title: Multiscale simulations suggest a mechanism for integrin inside-out activation.
abstract: 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 β-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 αIIb/β3 dimer by the talin head domain was probed using multiscale molecular dynamics simulations. A number of novel insights emerge from these studies, including (i) the importance of the integrin αIIb subunit F992 and F993 residues in stabilizing the "off" state of the αIIb/β3 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 β transmembrane (TM) domain, (iv) an increase in the tilt angle of the β TM domain relative to the bilayer normal helps to destabilize the α/β 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.
authors: Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, United Kingdom.
authors: Antreas C
authors: AC
authors: Kalli
authors: Iain D
authors: ID
authors: Campbell
authors: Mark S P
authors: MS
authors: Sansom
mesh_terms: D002462:Cell Membrane / Q000378:metabolism*; D019281:Dimerization; D039661:Integrin beta3 / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D046912:Multiprotein Complexes / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D040201:Platelet Membrane Glycoprotein IIb / Q000235:genetics / Q000378:metabolism*; D016608:Talin / Q000378:metabolism*
chemical_list: D039661:Integrin beta3; D046912:Multiprotein Complexes; D040201:Platelet Membrane Glycoprotein IIb; D016608:Talin