VWF (von Willebrand factor) — curation notes

UniProt: P04275 (VWF_HUMAN). 2813 aa precursor: signal peptide (1-22), propeptide
"von Willebrand antigen 2" / VWFpp (23-763; domains D1D2), mature VWF (764-2813;
D'D3-A1-A2-A3-D4-C1..C6-CTCK).

Deep research status

• just deep-research-falcon human VWF was launched in parallel with
  just fetch-gene-pmids human VWF (see bottom of this file for outcome).
• Literature below is from cached publications/PMID_*.md (mostly abstract-only) and
  the UniProt record.

Core biology (with provenance)

• Function summary: [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"]
• FVIII carrier: [file:human/VWF/VWF-uniprot.txt "Also acts as a chaperone for coagulation factor VIII, delivering it to the site of injury"]; PMID:9759493
• FVIII binding is high-affinity: PMID:7756647; D'D3 is the FVIII-binding region PMID:24928861; type 2N-like mutations R19W/H54Q (mature numbering) impair FVIII binding PMID:8562925.
• GPIb binding via A1 domain: PMID:10764791; crystal structures of A1–GPIbα [PMID:12183630, PMID:15039442]. Binding is shear/modulator-regulated PMID:11943773.
• Collagen binding: A3 is main site for collagen I/III [file:human/VWF/VWF-uniprot.txt "VWFA 3; main binding site for collagens type I and"]; collagen III site RGQOGVMGF PMID:16912226; collagen VI in subendothelium PMID:2056120.
• Integrin binding: αIIbβ3 binds RGD in C4 PMID:24928861; propeptide binds α4β1 (VLA-4) PMID:9079671.
• Platelet capture under high shear: PMID:8565074; aggregation at high shear PMID:24928861.
• Platelet signaling downstream of VWF–GPIb: PMID:12871509; PMID:14656219 GPIb-IX-V-driven Syk/PLCγ2 phosphorylation.

Biosynthesis, multimerization, storage

• Dimerization (CTCK, ER) and multimerization (D3, Golgi), propeptide acts as pH-dependent oxidoreductase/chaperone: PMID:17895385; Cys1099/Cys1142 essential.
• Low pH and Ca2+ drive tubule assembly of D1D2 + D'D3 in WPB PMID:18182488; C-terminal dimeric bouquet at acidic pH PMID:21857647.
• ER chaperone clients: binds BiP, Grp94, ERp72, calnexin, calreticulin PMID:10887119; transient BiP association PMID:3121636. NB: the GO "immunoglobulin binding" annotation from PMID:3121636 appears to derive from BiP's alias "heavy chain binding protein" — VWF was shown to associate with BiP, not immunoglobulin.
• Storage in endothelial Weibel–Palade bodies [PMID:6754744; PMID:3082891; PMID:3087627 "Endothelial cells therefore concentrate a special subclass of very large and biologically potent vWf multimers in Weibel-Palade bodies"]; also platelet alpha granules [PMID:9759493 review; Reactome R-HSA-481007].
• Deposited in subendothelial / endothelial ECM [PMID:6754744 "on filaments of the extracellular matrix"; PMID:2839553].

Regulation by ADAMTS13

• ADAMTS13 cleaves Tyr1605-Met1606 in A2 PMID:16221672; binding Kd 14 nM, spacer domain required PMID:15824096; A3/A1 docking under flow PMID:12775718; VWF allosterically activates ADAMTS13 PMID:25512528; FVIII accelerates cleavage PMID:18492805. VWF is the substrate; "protease binding" is true but not a core function of VWF.

Disease

• von Willebrand disease types 1, 2 (2A, 2B, 2M, 2N), 3 (UniProt). Type 3 also causes FVIII deficiency (loss of carrier function).

Curation decisions summary

• Core MF: collagen binding; cell adhesion molecule binding (GPIbα — replaces protein binding rows); integrin binding; protein carrier chaperone for FVIII (replaces protein binding rows with F8); identical protein binding (multimerization).
• Core BP: hemostasis / blood coagulation; cell-substrate adhesion (platelet adhesion to injured vessel); NEW platelet aggregation (comparator: fibrinogen FGA/FGB/FGG carry GO:0070527 as bridging ligands; VWF performs the bridging); NEW protein stabilization (VWF itself protects FVIII from clearance).
• Core CC: extracellular region, Weibel-Palade body, platelet alpha granule, extracellular matrix.
• ECM structural constituent: over-annotation (VWF is adhesive bridge, not a structural-integrity component).
• Immunoglobulin binding: MODIFY to protein-folding chaperone binding (BiP).
• Note: GO:0005615 extracellular space is obsolete in current GO (verified via QuickGO 2026-10), so not proposed.

Deep research outcome

• Falcon deep research succeeded: VWF-deep-research-falcon.md (2026-10-05). Its synthesis
  agrees with the decisions above (adhesive scaffold + FVIII carrier, not an enzyme; TIL/CK
  modules are structural folds, no protease-inhibitor activity; A1 also contributes to WPB tubule
  geometry; angiogenic roles via WPB/Ang-2 are secondary and mechanistically unresolved).
  It reports ~0.5 nM FVIII Kd and >95% of plasma FVIII VWF-bound (citing Lenting et al. 2024 Blood,
  doi:10.1182/blood.2023023277 — not cached here, so not used as supporting text).
• No new GO annotations proposed from the angiogenesis literature (indirect, mechanism unresolved);
  raised as a suggested question instead.