Molecular modeling of the seven tandem leucine-rich repeats within the ligand-binding region of platelet glycoprotein Ib alpha.
Platelet glycoprotein (GP)Ib-IX-V mediates von Willebrand Factor (vWF)-dependent adhesion to vascular subendothelium at high shear in (patho)physiological thrombus formation. The ligand-binding domain of GPIb-IX-V is within the N-terminal 282 residues of GPIb alpha, that contains seven tandem leucine-rich repeats (Leu36-Ala200). Repeats 2-4 are critical for vWF binding. In this study, we have built molecular models of the seven leucine-rich repeats of human, canine and mouse GPIb alpha, providing novel insights into the species-specific interaction between human vWF and its receptor. Interestingly, a major difference between the models was a large negatively charged patch on the concave face of human, but not canine, repeats 2-4. In addition, five individual mutations within the leucine-rich repeats of GPIb alpha associated with the bleeding disorder Bernard-Soulier syndrome, that result in dysfunctional vWF binding, were mapped to the model of human GPIb alpha. This provides the basis for relating these genetic lesions to abnormal function of the receptor.
Whisstock
James C
JC
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
Shen
Yang
Y
López
José A
JA
Andrews
Robert K
RK
Berndt
Michael C
MC
D000595:Amino Acid Sequence; D000818:Animals; D001606:Bernard-Soulier Syndrome / Q000235:genetics*; D018360:Crystallography, X-Ray; D004285:Dogs; D006801:Humans; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment; D013045:Species Specificity; D055672:Static Electricity; D013329:Structure-Activity Relationship; D020080:Tandem Repeat Sequences / Q000235:genetics*; D014841:von Willebrand Factor / Q000378:metabolism*
D008024:Ligands; D019038:Platelet Glycoprotein GPIb-IX Complex; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D014841:von Willebrand Factor; C028254:von Willebrand factor receptor