Three-dimensional Model of Human Platelet Integrin αIIbβ3 in Solution Obtained by Small Angle Neutron Scattering

Integrin alpha IIb beta 3 is the major membrane protein and adhesion receptor at the surface of blood platelets, which after activation plays a key role in platelet plug formation in hemostasis and thrombosis. Small angle neutron scattering (SANS) and shape reconstruction algorithms allowed formation of a low resolution three-dimensional model of whole alpha IIb beta 3 in Ca2+/detergent solutions. Model projections after 90 degrees rotation along its long axis show an elongated and arched form (135 degrees) not observed before and a handgun form. This 20-nm-long structure is well defined, despite alpha IIb beta 3 multidomain nature and expected segmental flexibility, with the largest region at the top, followed by two narrower and smaller regions at the bottom. Docking of this SANS envelope into the high resolution structure of alpha IIb beta 3, reconstructed from crystallographic and NMR data, shows that the solution structure is less constrained, allows tentative assignment of the disposition of the alpha IIb and beta 3 sub-units and their domains within the model, and points out the structural analogies and differences of the SANS model with the crystallographic models of the recombinant ectodomains of alpha IIb beta 3 and alpha V beta 3 and with the cryo-electron microscopy model of whole alpha IIb beta 3. The ectodomain is in the bent configuration at the top of the model, where alpha IIb and beta 3 occupy the concave and convex sides, respectively, at the arched projection, with their bent knees at its apex. It follows the narrower transmembrane region and the cytoplasmic domains at the bottom end. alpha IIb beta 3 aggregated in Mn2+/detergent solutions, which impeded to get its SANS model.