Modeling and molecular dynamics of HPA-1a and -1b polymorphisms: effects on the structure of the β3 subunit of the αIIbβ3 integrin

• Published in: PloS one 2012, Vol.7 (11), p.e47304
• Main Authors: Jallu, Vincent, Poulain, Pierre, Fuchs, Patrick F J, Kaplan, Cecile, de Brevern, Alexandre G
• Format: Article
• Language: English
• Subjects: Algorithms; Alleles; Antigens; Antigens, Human Platelet; Antigens, Human Platelet - chemistry; Antigens, Human Platelet - genetics; Biochemistry, Molecular Biology; Bioinformatics; Biology; Blood platelets; Bond strength; Chemistry; Computer Science; Computer simulation; Dynamic structural analysis; Epitopes; Epitopes - chemistry; Epitopes - genetics; Flexibility; Genotype; Hematology; Human health and pathology; Humans; Immune response; Immune system; Isoimmunization; Knee; Leucine; Life Sciences; Medicine; Models, Genetic; Molecular dynamics; Molecular Dynamics Simulation; Mutagenesis; Mutation; Platelet Glycoprotein GPIIb-IIIa Complex; Platelet Glycoprotein GPIIb-IIIa Complex - chemistry; Platelet Glycoprotein GPIIb-IIIa Complex - genetics; Platelets; Polymorphism; Polymorphism, Genetic; Proline; Proteins; Quantitative Methods; Risk factors; Three dimensional models; Thrombocytopenia; Thromboembolism; Thrombosis
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0047304

The HPA-1 alloimmune system carried by the platelet integrin αIIbβ3 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 β3 subunit. Although the structure of αIIbβ3 is available, little is known about structural effects of the L33P substitution and its consequences on immune response and integrin functions. A complete 3D model of the L33-β3 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 β3 form. These analyses also showed major structural flexibility of all three domains in both forms, but increased flexibility in the P33 β3 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. These results provide a better understanding of HPA-1 epitopes complexity and alloimmunization prevalence of HPA-1a. P33 gain of structure flexibility in the β3 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 β3 structure that suggest possible effects on the alloimmune response and platelet function.