The many faces of platelet glycoprotein Ibalpha--thrombin interaction.
The platelet glycoprotein receptor regulates the adhesion of blood platelets to damaged blood vessel walls and the subsequent platelet aggregation. One of the subunits, platelet glycoprotein Ibalpha (GpIbalpha), binds thrombin, a serine protease with both procoagulant and anticoagulant activities. Two groups reported the crystal structures of the complex between thrombin and the N-terminal extracellular domain (leucine-rich repeat [LRR] domain) of GpIbalpha. In both these structures, GpIbalpha was reported to bind two thrombin molecules, but both the primary and secondary thrombin binding sites differed between them. We performed a detailed comparison of the two structures to look for insights that may explain the differences. Our results show that the 1:1 GpIbalpha-thrombin complex detected in solution between the crystallized proteins is likely the only strong interaction. The anionic sequence (residues 268-284) of GpIbalpha is likely responsible for the initial interaction with thrombin and the interaction with the rest of LRR domain of GpIbalpha occurs subsequently and may alternate between two or more different binding modes. Our modelling suggests the interaction between GpIbalpha and thrombin is highly pH-dependent and a small change in pH is likely to contribute to the formation of alternate binding modes. The differences in the crystal structures reported for the GpIbalpha-thrombin complex suggest a fascinating plasticity in this protein-protein interaction that may be biologically significant.
Kobe
B
B
School of Chemistry and Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia. b.kobe@uq.edu.au
Guncar
G
G
Buchholz
R
R
Huber
T
T
Maco
B
B
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D003460:Crystallization; D018360:Crystallography, X-Ray; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D055672:Static Electricity; D013917:Thrombin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D019038:Platelet Glycoprotein GPIb-IX Complex; D013917:Thrombin