Multiscale Simulations Suggest a Mechanism for Integrin Inside-Out Activation

Abstract

Integrins are large heterodimeric cell surface adhesion receptors which are central components of focal adhesion complexes and are crucial for a variety of signal transduction events. They are ‘activated’ to a high affinity state by the formation of an intracellular complex between the integrin β-subunit tail, the membrane and talin, a process known as ‘inside-out activation’. The head domain of talin plays a key role in the formation of this complex. In this study, activation of the integrin αIIb/β3 dimer by the talin head domain was probed using a multiscale approach that combines coarse-grained and atomistic molecular dynamics (MD) simulations. A number of novel insights emerge from these studies including: i) the important role of residues F992 and F993 of the integrin αIIb subunit in stabilizing the αIIb/β3 dimer ‘off’ state; ii) the crucial role of negatively charged moieties in talin F2-F3/membrane interactions; iii) how interactions of the talin F2-F3 domain with negatively charged lipid headgroups in the membrane induce a reorientation of the β transmembrane (TM) domain; iv) how an increase in the tilt angle of the β TM domain relative to the bilayer normal helps to destabilize the α/β TM interaction promoting a scissor-like motion of the integrin TM helices. On the basis of these results, a model of integrin inside-out activation by talin is proposed which explains how talin facilitates the rearrangement of the α and β integrin TM subunits, thus switching the integrin conformation towards an active high affinity state.