Modeling and Molecular Dynamics of HPA-1a and -1b Polymorphisms: Effects on the Structure of the b3 Subunit of the aIIbb3 Integrin

Background: The HPA-1 alloimmune system carried by the platelet integrin aIIbb3 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 b3 subunit. Although the structure of aIIbb3 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-b3 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 b3 form. These analyses also showed major structural flexibility of all three domains in both forms, but increased flexibility in the P33 b3 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 b3 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 b3 structure that suggest possible effects on the alloimmune response and platelet function. Citation: Jallu V, Poulain P, Fuchs PFJ, Kaplan C, de Brevern AG (2012) Modeling and Molecular Dynamics of HPA-1a and -1b Polymorphisms: Effects on the Structure of the b3 Subunit of the aIIbb3 Integrin. PLoS ONE 7(11): e47304. doi:10.1371/journal.pone.0047304 Editor: Toshiyuki Miyata, National Cerebral and Cardiovascular Center, Japan Received April 11, 2012; Accepted September 11, 2012; Published November 14, 2012 Copyright: 2012 Jallu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by grants from the Ministry of Research, University of Paris Diderot, The National Institute for Blood Transfusion (INTS) and the Institute for Health and Medical Research (INSERM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: [email protected] . These authors contributed equally to this work.