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1fns

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1fns, resolution 2.00Å ()
Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


Contents

CRYSTAL STRUCTURE OF THE VON WILLEBRAND FACTOR (VWF) A1 DOMAIN I546V MUTANT IN COMPLEX WITH THE FUNCTION BLOCKING FAB NMC4

Publication Abstract from PubMed

Platelet participation in hemostasis and arterial thrombosis requires the binding of glycoprotein (GP) Ibalpha to von Willebrand factor (vWF). Hemodynamic forces enhance this interaction, an effect mimicked by the substitution I546V in the vWF A1 domain. A water molecule becomes internalized near the deleted Ile methyl group. The change in hydrophobicity of the local environment causes positional changes propagated over a distance of 27 A. As a consequence, a major reorientation of a peptide plane occurs in a surface loop involved in GP Ibalpha binding. This distinct vWF conformation shows increased platelet adhesion and provides a structural model for the initial regulation of thrombus formation.

von Willebrand factor conformation and adhesive function is modulated by an internalized water molecule., Celikel R, Ruggeri ZM, Varughese KI, Nat Struct Biol. 2000 Oct;7(10):881-4. PMID:11017197

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

Disease

[VWF_HUMAN] Defects in VWF are the cause of von Willebrand disease type 1 (VWD1) [MIM:193400]. A common hemorrhagic disorder due to defects in von Willebrand factor protein and resulting in impaired platelet aggregation. Von Willebrand disease type 1 is characterized by partial quantitative deficiency of circulating von Willebrand factor, that is otherwise structurally and functionally normal. Clinical manifestations are mucocutaneous bleeding, such as epistaxis and menorrhagia, and prolonged bleeding after surgery or trauma.[1][2] Defects in VWF are the cause of von Willebrand disease type 2 (VWD2) [MIM:613554]. A hemorrhagic disorder due to defects in von Willebrand factor protein and resulting in impaired platelet aggregation. Von Willebrand disease type 2 is characterized by qualitative deficiency and functional anomalies of von Willebrand factor. It is divided in different subtypes including 2A, 2B, 2M and 2N (Normandy variant). The mutant VWF protein in types 2A, 2B and 2M are defective in their platelet-dependent function, whereas the mutant protein in type 2N is defective in its ability to bind factor VIII. Clinical manifestations are mucocutaneous bleeding, such as epistaxis and menorrhagia, and prolonged bleeding after surgery or trauma. Defects in VWF are the cause of von Willebrand disease type 3 (VWD3) [MIM:277480]. A severe hemorrhagic disorder due to a total or near total absence of von Willebrand factor in the plasma and cellular compartments, also leading to a profound deficiency of plasmatic factor VIII. Bleeding usually starts in infancy and can include epistaxis, recurrent mucocutaneous bleeding, excessive bleeding after minor trauma, and hemarthroses.

Function

[VWF_HUMAN] Important in the maintenance of hemostasis, 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. Also acts as a chaperone for coagulation factor VIII, delivering it to the site of injury, stabilizing its heterodimeric structure and protecting it from premature clearance from plasma.

About this Structure

1fns is a 3 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA.

Reference

  • Celikel R, Ruggeri ZM, Varughese KI. von Willebrand factor conformation and adhesive function is modulated by an internalized water molecule. Nat Struct Biol. 2000 Oct;7(10):881-4. PMID:11017197 doi:10.1038/79639
  1. Allen S, Abuzenadah AM, Hinks J, Blagg JL, Gursel T, Ingerslev J, Goodeve AC, Peake IR, Daly ME. A novel von Willebrand disease-causing mutation (Arg273Trp) in the von Willebrand factor propeptide that results in defective multimerization and secretion. Blood. 2000 Jul 15;96(2):560-8. PMID:10887119
  2. Bodo I, Katsumi A, Tuley EA, Eikenboom JC, Dong Z, Sadler JE. Type 1 von Willebrand disease mutation Cys1149Arg causes intracellular retention and degradation of heterodimers: a possible general mechanism for dominant mutations of oligomeric proteins. Blood. 2001 Nov 15;98(10):2973-9. PMID:11698279

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