Retain it as a secondary matrix context. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: ARBA:ARBA00084594 |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | MARK AS OVER ANNOTATED | Summary: A proteome-scale interaction map reports LOXL4 binding to UniProtKB:Q15645. Reason: The curated interaction may be valid, but generic protein binding is uninformative and a high-throughput binary edge does not define LOXL4's molecular function; no evidence-supported, more specific binding term is available. |
| GO:0005515 protein binding | IPI PMID:19060904 An empirical framework for binary interactome mapping. | MARK AS OVER ANNOTATED | Summary: A binary-interactome study reports LOXL4 binding to UniProtKB:Q15645. Reason: The high-throughput interaction may be valid, but generic protein binding does not describe LOXL4's molecular function and the screen does not justify a more informative GO binding term. |
| GO:0005515 protein binding | IPI PMID:23455924 A Y2H-seq approach defines the human protein methyltransfera... | MARK AS OVER ANNOTATED | Summary: A Y2H-seq methyltransferase interactome reports two LOXL4 interaction partners. Reason: The two source accessions are preserved, but the screen-derived interactions do not define a specific LOXL4 molecular function; generic protein binding is therefore over-annotated and no accurate replacement term is supported. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: A proteome-scale interactome reports LOXL4 binding to UniProtKB:Q15645. Reason: The high-throughput interaction may be valid, but it does not establish a stable complex or a specific LOXL4 binding function; generic protein binding is therefore over-annotated and no accurate replacement term is supported. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: A proteome-scale interactome reports LOXL4 binding to UniProtKB:Q92526. Reason: The interaction evidence does not define LOXL4's molecular function or a stable complex, so the uninformative generic protein-binding term is over-annotated. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: A neurodegenerative-disease interactome reports LOXL4 interactions with 16 source accessions. Reason: The heterogeneous proteome-scale interaction set may contain valid edges, but it does not define one coherent LOXL4 molecular function or stable complex; generic protein binding is therefore over-annotated. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: A cell-specific interactome reports LOXL4 binding to UniProtKB:Q92526. Reason: The dataset-level interaction may be valid, but it does not establish a specific LOXL4 molecular function or stable complex; generic protein binding is therefore over-annotated. |
| GO:0071953 elastic fiber | TAS PMID:23962539 Elastic fibres in health and disease. | KEEP AS NON CORE | Summary: A curator statement associates LOXL4 with elastic fibers using a family-level review. Reason: The cached review is abstract-only and does not expose the LOXL4-specific passage, so the curator's traceable statement is retained without claiming direct verification. Elastic fibers are a plausible secondary matrix location rather than the defining evidence for LOXL4 catalysis. |
| GO:0004720 protein-lysine 6-oxidase activity | IDA PMID:14551188 Expression and purification of enzymatically active forms of... | ACCEPT | Summary: Recombinant human LOXL4 displays beta-aminopropionitrile-sensitive amine-oxidase activity. Reason: The study directly establishes catalysis by purified LOXL4, while its reported substrate is benzylamine rather than protein lysine. The specific GO term is nevertheless supported holistically by the conserved lysyl-oxidase catalytic domain, IBA, and reaction/EC mappings; retain the curator's IDA annotation. Supporting Evidence: PMID:14551188 The purified LOXL4 proteins showed beta-aminopropionitrile-inhibitable activity of 0.022-0.032 units/mg toward a nonpeptidyl substrate, benzylamine. |
| GO:0043235 signaling receptor complex | IDA PMID:23382219 Structural basis for endosomal trafficking of diverse transm... | UNDECIDED | Summary: An IDA annotation places LOXL4 in a signaling receptor complex. Reason: The accessible full-text narrative concerns PX-FERM trafficking of transmembrane cargos and does not expose a LOXL4-specific result. Because the curator may have used supplementary evidence that is not visible here, retain the annotation as undecided rather than asserting misattribution or removing it. |
| GO:0070062 extracellular exosome | HDA PMID:19199708 Proteomic analysis of human parotid gland exosomes by multid... | KEEP AS NON CORE | Summary: Human parotid-gland exosome proteomics identifies LOXL4 in extracellular exosomes. Reason: Retain this curator-reviewed high-throughput localization with its exact parotid gland extension. It represents a tissue- and vesicle-specific occurrence rather than the general extracellular-matrix site of LOXL4 catalytic activity. |
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Download this section (compressed HTML)Q: Which endogenous human extracellular proteins and lysine sites are directly oxidized by LOXL4, and are collagen or elastin physiological substrates?
Q: Is endogenous secreted LOXL4 proteolytically processed, and does BMP1-family cleavage alter activity, substrate choice, or extracellular retention?
Q: Where does catalytically active endogenous LOXL4 partition among soluble extracellular space, matrix, elastic fibers, and extracellular vesicles?
Q: Which high-throughput LOXL4 interaction or receptor-complex observations are reproducible at endogenous abundance and compatible with its secretory pathway?
Experiment: Introduce an acute endogenous LOXL4 degron into primary human fibroblasts and chondrocytes, quantify matrix allysine sites and mature cross-links by targeted mass spectrometry, and rescue with wild-type or catalytic-dead LOXL4. Validate candidate collagen, elastin, and noncanonical substrates with purified enzyme.
Hypothesis: Human LOXL4 oxidizes a defined subset of extracellular-matrix lysine sites that cannot be inferred solely from mouse LOXC collagen activity.
Type: endogenous depletion and matrix redox proteomics
Experiment: Map endogenous extracellular LOXL4 termini and proteoforms by N-terminomics and top-down mass spectrometry, perturb BMP1-family proteases, and compare secretion and activity of endogenous cleavage-resistant and cleavage-mimetic alleles.
Hypothesis: Signal-peptide removal is sufficient for LOXL4 activity and BMP1-family cleavage is not an obligatory activation step.
Type: endogenous proteoform mapping and protease perturbation
Experiment: Endogenously tag LOXL4 in matrix-producing and salivary epithelial cells, then combine pulse-chase imaging with soluble-medium, matrix, membrane, and extracellular-vesicle fractionation. Measure LOXL4 abundance and activity with fraction-purity and protease-protection controls.
Hypothesis: Active LOXL4 partitions primarily with extracellular matrix rather than being a constitutive exosome cargo or membrane-associated protein.
Type: compartment-resolved endogenous localization
Experiment: Prioritize recurrent partners and test them by reciprocal endogenous proximity labeling, co-immunoprecipitation, and extracellular cross-linking in secreting human cells, with signal-peptide mutants and compartment-mismatched proteins as controls; separately re-examine the signaling-receptor-complex association.
Hypothesis: Most reported intracellular high-throughput partners do not form stable physiological complexes with secreted LOXL4.
Type: endogenous interaction and compartment validation
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The endogenous human protein substrates and modified lysine sites of LOXL4 are unknown, including whether collagen and elastin are direct physiological substrates.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Purified human LOXL4 oxidizes benzylamine in a BAPN-sensitive assay, whereas collagen-I and collagen-II activity was shown for mouse LOXC in conditioned medium. The ortholog result supports substrate plausibility but is not direct evidence for human LOXL4.
Significance: Direct substrate and site maps are needed to define LOXL4's contribution to human matrix cross-linking and distinguish it from other lysyl oxidases.
What would resolve it: Acutely deplete endogenous LOXL4 in primary human matrix-producing cells and map LOXL4-dependent allysine sites by quantitative carbonyl proteomics, followed by wild-type and catalytic-dead rescue and purified-enzyme validation.
Provenance (the field's own admissions):
Gap: Whether endogenous human LOXL4 is proteolytically processed after secretion, and whether any such cleavage regulates activity, substrate choice, or matrix retention, remains unresolved.
OPEN BIOLOGYCURATION RESIDUAL_SUBGAP
What is known: Recombinant human LOXL4 was secreted without evident processing, UniProt defines a signal peptide and chain but no propeptide, and its possible BMP1 cleavage is inferred rather than experimentally established.
Significance: Resolving the native proteoform boundary would prevent an inferred BMP1 cleavage event from being conflated with demonstrated propeptide-dependent activation.
What would resolve it: Map endogenous secreted LOXL4 termini and intact proteoforms by N-terminomics and top-down mass spectrometry, then perturb BMP1-family proteases and test activity of cleavage-resistant and cleavage-mimetic LOXL4 constructs.
Provenance (the field's own admissions):
Gap: The extracellular compartment in which endogenous human LOXL4 performs its main catalytic function, and the extent to which it resides in matrix, elastic fibers, or extracellular vesicles, are not directly resolved.
OPEN BIOLOGY CC_DARK
What is known: Human secretion is experimentally supported, extracellular-matrix and elastic-fiber localizations are phylogenetic or electronic/curator transfers, and parotid-exosome evidence is a tissue-specific high-throughput detection.
Significance: Compartment-resolved localization is necessary to connect LOXL4 catalysis to its native substrates without promoting dataset-level detections to a general site of action.
What would resolve it: Endogenously tag LOXL4 in relevant primary human cells and combine secretion pulse-chase imaging, matrix extraction, extracellular-vesicle fractionation, and activity-based detection with orthogonal fraction-purity controls.
Provenance (the field's own admissions):
Gap: The physiological relevance, compartmental compatibility, and directness of the reported high-throughput LOXL4 interaction partners and signaling-receptor-complex association are unresolved.
OPEN BIOLOGYCURATION MF_DARK
What is known: The source datasets report binary or co-association hits, but accessible records do not establish a LOXL4-specific mechanism, a stable complex, or that these interactions occur in the extracellular physiological context of LOXL4.
Significance: Validation is required before generic binding or receptor-complex annotations can be converted into an informative molecular function or complex model.
What would resolve it: Test prioritized partners at endogenous abundance in secreting human cells using reciprocal extracellular proximity labeling and co-complex analysis, with signal- peptide, catalytic-dead, and compartment-mismatched controls.
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