The enigmatic αIIb β-propeller: Structural Insights from the select mutations

Integrin αIIbβ3 is the predominant receptor for fibrinogen which mediates platelet aggregation, an important step in hemostasis and thrombosis. Several mutations have been reported in the genes encoding αIIb and β3 subunits among patients with Glanzmann thrombasthenia, of which 177 are in the β-propeller domain. The two subunits form a heterodimer at the interface between β-propeller and β-I domains of αIIb and β3 respectively with their stability critical for intracellular trafficking, surface expression, and ligand binding. Our study was aimed at retrieving the β-propeller mutations from various databases and study structural variations due to select mutations upon interaction with fibrinogen using molecular docking and molecular dynamics. Mutations were studied for their impact on phenotypic severity, structural stability, and evolutionary conservation. Molecular docking analysis and molecular dynamics simulations were carried out for αIIb-β3 complexes as well as αIIbβ3-fibrinogen complexes; in particular, E355K structure had more deviations, fluctuations, and other changes which compromised its structural stability and binding affinity when compared to both wild-type and G401C structures. Our comprehensive in silico analysis clearly reiterates that mutations in the β-propeller are not only responsible for structural changes in this domain but also have implications on the overall structure and function of integrin αIIbβ3.