by Vincent Jallu, Pierre Poulain, Patrick F. J. Fuchs, Cecile Kaplan, Alexandre G. de Brevern
The HPA-1 alloimmune system carried by the platelet integrin aIIbß3 is the primary cause of alloimmune thrombocytopenia in Caucasians and the HPA-1b allele might be a risk factor for thrombosis. HPA-1a and -1b alleles are defined by a leucine and a proline, respectively, at position 33 in the ß3 subunit. Although the structure of aIIbß3 is available, little is known about structural effects of the L33P substitution and its consequences on immune response and integrin functions. Methodology/Principal Findings
A complete 3D model of the L33-ß3 extracellular domain was built and a P33 model was obtained by in silico mutagenesis. We then performed molecular dynamics simulations. Analyses focused on the PSI, I-EGF-1, and I-EGF-2 domains and confirmed higher exposure of residue 33 in the L33 ß3 form. These analyses also showed major structural flexibility of all three domains in both forms, but increased flexibility in the P33 ß3 form. The L33P substitution does not alter the local structure (residues 33 to 35) of the PSI domain, but modifies the structural equilibrium of the three domains. Conclusions
These results provide a better understanding of HPA-1 epitopes complexity and alloimmunization prevalence of HPA-1a. P33 gain of structure flexibility in the ß3 knee may explain the increased adhesion capacity of HPA-1b platelets and the associated thrombotic risk. Our study provides important new insights into the relationship between HPA-1 variants and ß3 structure that suggest possible effects on the alloimmune response and platelet function.