ADAMTSL4 (ADAMTS-like protein 4) is a secreted extracellular matrix glycoprotein that functions as a matricellular regulator of fibrillin microfibril organization. Despite its name suggesting similarity to ADAMTS proteases, ADAMTSL4 lacks the catalytic metalloprotease and disintegrin-like domains characteristic of that family, indicating it is non-enzymatic. The protein contains thrombospondin type-1 repeats, PLAC, and spacer domains. ADAMTSL4 localizes to the ECM of the ocular anterior segment and plays a critical role in the assembly, organization, and anchorage of fibrillin-rich microfibrils that form the lens zonular fibers (ciliary zonule). Biallelic loss-of-function variants in ADAMTSL4 cause autosomal recessive isolated ectopia lentis (lens dislocation) and ectopia lentis et pupillae, without systemic Marfan-like features, reflecting its specialized role in zonular fiber stability. The protein is expressed in ocular tissues including lens epithelium and periocular structures, and binds directly to fibrillin-1 microfibrils, promoting their biogenesis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0006915 apoptotic process | IEA GO_REF:0000043 | MARK AS OVER ANNOTATED | Summary: This annotation is inferred from the UniProt keyword "Apoptosis" (KW-0053), which was likely added based on PMID:16364318. The deep research on ADAMTSL4 contains no evidence of an evolved function in apoptosis. ADAMTSL4 is a secreted ECM glycoprotein that functions in fibrillin microfibril organization for lens zonular integrity. The apoptosis keyword likely derives from a single correlation study in ovarian cancer cells, not from ADAMTSL4's core biological function. Reason: ADAMTSL4 is an ECM protein whose primary function is organizing fibrillin microfibrils in the lens zonule. Biallelic loss causes ectopia lentis (lens dislocation), not apoptosis-related disease. The UniProt keyword derives from a correlation study (PMID:16364318) in cancer cells that does not establish apoptosis as a core function. Supporting Evidence: PMID:21989719 ADAMTSL4 is a secreted glycoprotein that is widely distributed in the human eye PMID:19200529 mutations in ADAMTSL4 are responsible for autosomal-recessive simple ectopia lentis |
| GO:0005515 protein binding | IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in... | REMOVE | Summary: This annotation derives from a large-scale yeast two-hybrid interactome mapping study that tested approximately 8,100 ORFs for pairwise interactions. The study does not identify specific biologically meaningful interactions for ADAMTSL4. Reason: The term "protein binding" (GO:0005515) is uninformative and does not describe ADAMTSL4's actual molecular function. High-throughput Y2H screens can detect many interactions that may not be physiologically relevant. For an ECM protein like ADAMTSL4, more specific interaction terms (e.g., fibrillin binding) would be appropriate. Supporting Evidence: PMID:16189514 Here we describe an initial version of a proteome-scale map of human binary protein-protein interactions |
| GO:0005515 protein binding | IPI PMID:16364318 Cathepsin B and its interacting proteins, bikunin and TSRC1,... | REMOVE | Summary: This annotation is based on PMID:16364318, which identified ADAMTSL4 (then called TSRC1) as a cathepsin B binding protein in a yeast two-hybrid screen studying TNF-induced apoptosis of ovarian cancer cells. The interaction was confirmed in vitro and in vivo. Reason: While the cathepsin B interaction may be real, "protein binding" is an uninformative term. More importantly, this interaction was identified in a cancer cell apoptosis context that does not reflect ADAMTSL4's evolved function as an ECM protein involved in fibrillin microfibril organization. The biological relevance of this interaction to ADAMTSL4's core function is unclear. Supporting Evidence: PMID:16364318 Two cathepsin B binding proteins, bikunin and TSRC1, were identified by yeast two-hybrid method and the interactions were confirmed in vitro and in vivo |
| GO:0005515 protein binding | IPI PMID:19060904 An empirical framework for binary interactome mapping. | REMOVE | Summary: This annotation derives from a framework study for binary interactome mapping that assessed quality parameters of Y2H screens. It does not provide specific information about ADAMTSL4 interactions. Reason: The term "protein binding" is uninformative. This is a methodological study about interactome mapping quality, not a focused study of ADAMTSL4 function. No specific biologically meaningful interaction is identified. Supporting Evidence: PMID:19060904 Here we describe a framework that uses an empirically-based approach to rigorously dissect quality parameters |
| GO:0005515 protein binding | IPI PMID:23088713 Protein interactions of the transcription factor Hoxa1. | REMOVE | Summary: This annotation derives from a systematic Y2H screen for Hoxa1 interactors. ADAMTSL4 was identified as one of 59 Hoxa1 interactors, with 45 confirmed by affinity co-purification. The biological significance of ADAMTSL4-Hoxa1 interaction is unclear. Reason: The term "protein binding" is uninformative. While the Hoxa1 interaction may be detectable by Y2H, there is no evidence this represents a physiologically relevant interaction for ADAMTSL4's ECM function. Hoxa1 is a nuclear transcription factor while ADAMTSL4 is a secreted ECM protein, making their in vivo interaction unlikely. Supporting Evidence: PMID:23088713 To investigate the mode of action of mammalian Hoxa1, we characterized its interactome by a systematic yeast two-hybrid screening against ~12,200 ORF-derived polypeptides |
| GO:0005515 protein binding | IPI PMID:29758265 Interactions between lysyl oxidases and ADAMTS proteins sugg... | MODIFY | Summary: This study identified ADAMTSL4 as a potential interactor of lysyl oxidase (LOX) in a Y2H screen. The study demonstrates that several members of the LOX and ADAMTS/ADAMTSL families interact with one another, which is biologically meaningful given both families function in microfibril and elastic fiber formation in the ECM. Reason: While the generic "protein binding" term should be avoided, this interaction is potentially meaningful in the context of ADAMTSL4's ECM function. LOX enzymes crosslink ECM proteins, and ADAMTSL proteins are involved in microfibril organization. A more specific term for this ECM-relevant interaction would be appropriate. Proposed replacements: protein-macromolecular complex adaptor activity Supporting Evidence: PMID:29758265 A yeast two-hybrid screen to identify lysyl oxidase (LOX) binding proteins identified ADAMTSL4 as a potential interactor |
| GO:0005614 interstitial matrix | IEA GO_REF:0000107 | ACCEPT | Summary: This annotation is transferred from experimentally verified manual GO annotation data to orthologs using Ensembl Compara. ADAMTSL4 is a secreted ECM glycoprotein that localizes to the extracellular matrix. Reason: ADAMTSL4 is well-established as a secreted ECM protein. It localizes to the interstitial matrix, particularly in ocular tissues where it functions in fibrillin microfibril organization. This localization is consistent with its core function. Supporting Evidence: PMID:21989719 ADAMTSL4 is a secreted glycoprotein that is widely distributed in the human eye |
| GO:0031012 extracellular matrix | IEA GO_REF:0000107 | ACCEPT | Summary: This annotation indicates ADAMTSL4 localization to the extracellular matrix, transferred from ortholog data via Ensembl Compara. Reason: ADAMTSL4 is a secreted glycoprotein that functions in the ECM. Its localization to the extracellular matrix is well-established and represents its core site of action. Supporting Evidence: PMID:21989719 ADAMTSL4 colocalized with fibrillin-1 microfibrils in the ECM of these cells |
| GO:0031012 extracellular matrix | HDA PMID:28327460 Comprehensive proteomic characterization of stem cell-derive... | ACCEPT | Summary: This annotation derives from a comprehensive proteomic characterization of stem cell-derived extracellular matrices. The study detected ADAMTSL4 in ECM preparations from mesenchymal stem cells and fibroblasts using mass spectrometry. Reason: Detection of ADAMTSL4 in ECM-enriched fractions by mass spectrometry provides direct experimental evidence for its localization to the extracellular matrix, consistent with its known function as a secreted ECM protein. Supporting Evidence: PMID:28327460 Here, we characterized and compared the protein composition of ECM produced in vitro by bone marrow-derived MSC, adipose-derived MSC and neonatal fibroblasts from different donors, employing quantitative proteomic methods |
| GO:0031012 extracellular matrix | HDA PMID:25037231 Extracellular matrix signatures of human primary metastatic ... | ACCEPT | Summary: This annotation derives from a proteomic study characterizing ECM signatures of human colorectal cancers and liver metastases. ADAMTSL4 was detected in ECM-enriched fractions from tissue samples. Reason: Mass spectrometry detection of ADAMTSL4 in ECM-enriched fractions confirms its localization to the extracellular matrix. This is consistent with ADAMTSL4's known function as a secreted ECM glycoprotein. Supporting Evidence: PMID:25037231 We have used enrichment of extracellular matrix (ECM) from human patient samples and proteomics to define the ECM composition of primary colon carcinomas and their metastases to liver |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-5173005 | ACCEPT | Summary: This annotation indicates ADAMTSL4 transits through the ER lumen, based on Reactome pathway data for B3GALTL-mediated glucose transfer to O-fucosylated proteins. ADAMTSL4's thrombospondin type-1 repeats undergo O-fucosylation in the ER. Reason: As a secreted protein with TSR domains that undergo O-fucosylation and O-glucosylation, ADAMTSL4 must transit through the ER lumen during its biosynthesis and post-translational modification. This localization reflects its secretory pathway transit, not a functional localization. Supporting Evidence: UniProt:Q6UY14 Fucosylated repeats can then be further glycosylated by the addition of a beta-1,3- glucose residue by the glucosyltransferase, B3GALTL |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-5173192 | ACCEPT | Summary: This annotation derives from Reactome pathway data for POFUT2-mediated fucose transfer to TSR domain-containing proteins, which occurs in the ER lumen. Reason: ADAMTSL4 contains multiple TSR domains that are O-fucosylated by POFUT2 in the ER lumen. This is a required post-translational modification for proper secretion of ADAMTS/ADAMTSL family members. Supporting Evidence: UniProt:Q6UY14 Fucosylation mediates the efficient secretion of ADAMTS family members |
| GO:0005788 endoplasmic reticulum lumen | TAS Reactome:R-HSA-6785565 | ACCEPT | Summary: This annotation relates to the pathway for defective B3GALTL, which fails to transfer glucose to O-fucosylated proteins. ADAMTSL4 is a substrate for this glycosylation pathway. Reason: This annotation reflects ADAMTSL4's processing through the ER as a secreted glycoprotein that undergoes O-fucosylation and O-glucosylation on its TSR domains. The pathway annotation is accurate for understanding ADAMTSL4's biosynthesis. Supporting Evidence: UniProt:Q6UY14 N- and C- glycosylations can also facilitate secretion (By similarity) |
| GO:0002020 protease binding | IPI PMID:16364318 Cathepsin B and its interacting proteins, bikunin and TSRC1,... | KEEP AS NON CORE | Summary: This annotation indicates ADAMTSL4 binds cathepsin B, based on the Y2H screen in PMID:16364318 that studied TNF-induced apoptosis of ovarian cancer cells. Reason: While the cathepsin B interaction was confirmed experimentally, it was identified in a cancer cell context unrelated to ADAMTSL4's core ECM function. The biological relevance of this interaction to ADAMTSL4's normal physiology in zonular fiber organization is unclear. This may represent a pleiotropic or context-dependent interaction rather than a core function. Supporting Evidence: PMID:16364318 Two cathepsin B binding proteins, bikunin and TSRC1, were identified by yeast two-hybrid method and the interactions were confirmed in vitro and in vivo |
| GO:0043065 positive regulation of apoptotic process | IDA PMID:16364318 Cathepsin B and its interacting proteins, bikunin and TSRC1,... | MARK AS OVER ANNOTATED | Summary: This IDA annotation is based on PMID:16364318, which reported that overexpression of TSRC1 (ADAMTSL4) had an effect on TNF-induced apoptosis of OV-90 ovarian cancer cells, opposite to the suppressive effect of bikunin overexpression. Reason: This annotation represents a correlation study in cancer cells that does not establish apoptosis regulation as ADAMTSL4's evolved function. ADAMTSL4 is consistently identified as an ECM protein for fibrillin microfibril organization, with no mention of apoptosis as a core function. Biallelic ADAMTSL4 loss causes ectopia lentis (lens dislocation due to zonular fiber defects), not apoptosis-related pathology. Any effect on apoptosis in cancer cells likely reflects a secondary or pleiotropic effect of perturbing an ECM protein, not an evolved apoptotic function. Supporting Evidence: PMID:16364318 TSRC1 overexpression had an opposite effect on apoptosis PMID:21989719 ADAMTSL4 colocalized with fibrillin-1 microfibrils in the ECM of these cells PMID:19200529 mutations in ADAMTSL4 are responsible for autosomal-recessive simple ectopia lentis |
| GO:0001527 microfibril | TAS PMID:21989719 ADAMTSL4, a secreted glycoprotein widely distributed in the ... | NEW | Summary: ADAMTSL4 binds to fibrillin-1 microfibrils and accelerates microfibril biogenesis. This localization is directly relevant to its core function in zonular fiber organization. Reason: Multiple studies demonstrate ADAMTSL4 colocalizes with and binds fibrillin-1 microfibrils in the eye ECM. This annotation better captures ADAMTSL4's specific localization than the broader "extracellular matrix" term. Supporting Evidence: PMID:21989719 ADAMTSL4 colocalized with fibrillin-1 microfibrils in the ECM of these cells |
| GO:0030198 extracellular matrix organization | TAS PMID:21989719 ADAMTSL4, a secreted glycoprotein widely distributed in the ... | NEW | Summary: ADAMTSL4's core function is organizing fibrillin-rich microfibrils in the ECM, particularly in the lens zonule. This biological process annotation captures its primary role. Reason: The literature consistently describes ADAMTSL4 as facilitating fibrillin microfibril biogenesis and organization. This is the protein's core biological process. Supporting Evidence: PMID:21989719 Enhanced fibrillin-1 deposition in the presence of ADAMTSL4 file:genes/human/ADAMTSL4/ADAMTSL4-deep-research-falcon.md ADAMTSL4 contributes to fibrillin-rich microfibril assembly and zonule stabilization |
| GO:0050840 extracellular matrix binding | NAS | NEW | Summary: Added to align core_functions with existing annotations. Reason: Core function term not present in existing_annotations. Supporting Evidence: PMID:21989719 ADAMTSL4 colocalized with fibrillin-1 microfibrils in the ECM of these cells |
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Download this section (compressed HTML)Q: Does ADAMTSL4 directly crosslink fibrillin-1 microfibrils or does it recruit crosslinking enzymes like LOX?
Q: What is the specific binding interface between ADAMTSL4 and fibrillin-1?
Q: Are there tissue-specific isoforms of ADAMTSL4 with different functions?
Experiment: Structural studies (cryo-EM or X-ray) of ADAMTSL4 bound to fibrillin-1 microfibrils to determine binding interface
Hypothesis: ADAMTSL4 binds fibrillin-1 through its TSR domains
Type: structural biology
Experiment: Conditional knockout studies to assess ADAMTSL4 function in non-ocular tissues
Hypothesis: ADAMTSL4 may have additional ECM organizing functions outside the lens zonule
Type: mouse genetics
Experiment: Proteomics to identify the complete ADAMTSL4 interactome in lens zonule tissue
Hypothesis: ADAMTSL4 interacts with additional ECM proteins beyond fibrillin-1
Type: mass spectrometry proteomics
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