Multiscale simulations suggest a mechanism for integrin inside-out activation

Integrins are large cell-surface adhesion receptors that can be activated to a high affinity state by the formation of an intracellular complex between the integrin beta-subunit tail, the membrane, and talin. The F2 and F3 subdomains of the talin head play a key role in formation of this complex. Here, activation of the integrin aIIb/beta 3 dimer by the talin head domain was probed using multi-scale molecular dynamics simulations. A number of novel insights emerge from these studies, including (i) the importance of the integrin alpha IIb subunit F992 and F993 residues in stabilizing the "off" state of the alpha IIb/beta 3 dimer, (ii) a crucial role for negatively charged groups in the F2-F3/membrane interaction, (iii) binding of the talin F2-F3 domain to negatively charged lipid headgroups in the membrane induces a reorientation of the beta transmembrane (TM) domain, (iv) an increase in the tilt angle of the beta TM domain relative to the bilayer normal helps to destabilize the alpha/beta TM interaction and promote a scissor-like movement of the integrin TM helices. These results, combined with various published experimental observations, suggest a model for the mechanism of inside-out activation of integrins by talin.