1sq0
Crystal Structure of the Complex of the Wild-type Von Willebrand Factor A1 domain and Glycoprotein Ib alpha at 2.6 Angstrom Resolution
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OverviewOverview
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). Here we report the, 2.6-A crystal structure of a complex comprised of the extracellular domain, of GpIbalpha and the wild-type A1 domain of VWF. A direct comparison of, this structure to a GpIbalpha-A1 complex containing "gain-of-function", mutations, A1-R543Q and GpIbalpha-M239V, reveals specific structural, differences between these complexes at sites near the two GpIbalpha-A1, binding interfaces. At the smaller interface, differences in interaction, show that the alpha1-beta2 loop of A1 serves as a conformational switch, alternating between an open alpha1-beta2 isomer that allows faster, dissociation of GpIbalpha-A1, as observed in the wild-type complex, and an, extended isomer that favors tight association as seen in the complex, containing A1 with a type 2B von Willebrand Disease (VWD) mutation, associated with spontaneous binding to GpIbalpha. At the larger interface, differences in interaction associated with the GpIbalpha-M239V, platelet-type VWD mutation are minor and localized but feature discrete, gamma-turn conformers at the loop end of the beta-hairpin structure. The, beta-hairpin, stabilized by a strong classic gamma-turn as seen in the, mutant complex, relates to the increased affinity of A1 binding, and the, beta-hairpin with a weak inverse gamma-turn observed in the wild-type, complex corresponds to the lower affinity state of GpIbalpha. These, findings provide important details that add to our understanding of how, both type 2B and platelet-type VWD mutations affect GpIbalpha-A1 binding, affinity.
DiseaseDisease
Known diseases associated with this structure: Bernard-Soulier syndrome, type A OMIM:[606672], Nonarteritic anterior ischemic optic neuropathy, susceptibility to OMIM:[606672], von Willebrand disease OMIM:[193400], von Willebrand disease, platelet-type OMIM:[606672]
About this StructureAbout this Structure
1SQ0 is a Protein complex structure of sequences from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Crystal structure of the wild-type von Willebrand factor A1-glycoprotein Ibalpha complex reveals conformation differences with a complex bearing von Willebrand disease mutations., Dumas JJ, Kumar R, McDonagh T, Sullivan F, Stahl ML, Somers WS, Mosyak L, J Biol Chem. 2004 May 28;279(22):23327-34. Epub 2004 Mar 23. PMID:15039442
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