Molecular Dynamics Analysis of a Novel beta 3 Pro189Ser Mutation in a Patient with Glanzmann Thrombasthenia Differentially Affecting alpha IIb beta 3 and alpha v beta 3 Expression

作者：Laguerre Michel; Sabi Essa; Daly Martina; Stockley Jacqueline; Nurden Paquita; Pillois Xavier; Nurden Alan T^*

来源：PLos One, 2013, 8(11): e78683.

DOI：10.1371/journal.pone.0078683

Mutations in ITGA2B and ITGB3 cause Glanzmann thrombasthenia, an inherited bleeding disorder in which platelets fail to aggregate when stimulated. Whereas an absence of expression or qualitative defects of alpha IIb beta 3 mainly affect platelets and megakaryocytes, alpha v beta 3 has a widespread tissue distribution. Little is known of how amino acid substitutions of beta 3 comparatively affect the expression and structure of both integrins. We now report computer modelling including molecular dynamics simulations of extracellular head domains of alpha IIb beta 3 and alpha v beta 3 to determine the role of a novel b3 Pro189Ser (P163S in the mature protein) substitution that abrogates alpha IIb beta 3 expression in platelets while allowing synthesis of alpha v beta 3. Transfection of wild-type and mutated integrins in CHO cells confirmed that only alpha v beta 3 surface expression was maintained. Modeling initially confirmed that replacement of alpha II beta by alpha v in the dimer results in a significant decrease in surface contacts at the subunit interface. For alpha IIb beta 3, the presence of beta 3S163 specifically displaces an alpha-helix starting at position 259 and interacting with beta 3R261 while there is a moderate 11% increase in intra-subunit H-bonds and a very weak decrease in the global H-bond network. In contrast, for alpha v beta 3, S163 has different effects with b3R261 coming deeper into the propeller with a 43% increase in intra-subunit H-bonds but with little effect on the global H-bond network. Compared to the WT integrins, the P163S mutation induces a small increase in the inter-subunit fluctuations for alpha IIb beta 3 but a more rigid structure for alpha v beta 3. Overall, this mutation stabilizes alpha v beta 3 despite preventing alpha IIb beta 3 expression.

• 出版日期2013-11-13
• 单位河南工业大学