Integrin αIIbβ3 intermediates: From molecular dynamics to adhesion assembly

The platelet integrin aIIbb3 undergoes long-range conformational transitions associated with its functional conversion from inactive (low-affinity) to active (high-affinity) during hemostasis. Although new conformations that are inter-mediate between the well-characterized bent and extended states have been identified, their molecular dynamic properties and functions in the assembly of adhesions remain largely unexplored. In this study, we evaluated the properties of interme-diate conformations of integrin aIIbb3 and characterized their effects on the assembly of adhesions by combining all-atom simulations, principal component analysis, and mesoscale modeling. Our results show that in the low-affinity, bent conforma-tion, the integrin ectodomain tends to pivot around the legs; in intermediate conformations, the headpiece becomes partially extended, away from the lower legs. In the fully open, active state, aIIbb3 is flexible, and the motions between headpiece and lower legs are accompanied by fluctuations of the transmembrane helices. At the mesoscale, bent integrins form only unstable adhesions, but intermediate or open conformations stabilize the adhesions. These studies reveal a mechanism by which small variations in ligand binding affinity and enhancement of the ligand-bound lifetime in the presence of actin retrograde flow stabilize aIIbb3 integrin adhesions.

Automated summary

The platelet integrin aIIbb3 undergoes conformational transitions from inactive to active states during hemostasis. The properties and functions of intermediate conformations, which are between the well-characterized bent and extended states, are largely unexplored. In this study, the researchers evaluated the properties of intermediate conformations of integrin aIIbb3 and found that they stabilize adhesions. These findings provide insights into the mechanisms of aIIbb3 integrin adhesion stability.