1SQ0

Crystal Structure of the Complex of the Wild-type Von Willebrand Factor A1 domain and Glycoprotein Ib alpha at 2.6 Angstrom Resolution

Summary for 1SQ0

• Entry DOI: 10.2210/pdb1sq0/pdb
• Related: 1AUQ 1M0Z 1M10 1OOK 1P8V
• Descriptor: Von Willebrand factor (vWF) [Contains: Von Willebrand antigen II], Platelet glycoprotein Ib alpha chain (Glycoprotein Ibalpha) (GP-Ib alpha) (GPIbA) (GPIb-alpha) (CD42B-alpha) (CD42B) [Contains: Glycocalicin] (3 entities in total)
• Functional Keywords: leucine rich repeat (lrr), right-handed beta-alpha superhelix); integrin a (or i) domain fold, blood clotting
• Biological source: Homo sapiens (human); More
• Cellular location: Secreted: P04275; Membrane; Single-pass type I membrane protein: P07359
• Total number of polymer chains: 2
• Total formula weight: 56550.86

Authors

Dumas, J.J.,Kumar, R.,McDonagh, T.,Sullivan, F.,Stahl, M.L.,Somers, W.S.,Mosyak, L. (deposition date: 2004-03-17, release date: 2004-04-13, Last modification date: 2021-10-27)

Primary citation

Dumas, J.J.,Kumar, R.,McDonagh, T.,Sullivan, F.,Stahl, M.L.,Somers, W.S.,Mosyak, L.
Crystal structure of the wild-type von Willebrand factor A1-glycoprotein Ibalpha complex reveals conformation differences with a complex bearing von Willebrand disease mutations
J.Biol.Chem., 279:23327-23334, 2004

PubMed Abstract: 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.

PubMed: 15039442
DOI: 10.1074/jbc.M401659200

Experimental method

X-RAY DIFFRACTION (2.6 Å)