Crystal structure of the wild-type von Willebrand factor A1-glycoprotein Ibalpha complex reveals conformation differences with a complex bearing von Willebrand disease mutations.
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.
Dumas
John J
JJ
Department of Chemical and Screening Sciences, Wyeth, Cambridge, Massachusetts 02140, USA.
Kumar
Ravindra
R
McDonagh
Thomas
T
Sullivan
Francis
F
Stahl
Mark L
ML
Somers
William S
WS
Mosyak
Lidia
L
D001665:Binding Sites / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D014842:von Willebrand Diseases / Q000235:genetics; D014841:von Willebrand Factor / Q000737:chemistry* / Q000235:genetics
D019038:Platelet Glycoprotein GPIb-IX Complex; D014841:von Willebrand Factor