von Willebrand factor (VWF) is a very large, multimeric plasma glycoprotein synthesized by vascular endothelial cells and megakaryocytes. The precursor carries a propeptide (D1D2, von Willebrand antigen II) that acts as a pH-dependent intramolecular chaperone/oxidoreductase: pro-VWF dimerizes via C-terminal cystine-knot domains in the ER and is assembled into disulfide-linked multimers via D3 domains in the acidic Golgi, then packed as helical tubules into endothelial Weibel-Palade bodies or platelet alpha granules for regulated secretion. In plasma and the subendothelial matrix, VWF is the essential bridging molecule of primary hemostasis: its A3 (and A1) domains bind exposed collagens, and under high shear the elongated multimers expose A1 to capture platelets via glycoprotein Ib-alpha (GPIb-IX-V), while an RGD motif in C4 engages integrin alphaIIb-beta3 to support firm adhesion and platelet aggregation. VWF also binds coagulation factor VIII through D'D3, acting as its carrier and protecting it from clearance. Multimer size is regulated by ADAMTS13 cleavage within the force-sensitive A2 domain. Deficiency or dysfunction causes von Willebrand disease (types 1, 2A/2B/2M/2N, 3), the most common inherited bleeding disorder.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0002020 protease binding | IDA PMID:15824096 Binding of ADAMTS13 to von Willebrand factor. | KEEP AS NON CORE | Summary: VWF binds the metalloprotease ADAMTS13 with nM affinity (Kd 14 nM, spacer domain required); VWF is the physiological substrate of ADAMTS13. Reason: The binding is experimentally solid, but VWF binds ADAMTS13 as its substrate (cleavage at Tyr1605-Met1606 in A2), so protease binding describes how VWF size is regulated rather than a function VWF executes in hemostasis. Retained as non-core. Supporting Evidence: PMID:15824096 The stoichiometry of binding was one ADAMTS13 per two von Willebrand factor monomers, and the K(d) was 14 nm. PMID:16221672 ADAMTS13 controls the multimeric size of circulating von Willebrand factor (VWF) by cleaving the Tyr1605-Met1606 bond in theA2 domain. |
| GO:0002020 protease binding | IPI PMID:12775718 ADAMTS-13 metalloprotease interacts with the endothelial cel... | KEEP AS NON CORE | Summary: ADAMTS13-coated beads adhere to VWF and ULVWF strings under flow, with the A3 (and A1) domain acting as docking site for the protease. Reason: Direct ADAMTS13-VWF interaction is well supported; VWF is the protease substrate, so the term is correct but not a core function of VWF. Supporting Evidence: PMID:12775718 Here we report the direct interaction between ADAMTS-13 and VWF under both static and flowing conditions. |
| GO:0005178 integrin binding | IPI PMID:9079671 Propolypeptide of von Willebrand factor is a novel ligand fo... | ACCEPT | Summary: The VWF propeptide (von Willebrand antigen 2) is a ligand for integrin alpha4beta1 (VLA-4), mapped to residues 395-409; mature VWF additionally binds platelet integrin alphaIIb-beta3 via the RGD motif in C4. Reason: Integrin binding is a genuine VWF molecular function: the mature subunit binds alphaIIbbeta3 through its RGD cell attachment site (UniProt motif 2507-2509), and the propeptide binds alpha4beta1 as shown here. Accepted. Supporting Evidence: PMID:9079671 These results strongly suggest that pp-vWF is a novel physiological ligand for VLA-4. PMID:24928861 Platelet integrin Ξ± IIb Ξ² 3 binds an RGD motif in the VWC4 module |
| GO:0005201 extracellular matrix structural constituent | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: PAINT IBA propagation of ECM structural constituent to VWF from a broad node of the VWF-domain/mucin/SCO-spondin family (PTHR11339). Reason: GO:0005201 describes contribution to the structural integrity of the ECM. VWF is deposited into the subendothelial matrix and binds collagens, but its role there is that of an adhesive bridge that captures platelets under flow, not a load-bearing structural component of the matrix. VWD causes bleeding, not connective-tissue fragility. Matrisome classification ('ECM glycoprotein') is supported by the ECM location annotations instead. The PTN000885756 node spans diverse VWD-domain proteins; for VWF itself the adhesive bridging function is the better-supported description. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: PANTHER:PTN000885756 SUPPORTS SOURCE BUT NOT TARGET Broad VWD-domain family ancestor; a structural-matrix role may fit some descendants, but VWF's matrix role is adhesive bridging of platelets rather than structural integrity. MGI:MGI:1339364 SUPPORTS SOURCE BUT NOT TARGET Mouse family member providing the descendant evidence; its matrix role does not transfer as a structural function to VWF. Supporting Evidence: file:human/VWF/VWF-uniprot.txt it promotes adhesion of platelets to the sites of vascular injury by forming a molecular bridge between sub-endothelial collagen matrix and platelet-surface receptor complex GPIb-IX-V file:human/VWF/VWF-uniprot.txt Secreted, extracellular space, extracellular matrix |
| GO:0005201 extracellular matrix structural constituent | RCA PMID:23979707 SILAC-based proteomics of human primary endothelial cell mor... | MARK AS OVER ANNOTATED | Summary: RCA annotation derived from matrisome proteomics/classification, in which VWF is detected in ECM-enriched fractions. Reason: GO:0005201 describes contribution to the structural integrity of the ECM. VWF is deposited into the subendothelial matrix and binds collagens, but its role there is that of an adhesive bridge that captures platelets under flow, not a load-bearing structural component of the matrix. VWD causes bleeding, not connective-tissue fragility. Matrisome classification ('ECM glycoprotein') is supported by the ECM location annotations instead. Detection in an ECM-enriched proteome supports ECM location, not a structural molecular function. Supporting Evidence: PMID:23979707 a detailed proteomic profile of the extracellular matrix secreted by endothelial cells identified CLEC14A as a matrix component file:human/VWF/VWF-uniprot.txt it promotes adhesion of platelets to the sites of vascular injury by forming a molecular bridge between sub-endothelial collagen matrix and platelet-surface receptor complex GPIb-IX-V |
| GO:0005201 extracellular matrix structural constituent | RCA PMID:25037231 Extracellular matrix signatures of human primary metastatic ... | MARK AS OVER ANNOTATED | Summary: RCA annotation derived from matrisome proteomics/classification, in which VWF is detected in ECM-enriched fractions. Reason: GO:0005201 describes contribution to the structural integrity of the ECM. VWF is deposited into the subendothelial matrix and binds collagens, but its role there is that of an adhesive bridge that captures platelets under flow, not a load-bearing structural component of the matrix. VWD causes bleeding, not connective-tissue fragility. Matrisome classification ('ECM glycoprotein') is supported by the ECM location annotations instead. Detection in an ECM-enriched proteome supports ECM location, not a structural molecular function. Supporting Evidence: PMID:25037231 We have used enrichment of extracellular matrix (ECM) from human patient samples and proteomics to define the ECM composition file:human/VWF/VWF-uniprot.txt it promotes adhesion of platelets to the sites of vascular injury by forming a molecular bridge between sub-endothelial collagen matrix and platelet-surface receptor complex GPIb-IX-V |
| GO:0005201 extracellular matrix structural constituent | RCA PMID:28675934 Characterization of the Extracellular Matrix of Normal and D... | MARK AS OVER ANNOTATED | Summary: RCA annotation derived from matrisome proteomics/classification, in which VWF is detected in ECM-enriched fractions. Reason: GO:0005201 describes contribution to the structural integrity of the ECM. VWF is deposited into the subendothelial matrix and binds collagens, but its role there is that of an adhesive bridge that captures platelets under flow, not a load-bearing structural component of the matrix. VWD causes bleeding, not connective-tissue fragility. Matrisome classification ('ECM glycoprotein') is supported by the ECM location annotations instead. Detection in an ECM-enriched proteome supports ECM location, not a structural molecular function. Supporting Evidence: PMID:28675934 We provide here optimized protocols to solubilize ECM proteins from normal or tumor tissues file:human/VWF/VWF-uniprot.txt it promotes adhesion of platelets to the sites of vascular injury by forming a molecular bridge between sub-endothelial collagen matrix and platelet-surface receptor complex GPIb-IX-V |
| GO:0005515 protein binding | IPI PMID:11943773 Identification of the regulatory elements of the human von W... | MODIFY | Summary: Deletion mapping of regions flanking the A1 disulfide loop showed they regulate (inhibit) GPIb binding; interactor recorded is GP1BB (GPIb-IX-V complex). Reason: Generic protein binding is uninformative. The interaction with platelet GPIb (GP1BA/GP1BB, the GPIb-IX-V adhesion receptor) via the VWF A1 domain is the key adhesive interaction of VWF; it is better captured as cell adhesion molecule binding (GO:0050839), the term used for the analogous bridging ligand fibrinogen. The interaction itself is not in doubt. Proposed replacements: cell adhesion molecule binding Supporting Evidence: PMID:11943773 GPIb binding sites have been assigned in the VWF A1 domain |
| GO:0005515 protein binding | IPI PMID:12183630 Structures of glycoprotein Ibalpha and its complex with von ... | MODIFY | Summary: Crystal structure of the GPIbalpha N-terminal domain in complex with the VWF A1 domain. Reason: Generic protein binding is uninformative. The interaction with platelet GPIb (GP1BA/GP1BB, the GPIb-IX-V adhesion receptor) via the VWF A1 domain is the key adhesive interaction of VWF; it is better captured as cell adhesion molecule binding (GO:0050839), the term used for the analogous bridging ligand fibrinogen. The interaction itself is not in doubt. Proposed replacements: cell adhesion molecule binding Supporting Evidence: PMID:12183630 Here we present structures of the GpIbalpha amino-terminal domain and its complex with the VWF domain A1. |
| GO:0005515 protein binding | IPI PMID:15039442 Crystal structure of the wild-type von Willebrand factor A1-... | MODIFY | Summary: 2.6 A crystal structure of wild-type VWF A1 bound to GPIbalpha. Reason: Generic protein binding is uninformative. The interaction with platelet GPIb (GP1BA/GP1BB, the GPIb-IX-V adhesion receptor) via the VWF A1 domain is the key adhesive interaction of VWF; it is better captured as cell adhesion molecule binding (GO:0050839), the term used for the analogous bridging ligand fibrinogen. The interaction itself is not in doubt. Proposed replacements: cell adhesion molecule binding Supporting Evidence: PMID:15039442 The adhesion of platelets to the subendothelium of blood vessels at sites of vascular injury under high shear conditions is mediated by a direct interaction between the platelet receptor glycoprotein Ibalpha (GpIbalpha) and the A1 domain of the von Willebrand factor (VWF). |
| GO:0005515 protein binding | IPI PMID:16221672 ADAMTS13 substrate recognition of von Willebrand factor A2 d... | MODIFY | Summary: Binding of ADAMTS13 to VWF A2-domain fragments (SPR; KD 20 nM) and identification of A2 residues needed for recognition and cleavage. Reason: Generic protein binding is uninformative. The partner is the metalloprotease ADAMTS13, for which the more informative term protease binding (GO:0002020) exists and is already annotated; as VWF is the substrate this remains a non-core function. Proposed replacements: protease binding Supporting Evidence: PMID:16221672 Surface plasmon resonance demonstrated appreciable reduction in binding affinity between ADAMTS13 and VWF115 mutants |
| GO:0005515 protein binding | IPI PMID:16912226 A single high-affinity binding site for von Willebrand facto... | MODIFY | Summary: Mapping of a single high-affinity VWF-binding sequence (RGQOGVMGF) in collagen III using triple-helical peptides; binding is via VWF A3. Reason: Generic protein binding is uninformative; the partner is collagen type III (COL3A1), and the specific term collagen binding (GO:0005518) captures this core VWF function (A3 domain binding to fibrillar collagens). Proposed replacements: collagen binding Supporting Evidence: PMID:16912226 Thus, we identified the sequence RGQOGVMGF (O is hydroxyproline) as the minimal VWF-binding sequence in collagen III. |
| GO:0005515 protein binding | IPI PMID:18492805 Factor VIII accelerates proteolytic cleavage of von Willebra... | MODIFY | Summary: FVIII bound to VWF accelerates ADAMTS13 cleavage of VWF under shear; this depends on the high-affinity FVIII-VWF interaction (interactor F8). Reason: Generic protein binding is uninformative. VWF binds coagulation factor VIII with sub-nanomolar affinity through D'D3 and acts as its plasma carrier, delivering FVIII to platelet plugs and protecting it from clearance (loss in VWD type 2N/3 causes secondary FVIII deficiency). Protein carrier chaperone (GO:0140597; 'directly binding to a protein and delivering it either to an acceptor molecule or to a specific location') is the most informative available MF; GO has no specific factor VIII binding term. Proposed replacements: protein carrier chaperone Supporting Evidence: PMID:18492805 Our data suggest that FVIII plays a role in regulating proteolytic processing of VWF by ADAMTS13 under shear stress, which depends on the high-affinity interaction between FVIII and its carrier protein, VWF. |
| GO:0005515 protein binding | IPI PMID:18492805 Factor VIII accelerates proteolytic cleavage of von Willebra... | MODIFY | Summary: Same study, interactor ADAMTS13: VWF is cleaved by ADAMTS13 at Tyr1605-Met1606, accelerated by FVIII. Reason: Generic protein binding is uninformative. The partner is the metalloprotease ADAMTS13, for which the more informative term protease binding (GO:0002020) exists and is already annotated; as VWF is the substrate this remains a non-core function. Proposed replacements: protease binding Supporting Evidence: PMID:18492805 Proteolytic processing of von Willebrand factor (VWF) by ADAMTS13 metalloproteinase is crucial for normal hemostasis. |
| GO:0005515 protein binding | IPI PMID:25512528 Allosteric activation of ADAMTS13 by von Willebrand factor. | MODIFY | Summary: VWF binding to distal ADAMTS13 domains relieves ADAMTS13 autoinhibition (substrate-induced allosteric activation). Reason: Generic protein binding is uninformative. The partner is the metalloprotease ADAMTS13, for which the more informative term protease binding (GO:0002020) exists and is already annotated; as VWF is the substrate this remains a non-core function. The allosteric activation is a property of the substrate-enzyme encounter rather than an independent activator function of VWF. Proposed replacements: protease binding Supporting Evidence: PMID:25512528 We find that the distal T8-CUB2 domains markedly inhibit substrate cleavage, and binding of VWF or monoclonal antibodies to distal ADAMTS13 domains relieves this autoinhibition. |
| GO:0005515 protein binding | IPI PMID:27749002 Novel factor VIII variants with a modified furin cleavage si... | MODIFY | Summary: SPR measurement of affinities of furin-site-deleted FVIII variants for immobilized plasma VWF. Reason: Generic protein binding is uninformative. VWF binds coagulation factor VIII with sub-nanomolar affinity through D'D3 and acts as its plasma carrier, delivering FVIII to platelet plugs and protecting it from clearance (loss in VWD type 2N/3 causes secondary FVIII deficiency). Protein carrier chaperone (GO:0140597; 'directly binding to a protein and delivering it either to an acceptor molecule or to a specific location') is the most informative available MF; GO has no specific factor VIII binding term. Proposed replacements: protein carrier chaperone Supporting Evidence: PMID:27749002 The affinities of hFVIII variants for human plasmaβderived von Willebrand factor (VWF) were determined by surface plasmon resonance (SPR) |
| GO:0005515 protein binding | IPI PMID:2839553 Evidence that the primary binding site of von Willebrand fac... | MODIFY | Summary: Monoclonal antibody study of VWF binding to collagen types I and III versus endothelial matrix (interactor COL3A1). Reason: Generic protein binding is uninformative; the partner is collagen type III (COL3A1), and the specific term collagen binding (GO:0005518) captures this core VWF function (A3 domain binding to fibrillar collagens). Proposed replacements: collagen binding Supporting Evidence: PMID:2839553 CLB-RAg 201, an MAb against von Willebrand factor, completely inhibits the binding of von Willebrand factor to collagen type I and type III. |
| GO:0005515 protein binding | IPI PMID:7721887 Identification of three tyrosine residues of glycoprotein Ib... | MODIFY | Summary: Mutational analysis of sulfated tyrosines in GPIbalpha required for VWF (and thrombin) binding. Reason: Generic protein binding is uninformative. The interaction with platelet GPIb (GP1BA/GP1BB, the GPIb-IX-V adhesion receptor) via the VWF A1 domain is the key adhesive interaction of VWF; it is better captured as cell adhesion molecule binding (GO:0050839), the term used for the analogous bridging ligand fibrinogen. The interaction itself is not in doubt. Proposed replacements: cell adhesion molecule binding Supporting Evidence: PMID:7721887 The interaction between von Willebrand factor (vWF) and the platelet membrane glycoprotein (GP) Ib-IX-V complex is essential for platelet adhesion at sites of vascular injury under high shear stress flow conditions. |
| GO:0005515 protein binding | IPI PMID:7756647 The affinity and stoichiometry of binding of human factor VI... | MODIFY | Summary: Equilibrium binding of FVIII to immobilized and fluid-phase VWF (Kd about 0.2-0.3 nM). Reason: Generic protein binding is uninformative. VWF binds coagulation factor VIII with sub-nanomolar affinity through D'D3 and acts as its plasma carrier, delivering FVIII to platelet plugs and protecting it from clearance (loss in VWD type 2N/3 causes secondary FVIII deficiency). Protein carrier chaperone (GO:0140597; 'directly binding to a protein and delivering it either to an acceptor molecule or to a specific location') is the most informative available MF; GO has no specific factor VIII binding term. Proposed replacements: protein carrier chaperone Supporting Evidence: PMID:7756647 the dissociation constants (kd) for binding of factor VIII to vWF were 0.21 +/- 0.04 and 0.22 +/- 0.05 nmol/L PMID:9759493 VWF also is a carrier protein for blood clotting factor VIII, and this interaction is required for normal factor VIII survival in the circulation. |
| GO:0005515 protein binding | IPI PMID:8562925 The defective interaction between von Willebrand factor and ... | MODIFY | Summary: VWD patient mutations R19W/H54Q in the D' FVIII-binding domain impair binding of FVIII (interactor: FVIII heavy chain). Reason: Generic protein binding is uninformative. VWF binds coagulation factor VIII with sub-nanomolar affinity through D'D3 and acts as its plasma carrier, delivering FVIII to platelet plugs and protecting it from clearance (loss in VWD type 2N/3 causes secondary FVIII deficiency). Protein carrier chaperone (GO:0140597; 'directly binding to a protein and delivering it either to an acceptor molecule or to a specific location') is the most informative available MF; GO has no specific factor VIII binding term. Proposed replacements: protein carrier chaperone Supporting Evidence: PMID:8562925 confirms that the combined R19W and H54Q substitutions are the cause of the defective vWF/FVIII interaction in this patient PMID:9759493 VWF also is a carrier protein for blood clotting factor VIII, and this interaction is required for normal factor VIII survival in the circulation. |
| GO:0005518 collagen binding | IDA PMID:2056120 150-kD von Willebrand factor binding protein extracted from ... | ACCEPT | Summary: VWF binds type VI collagen extracted from vascular subendothelium; VWF also binds fibrillar collagens I and III through its A3 domain. Reason: Collagen binding is a core VWF activity that anchors VWF at sites of vascular injury so it can capture platelets. Supporting Evidence: PMID:2056120 Furthermore, we found that purified type VI collagen also bound vWF. file:human/VWF/VWF-uniprot.txt it promotes adhesion of platelets to the sites of vascular injury by forming a molecular bridge between sub-endothelial collagen matrix and platelet-surface receptor complex GPIb-IX-V |
| GO:0005576 extracellular region | HDA PMID:27068509 Extracellular matrix remodelling in response to venous hyper... | ACCEPT | Summary: Proteomic detection of VWF in ECM extracts of human veins. Reason: VWF is a secreted plasma and subendothelial matrix protein; extracellular region is correct. Supporting Evidence: PMID:27068509 Extracellular matrix proteins were enriched from venous tissues. file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | IDA PMID:10887119 A novel von Willebrand disease-causing mutation (Arg273Trp) ... | ACCEPT | Summary: Recombinant VWF is secreted from COS-7 cells; the R273W propeptide mutation impairs secretion. Reason: VWF is a secreted protein; extracellular region is correct. Supporting Evidence: PMID:10887119 Pulse-chase experiments showed that secretion of rVWFR273W was severely impaired compared with wild-type rVWF. file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic mapping from UniProt subcellular location (Secreted). Reason: Consistent with VWF being a secreted plasma protein. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | NAS PMID:14718574 The human plasma proteome: a nonredundant list developed by ... | ACCEPT | Summary: VWF is listed in the human plasma proteome. Reason: VWF circulates in plasma; extracellular region is correct. Supporting Evidence: PMID:14718574 We have merged four different views of the human plasma proteome, based on different methodologies, into a single nonredundant list of 1175 distinct gene products. file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-114670 | ACCEPT | Summary: Reactome (Reactome:R-HSA-114670) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-114671 | ACCEPT | Summary: Reactome (Reactome:R-HSA-114671) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-158118 | ACCEPT | Summary: Reactome (Reactome:R-HSA-158118) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-158137 | ACCEPT | Summary: Reactome (Reactome:R-HSA-158137) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-216072 | ACCEPT | Summary: Reactome (Reactome:R-HSA-216072) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-265425 | ACCEPT | Summary: Reactome (Reactome:R-HSA-265425) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-354066 | ACCEPT | Summary: Reactome (Reactome:R-HSA-354066) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-354073 | ACCEPT | Summary: Reactome (Reactome:R-HSA-354073) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-354087 | ACCEPT | Summary: Reactome (Reactome:R-HSA-354087) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-354124 | ACCEPT | Summary: Reactome (Reactome:R-HSA-354124) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-354149 | ACCEPT | Summary: Reactome (Reactome:R-HSA-354149) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-354165 | ACCEPT | Summary: Reactome (Reactome:R-HSA-354165) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-372693 | ACCEPT | Summary: Reactome (Reactome:R-HSA-372693) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-372697 | ACCEPT | Summary: Reactome (Reactome:R-HSA-372697) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-372705 | ACCEPT | Summary: Reactome (Reactome:R-HSA-372705) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-377640 | ACCEPT | Summary: Reactome (Reactome:R-HSA-377640) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-377641 | ACCEPT | Summary: Reactome (Reactome:R-HSA-377641) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-377643 | ACCEPT | Summary: Reactome (Reactome:R-HSA-377643) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-377644 | ACCEPT | Summary: Reactome (Reactome:R-HSA-377644) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-429415 | ACCEPT | Summary: Reactome (Reactome:R-HSA-429415) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-429441 | ACCEPT | Summary: Reactome (Reactome:R-HSA-429441) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-429529 | ACCEPT | Summary: Reactome (Reactome:R-HSA-429529) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-430073 | ACCEPT | Summary: Reactome (Reactome:R-HSA-430073) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-430076 | ACCEPT | Summary: Reactome (Reactome:R-HSA-430076) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-430096 | ACCEPT | Summary: Reactome (Reactome:R-HSA-430096) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-443402 | ACCEPT | Summary: Reactome (Reactome:R-HSA-443402) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-443418 | ACCEPT | Summary: Reactome (Reactome:R-HSA-443418) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-481007 | ACCEPT | Summary: Reactome (Reactome:R-HSA-481007) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9665809 | ACCEPT | Summary: Reactome (Reactome:R-HSA-9665809) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9666383 | ACCEPT | Summary: Reactome (Reactome:R-HSA-9666383) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9822522 | ACCEPT | Summary: Reactome (Reactome:R-HSA-9822522) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9822532 | ACCEPT | Summary: Reactome (Reactome:R-HSA-9822532) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9822539 | ACCEPT | Summary: Reactome (Reactome:R-HSA-9822539) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9822734 | ACCEPT | Summary: Reactome (Reactome:R-HSA-9822734) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9823065 | ACCEPT | Summary: Reactome (Reactome:R-HSA-9823065) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9823593 | ACCEPT | Summary: Reactome (Reactome:R-HSA-9823593) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9823706 | ACCEPT | Summary: Reactome (Reactome:R-HSA-9823706) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9824402 | ACCEPT | Summary: Reactome (Reactome:R-HSA-9824402) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9844241 | ACCEPT | Summary: Reactome (Reactome:R-HSA-9844241) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9844251 | ACCEPT | Summary: Reactome (Reactome:R-HSA-9844251) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-9934645 | ACCEPT | Summary: Reactome (Reactome:R-HSA-9934645) places VWF in the extracellular region as a participant in hemostasis-related reactions (platelet adhesion, ADAMTS13 cleavage, FVIII binding or alpha-granule release). Reason: VWF acts extracellularly in plasma and on the subendothelium; the Reactome location is correct. Supporting Evidence: file:human/VWF/VWF-uniprot.txt SUBCELLULAR LOCATION: Secreted |
| GO:0005783 endoplasmic reticulum | IDA PMID:6754744 Immunolocalization of von Willebrand protein in Weibel-Palad... | KEEP AS NON CORE | Summary: Immunoperoxidase EM detected VWF in the endoplasmic reticulum of endothelial cells, along with Weibel-Palade bodies and ECM filaments. Reason: The ER is a biosynthetic transit compartment where pro-VWF dimerizes; correct but not where VWF functions. Supporting Evidence: PMID:6754744 Thin sections of the peroxidase-stained cells showed decorated filaments close to the substratum and also specific deposits in the endoplasmic reticulum and Weibel-Palade bodies. |
| GO:0007155 cell adhesion | IDA PMID:10764791 Mapping the glycoprotein Ib-binding site in the von willebra... | MODIFY | Summary: Recombinant VWF A1 domain supports flow-dependent platelet adhesion; A1 mutations mapping the GPIb site reduce adhesion. Reason: Correct but general. The assay measures platelet adhesion to an immobilized VWF substrate, which is cell-substrate adhesion (GO:0031589), the term already supported by IBA for VWF. Proposed replacements: cell-substrate adhesion Supporting Evidence: PMID:10764791 The von Willebrand factor (vWF) mediates platelet adhesion to exposed subendothelium at sites of vascular injury. |
| GO:0007596 blood coagulation | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA for blood coagulation at the VWF subfamily node (PTN002602369), grounded in human and mouse VWF experimental data. Reason: VWF contributes to coagulation both by forming the primary platelet plug scaffold and by carrying and stabilizing FVIII, an essential cofactor of the intrinsic tenase; VWD type 3 causes secondary FVIII deficiency. The IBA node placement within the VWF clade is sound. Supporting Evidence: PMID:9759493 VWF also is a carrier protein for blood clotting factor VIII, and this interaction is required for normal factor VIII survival in the circulation. PMID:9759493 Von Willebrand factor (VWF) is a blood glycoprotein that is required for normal hemostasis file:human/VWF/VWF-deep-research-falcon.md region binds FVIII and protects it from premature clearance and proteolysis; VWF deficiency consequently lowers circulating FVIII. |
| GO:0007596 blood coagulation | IMP PMID:16409464 Mutations C1157F and C1234W of von Willebrand factor cause i... | ACCEPT | Summary: VWD mutations C1157F/C1234W in D3 cause defective multimerization, intracellular retention and reduced secretion, with low plasma VWF. Reason: Loss-of-function variants causing von Willebrand disease (a bleeding disorder) support VWF involvement in blood coagulation/hemostasis. Supporting Evidence: PMID:16409464 We identified heterozygous substitutions, C1157F and C1234W, in the VWF D3 domain in two unrelated families with unclassified and type 2A von Willebrand disease PMID:9759493 Von Willebrand factor (VWF) is a blood glycoprotein that is required for normal hemostasis |
| GO:0007599 hemostasis | IMP PMID:10887119 A novel von Willebrand disease-causing mutation (Arg273Trp) ... | ACCEPT | Summary: Homozygous R273W propeptide mutation causes VWF deficiency (VWD types 1/3) via defective multimerization and secretion. Reason: Hemostasis is the central biological process of VWF; VWD is the most common inherited bleeding disorder. Supporting Evidence: PMID:10887119 We concluded that the R273W mutation is responsible for the quantitative VWF deficiencies and aberrant multimer patterns observed in the affected family members. PMID:9759493 Von Willebrand factor (VWF) is a blood glycoprotein that is required for normal hemostasis |
| GO:0009611 response to wounding | TAS PMID:15029268 Platelet and von Willebrand factor interactions at the vesse... | KEEP AS NON CORE | Summary: Review of platelet-VWF interactions at the vessel wall in haemostasis and thrombosis. Reason: Response to wounding is a broad parent context; VWF acts in hemostasis after vascular injury, which is better captured by the hemostasis annotations. Retained as non-core. Supporting Evidence: PMID:15029268 The process of platelet thrombus formation contributes to the haemostatic response that prevents excessive blood loss after tissue injury |
| GO:0019865 immunoglobulin binding | IDA PMID:3121636 The relationship of N-linked glycosylation and heavy chain-b... | MODIFY | Summary: The cited study shows that VWF associates transiently with BiP (immunoglobulin heavy chain binding protein) in the ER of CHO cells; no immunoglobulin binding was assayed. Reason: The abstract explicitly states the measured interaction is with BiP, the ER Hsp70 chaperone historically named 'heavy chain binding protein'. Binding to BiP is chaperone binding, not binding to an immunoglobulin (GO:0019865). The interaction is correctly captured by protein-folding chaperone binding (GO:0051087), itself a non-core client property of VWF. Proposed replacements: protein-folding chaperone binding Supporting Evidence: PMID:3121636 vWF was transiently associated with BiP and efficiently secreted demonstrating that CHO cells are competent to secrete a highly glycosylated protein. |
| GO:0030168 platelet activation | IDA PMID:8565074 Initiation of platelet adhesion by arrest onto fibrinogen or... | KEEP AS NON CORE | Summary: GPIbalpha binding to immobilized VWF supports platelet translocation at high shear, allowing activated alphaIIb-beta3 to arrest platelets on VWF. Reason: VWF engagement of GPIb-IX-V triggers platelet signaling and integrin activation, so VWF contributes to platelet activation as an extracellular ligand. The primary VWF role is adhesion/bridging, so this is retained as non-core. Supporting Evidence: PMID:8565074 This eventually allows activated alpha IIb beta 3 to arrest platelets onto vWF under conditions not permissive of direct binding to fibrinogen. |
| GO:0030168 platelet activation | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA electronic annotation to platelet activation. Reason: Consistent with VWF acting as a GPIb-IX-V ligand that elicits platelet signaling; non-core relative to adhesion/bridging. Supporting Evidence: PMID:12871509 The interaction between von Willebrand factor (VWF) and glycoprotein (GP) Ib results in platelet agglutination and activation of many signaling intermediates. |
| GO:0030168 platelet activation | NAS PMID:12871509 von Willebrand factor (VWF)-dependent human platelet activat... | KEEP AS NON CORE | Summary: VWF-GPIb-dependent platelet activation (alpha granule and lysosomal release) using porcine VWF requires protein phosphatases. Reason: VWF is the agonist ligand; supports involvement in platelet activation, non-core. Supporting Evidence: PMID:12871509 The interaction between von Willebrand factor (VWF) and glycoprotein (GP) Ib results in platelet agglutination and activation of many signaling intermediates. |
| GO:0031012 extracellular matrix | HDA PMID:23979707 SILAC-based proteomics of human primary endothelial cell mor... | ACCEPT | Summary: VWF detected in ECM-enriched proteomic fractions. Reason: VWF is deposited into the subendothelial/endothelial ECM, where it is positioned to capture platelets upon injury; ECM location is correct. Supporting Evidence: PMID:23979707 a detailed proteomic profile of the extracellular matrix secreted by endothelial cells identified CLEC14A as a matrix component file:human/VWF/VWF-uniprot.txt Secreted, extracellular space, extracellular matrix |
| GO:0031012 extracellular matrix | HDA PMID:25037231 Extracellular matrix signatures of human primary metastatic ... | ACCEPT | Summary: VWF detected in ECM-enriched proteomic fractions. Reason: VWF is deposited into the subendothelial/endothelial ECM, where it is positioned to capture platelets upon injury; ECM location is correct. Supporting Evidence: PMID:25037231 We have used enrichment of extracellular matrix (ECM) from human patient samples and proteomics to define the ECM composition file:human/VWF/VWF-uniprot.txt Secreted, extracellular space, extracellular matrix |
| GO:0031012 extracellular matrix | HDA PMID:28675934 Characterization of the Extracellular Matrix of Normal and D... | ACCEPT | Summary: VWF detected in ECM-enriched proteomic fractions. Reason: VWF is deposited into the subendothelial/endothelial ECM, where it is positioned to capture platelets upon injury; ECM location is correct. Supporting Evidence: PMID:28675934 We provide here optimized protocols to solubilize ECM proteins from normal or tumor tissues file:human/VWF/VWF-uniprot.txt Secreted, extracellular space, extracellular matrix |
| GO:0031012 extracellular matrix | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA: extracellular matrix (is_active_in) for the VWD-domain family node, with human VWF among the experimental sources. Reason: VWF binds collagen and is retained in the subendothelial matrix, the site at which it supports platelet adhesion. The human VWF appearing among sources reflects its own experimental grounding. Supporting Evidence: file:human/VWF/VWF-uniprot.txt Secreted, extracellular space, extracellular matrix PMID:6754744 on filaments of the extracellular matrix |
| GO:0031012 extracellular matrix | IDA PMID:6754744 Immunolocalization of von Willebrand protein in Weibel-Palad... | ACCEPT | Summary: Immunofluorescence shows VWF on filaments of the endothelial extracellular matrix. Reason: Direct observation of VWF in endothelial ECM. Supporting Evidence: PMID:6754744 on filaments of the extracellular matrix |
| GO:0031091 platelet alpha granule | NAS PMID:9759493 Biochemistry and genetics of von Willebrand factor. | ACCEPT | Summary: Review stating VWF storage; VWF synthesized by megakaryocytes is stored in platelet alpha granules. Reason: Platelet alpha granules are one of the two storage pools of VWF (with Weibel-Palade bodies); well established. Supporting Evidence: PMID:9759493 Mutations in VWD can disrupt this complex biosynthetic process at several steps to impair the assembly, intracellular targeting, or secretion of VWF multimers. file:human/VWF/VWF-uniprot.txt Note=Localized to storage granules. |
| GO:0031093 platelet alpha granule lumen | TAS Reactome:R-HSA-481007 | ACCEPT | Summary: Reactome: VWF is among alpha-granule cargo released on platelet activation. Reason: VWF is a soluble cargo of the platelet alpha granule lumen. Supporting Evidence: file:human/VWF/VWF-uniprot.txt Note=Localized to storage granules. |
| GO:0031589 cell-substrate adhesion | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA for cell-substrate adhesion at the VWF subfamily node, with human VWF as an experimental source. Reason: VWF immobilized on collagen/subendothelium mediates adhesion of platelets to the injured vessel wall; this is the core adhesive process of VWF. Supporting Evidence: file:human/VWF/VWF-uniprot.txt it promotes adhesion of platelets to the sites of vascular injury by forming a molecular bridge between sub-endothelial collagen matrix and platelet-surface receptor complex GPIb-IX-V PMID:9759493 VWF mediates the adhesion of platelets to sites of vascular damage by binding to specific platelet membrane glycoproteins and to constituents of exposed connective tissue. |
| GO:0031589 cell-substrate adhesion | IDA PMID:9079671 Propolypeptide of von Willebrand factor is a novel ligand fo... | ACCEPT | Summary: Cells expressing alpha4beta1 adhere to the immobilized VWF propeptide. Reason: Correct: cells adhere to immobilized VWF propeptide via alpha4beta1. Cell-substrate adhesion is a core VWF process (platelet adhesion to subendothelium-bound VWF); this assay concerns the propeptide and leukocyte/melanoma cells, but the term is accepted consistently with the IBA/IEA rows. Supporting Evidence: PMID:9079671 Human leukemia cell lines that express alpha4beta1 integrin (very late antigen-4, VLA-4), but not cell lines which lack VLA-4, attached well to pp-vWF substrate |
| GO:0031589 cell-substrate adhesion | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA electronic annotation to cell-substrate adhesion. Reason: Consistent with VWF-mediated platelet adhesion to subendothelium. Supporting Evidence: file:human/VWF/VWF-uniprot.txt it promotes adhesion of platelets to the sites of vascular injury by forming a molecular bridge between sub-endothelial collagen matrix and platelet-surface receptor complex GPIb-IX-V |
| GO:0033093 Weibel-Palade body | IDA PMID:3082891 Initial glycosylation and acidic pH in the Golgi apparatus a... | ACCEPT | Summary: Weak base treatment disrupted targeting of newly synthesized VWF into Weibel-Palade bodies in HUVECs. Reason: Weibel-Palade bodies are the endothelial storage organelle of VWF, whose biogenesis VWF itself drives. Supporting Evidence: PMID:3082891 the weak base interfered with the targeting of newly synthesized vWf into Weibel-Palade bodies |
| GO:0033093 Weibel-Palade body | IDA PMID:3087627 Inducible secretion of large, biologically potent von Willeb... | ACCEPT | Summary: Very large VWF multimers are stored in and released from Weibel-Palade bodies on stimulation. Reason: Core storage location of VWF. Supporting Evidence: PMID:3087627 Endothelial cells therefore concentrate a special subclass of very large and biologically potent vWf multimers in Weibel-Palade bodies |
| GO:0033093 Weibel-Palade body | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA electronic annotation to Weibel-Palade body. Reason: Consistent with experimental data. Supporting Evidence: PMID:6754744 These data suggest that the Weibel-Palade bodies of endothelial cells are storage and/or processing organelles for von Willebrand protein. |
| GO:0042802 identical protein binding | IPI PMID:10887119 A novel von Willebrand disease-causing mutation (Arg273Trp) ... | ACCEPT | Summary: VWF forms dimers in the ER; R273W impairs multimerization but not dimerization. Reason: VWF self-association (CTCK-mediated dimerization in the ER, D3-mediated disulfide multimerization in the Golgi, and pH-dependent tubular packing) is essential for its hemostatic activity, since only large multimers are fully active. Supporting Evidence: PMID:10887119 However, the mutation did not affect the ability of VWF to form dimers in the endoplasmic reticulum (ER). PMID:17895385 Von Willebrand factor (VWF) dimerizes through C-terminal CK domains, and VWF dimers assemble into multimers in the Golgi by forming intersubunit disulfide bonds between D3 domains. |
| GO:0042802 identical protein binding | IPI PMID:16409464 Mutations C1157F and C1234W of von Willebrand factor cause i... | ACCEPT | Summary: D3 cysteine mutations impair VWF multimerization. Reason: VWF self-association (CTCK-mediated dimerization in the ER, D3-mediated disulfide multimerization in the Golgi, and pH-dependent tubular packing) is essential for its hemostatic activity, since only large multimers are fully active. Supporting Evidence: PMID:16409464 The D3 domain of von Willebrand factor (VWF) is involved in the multimerization process of the protein through the formation of disulfide bridges. |
| GO:0042802 identical protein binding | IPI PMID:17895385 Two Cys residues essential for von Willebrand factor multime... | ACCEPT | Summary: Cys1099 and Cys1142 are essential for D3-D3 intersubunit disulfide bonding during VWF multimer assembly. Reason: VWF self-association (CTCK-mediated dimerization in the ER, D3-mediated disulfide multimerization in the Golgi, and pH-dependent tubular packing) is essential for its hemostatic activity, since only large multimers are fully active. Supporting Evidence: PMID:17895385 Therefore, Cys(1099) and Cys(1142) are essential for the oxidoreductase mechanism of VWF multimerization. |
| GO:0042802 identical protein binding | IPI PMID:18182488 Assembly of Weibel-Palade body-like tubules from N-terminal ... | ACCEPT | Summary: Propeptide (D1D2) and D'D3 dimers assemble into helical tubules in vitro at low pH with Ca2+. Reason: VWF self-association (CTCK-mediated dimerization in the ER, D3-mediated disulfide multimerization in the Golgi, and pH-dependent tubular packing) is essential for its hemostatic activity, since only large multimers are fully active. Supporting Evidence: PMID:18182488 tubules contain a repeating unit of one D'D3 dimer and two propeptides arranged in a right-handed helix with 4.2 units per turn |
| GO:0042802 identical protein binding | IPI PMID:18492805 Factor VIII accelerates proteolytic cleavage of von Willebra... | ACCEPT | Summary: VWF self-association recorded in an ADAMTS13 cleavage study using VWF multimers. Reason: VWF self-association (CTCK-mediated dimerization in the ER, D3-mediated disulfide multimerization in the Golgi, and pH-dependent tubular packing) is essential for its hemostatic activity, since only large multimers are fully active. Supporting Evidence: PMID:18492805 Multimer analysis reveals that FVIII preferentially accelerates the cleavage of high-molecular-weight multimers. PMID:17895385 Von Willebrand factor (VWF) dimerizes through C-terminal CK domains, and VWF dimers assemble into multimers in the Golgi by forming intersubunit disulfide bonds between D3 domains. |
| GO:0042802 identical protein binding | IPI PMID:21857647 A pH-regulated dimeric bouquet in the structure of von Wille... | ACCEPT | Summary: EM structure of the C-terminal dimeric bouquet of VWF at acidic pH. Reason: VWF self-association (CTCK-mediated dimerization in the ER, D3-mediated disulfide multimerization in the Golgi, and pH-dependent tubular packing) is essential for its hemostatic activity, since only large multimers are fully active. Supporting Evidence: PMID:21857647 At the acidic pH of the trans-Golgi and Weibel-Palade bodies (WPBs), but not at the alkaline pH of secretion, the C-terminal βΌ1350 residues of von Willebrand factor (VWF) zip up into an elongated, dimeric bouquet. |
| GO:0051087 protein-folding chaperone binding | IDA PMID:10887119 A novel von Willebrand disease-causing mutation (Arg273Trp) ... | KEEP AS NON CORE | Summary: VWF associates with ER chaperones BiP, Grp94, ERp72, calnexin and calreticulin during biosynthesis. Reason: VWF is a client of ER folding chaperones; the binding is real but reflects its folding/quality control, not a function it performs. Non-core. Supporting Evidence: PMID:10887119 The R273W mutation did not affect the ability of VWF to bind to BiP, Grp94, ERp72, calnexin, and calreticulin in COS-7 cells. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | MARK AS OVER ANNOTATED | Summary: VWF detected in the urinary exosome proteome. Reason: High-throughput detection of an abundant plasma protein in urinary vesicle preparations does not indicate a functional exosomal location for VWF. Supporting Evidence: PMID:19056867 Here, we used LC-MS/MS to profile the proteome of human urinary exosomes. |
| GO:0140149 non-collagenous component of interstitial matrix | TAS PMID:36399478 MatrisomeDB 2.0: 2023 updates to the ECM-protein knowledge d... | KEEP AS NON CORE | Summary: MatrisomeDB classification of VWF as a non-collagenous ECM glycoprotein. Reason: VWF is a matrisome glycoprotein deposited in subendothelial matrix; the location is acceptable but subsidiary to the broader ECM and secreted locations. Supporting Evidence: PMID:36399478 Over the past decade, mass-spectrometry-based proteomics has become the method of choice to profile the composition of the ECM, or the matrisome, of tissues. file:human/VWF/VWF-uniprot.txt Secreted, extracellular space, extracellular matrix |
| GO:1902533 positive regulation of intracellular signal transduction | IDA PMID:14656219 Glycoproteins VI and Ib-IX-V stimulate tyrosine phosphorylat... | KEEP AS NON CORE | Summary: VWF (with botrocetin) engaging GPIb-IX-V stimulates tyrosine phosphorylation of Syk and PLCgamma2 in platelets. Reason: VWF acts as the extracellular ligand that initiates GPIb-IX-V signaling; regulation of intracellular signal transduction is a downstream consequence in platelets rather than a core VWF function. Supporting Evidence: PMID:14656219 Glycoproteins GPVI and GPIb-IX-V stimulate robust tyrosine phosphorylation of Syk and PLCg2 (phospholipase Cg2) in washed platelets |
| GO:0070527 platelet aggregation | TAS PMID:24928861 von Willebrand factor, Jedi knight of the bloodstream. | NEW | Summary: VWF bridges platelets under high shear: GPIbalpha binding to A1 and alphaIIb-beta3 binding to the C4 RGD motif allow multimeric VWF to link platelets together. Reason: VWF itself performs the bridging step (as fibrinogen does at low shear); fibrinogen chains FGA/FGB/FGG carry GO:0070527 by IDA/IBA in GOA, so this is not a substrate-type case but the same ligand-bridge role. VWD causes impaired platelet aggregation. Supporting Evidence: PMID:24928861 Extension above a threshold shear correlates with activation of VWF-dependent aggregation of platelets in stirred cuvettes PMID:24928861 Platelet integrin Ξ± IIb Ξ² 3 binds an RGD motif in the VWC4 module file:human/VWF/VWF-uniprot.txt resulting in impaired platelet aggregation |
| GO:0050821 protein stabilization | TAS PMID:9759493 Biochemistry and genetics of von Willebrand factor. | NEW | Summary: VWF binds and stabilizes coagulation factor VIII in plasma, protecting it from premature clearance. Reason: The stabilizing work is done by VWF itself (binding FVIII via D'D3); without VWF (VWD type 3) or with FVIII-binding mutations (type 2N), FVIII survival is reduced. This complements the proposed protein carrier chaperone MF. Supporting Evidence: PMID:9759493 VWF also is a carrier protein for blood clotting factor VIII, and this interaction is required for normal factor VIII survival in the circulation. file:human/VWF/VWF-uniprot.txt stabilizing its heterodimeric structure and protecting it from premature clearance from plasma PMID:24928861 binding to and stabilization of FVIII |
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Download this section (compressed HTML)Q: Should GO have a specific 'coagulation factor VIII binding' molecular function term (or is protein carrier chaperone the intended home) for VWF D'D3 binding to FVIII?
Q: Is GO:0005201 extracellular matrix structural constituent appropriate at PANTHER node PTN000885756 for VWF, given that VWF's matrix role is adhesive bridging rather than structural integrity?
Q: How exactly does elongational force convert A1 into a high-affinity GPIb-alpha binding state in full-length multimers in vivo, and which autoinhibitory modules are released?
Q: Does VWF act directly in endothelial angiogenic signaling (e.g. via integrin alphaVbeta3 or VEGFR2), or is the angiogenic phenotype of VWF deficiency an indirect consequence of disrupted Weibel-Palade body storage of angiopoietin-2?
Q: What is the physiological role, if any, of the circulating VWF propeptide binding to integrin alpha4beta1 on leukocytes?
Experiment: Single-molecule force spectroscopy (optical tweezers) on full-length VWF and A1 flanking-region mutants, measuring GPIb-alpha bond lifetimes as a function of force.
Hypothesis: Tensile force on VWF multimers relieves A1 autoinhibition by flanking sequences, increasing GPIb-alpha affinity.
Type: biophysics
Experiment: Cryo-EM of the full FVIII-D'D3 complex combined with mouse Vwf knock-in of type 2N variants to correlate interface disruption with FVIII half-life.
Hypothesis: The D'D3 interface for FVIII is the determinant of FVIII plasma survival.
Type: structural biology
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