Details

Autor(en) / Beteiligte

• Jallu, Vincent
• Poulain, Pierre
• Fuchs, Patrick F. J
• Kaplan, Cecile
• de Brevern, Alexandre G

Titel

Modeling and Molecular Dynamics of HPA-1a and -1b Polymorphisms: Effects on the Structure of the [beta]3 Subunit of the [alpha]IIb[beta]3 Integrin

Ist Teil von

• PloS one, 2012-11, Vol.7 (11), p.e47304

Ort / Verlag

Public Library of Science

Erscheinungsjahr

2012

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• The HPA-1 alloimmune system carried by the platelet integrin [alpha]IIb[beta]3 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 [beta]3 subunit. Although the structure of [alpha]IIb[beta]3 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-[beta]3 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 [beta]3 form. These analyses also showed major structural flexibility of all three domains in both forms, but increased flexibility in the P33 [beta]3 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 [beta]3 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 [beta]3 structure that suggest possible effects on the alloimmune response and platelet function.