Abstract
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 αIIbβ3 mainly affect platelets and megakaryocytes, αvβ3 has a widespread tissue distribution. Little is known of how amino acid substitutions of β3 comparatively affect the expression and structure of both integrins. We now report computer modelling including molecular dynamics simulations of extracellular head domains of αIIbβ3 and αvβ3 to determine the role of a novel β3 Pro189Ser (P163S in the mature protein) substitution that abrogates αIIbβ3 expression in platelets while allowing synthesis of αvβ3. Transfection of wild-type and mutated integrins in CHO cells confirmed that only αvβ3 surface expression was maintained. Modeling initially confirmed that replacement of αIIb by αv in the dimer results in a significant decrease in surface contacts at the subunit interface. For αIIbβ3, the presence of β3S163 specifically displaces an α-helix starting at position 259 and interacting with β3R261 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 αvβ3, S163 has different effects with β3R261 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 αIIbβ3 but a more rigid structure for αvβ3. Overall, this mutation stabilizes αvβ3 despite preventing αIIbβ3 expression.
Highlights
Glanzmann thrombasthenia (GT) is a rare inherited disease of platelet aggregation caused by quantitative and/or qualitative deficiencies of the aIIbb3 integrin [1,2,3]
GT is given by a large variety of nonsense and missense mutations, gene rearrangements including small insertions or deletions, splice site defects and frameshifts that occur across the 45 exons that compose ITGA2B and ITGB3 [2,3]
Mutations in ITGA2B are specific for aIIbb3, but those effecting ITGB3 extend to both b3-containing integrins and potentially concern all cell types expressing avb3
Summary
Glanzmann thrombasthenia (GT) is a rare inherited disease of platelet aggregation caused by quantitative and/or qualitative deficiencies of the aIIbb integrin [1,2,3]. GT is given by a large variety of nonsense and missense mutations, gene rearrangements including small insertions or deletions, splice site defects and frameshifts that occur across the 45 exons that compose ITGA2B and ITGB3 [2,3]. Whereas aIIb is mostly confined to the MK lineage, b3 is present as avb, a major integrin of vascular, blood and tissue cells; in contrast, avb is a very minor component in platelets [6,7,8]. Mutations in ITGA2B are specific for aIIbb, but those effecting ITGB3 extend to both b3-containing integrins and potentially concern all cell types expressing avb. While a majority of ITGB3 mutations affect b3 expression, missense mutations can have different effects on the capacity of b3 to interact with aIIb and av. While permitting the expression of both integrins they may affect their function differently [9,10,11,12,13]
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