title: Conformational changes in talin on binding to anionic phospholipid membranes facilitate signaling by integrin transmembrane helices.
abstract: Integrins are heterodimeric (αβ) cell surface receptors that are activated to a high affinity state by the formation of a complex involving the α/β integrin transmembrane helix dimer, the head domain of talin (a cytoplasmic protein that links integrins to actin), and the membrane. The talin head domain contains four sub-domains (F0, F1, F2 and F3) with a long cationic loop inserted in the F1 domain. Here, we model the binding and interactions of the complete talin head domain with a phospholipid bilayer, using multiscale molecular dynamics simulations. The role of the inserted F1 loop, which is missing from the crystal structure of the talin head, PDB:3IVF, is explored. The results show that the talin head domain binds to the membrane predominantly via cationic regions on the F2 and F3 subdomains and the F1 loop. Upon binding, the intact talin head adopts a novel V-shaped conformation which optimizes its interactions with the membrane. Simulations of the complex of talin with the integrin α/β TM helix dimer in a membrane, show how this complex promotes a rearrangement, and eventual dissociation of, the integrin α and β transmembrane helices. A model for the talin-mediated integrin activation is proposed which describes how the mutual interplay of interactions between transmembrane helices, the cytoplasmic talin protein, and the lipid bilayer promotes integrin inside-out activation.
authors.affiliation: Department of Biochemistry, University of Oxford, Oxford, United Kingdom.
authors.forename: Antreas C
authors.initials: AC
authors.lastname: Kalli
authors.forename: Iain D
authors.initials: ID
authors.lastname: Campbell
authors.forename: Mark S P
authors.initials: MS
authors.lastname: Sansom
mesh_terms: D016023:Integrins / Q000737:chemistry* / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D010743:Phospholipids / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D016608:Talin / Q000737:chemistry* / Q000378:metabolism
chemical_list: D016023:Integrins; D010743:Phospholipids; D016608:Talin