The structure of the talin/integrin complex at a lipid bilayer: an NMR and MD simulation study.
Integrins are cell surface receptors crucial for cell migration and adhesion. They are activated by interactions of the talin head domain with the membrane surface and the integrin β cytoplasmic tail. Here, we use coarse-grained molecular dynamic simulations and nuclear magnetic resonance spectroscopy to elucidate the membrane-binding surfaces of the talin head (F2-F3) domain. In particular, we show that mutations in the four basic residues (K258E, K274E, R276E, and K280E) in the F2 binding surface reduce the affinity of the F2-F3 for the membrane and modify its orientation relative to the bilayer. Our results highlight the key role of anionic lipids in talin/membrane interactions. Simulation of the F2-F3 in complex with the α/β transmembrane dimer reveals information for its orientation relative to the membrane. Our studies suggest that the perturbed orientation of talin relative to the membrane in the F2 mutant would be expected to in turn perturb talin/integrin interactions.
Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
Antreas C
AC
Kalli
Kate L
KL
Wegener
Benjamin T
BT
Goult
Nicholas J
NJ
Anthis
Iain D
ID
Campbell
Mark S P
MS
Sansom
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D006801:Humans; D019012:Integrin beta1 / Q000737:chemistry* / Q000378:metabolism; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008563:Membrane Lipids / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D009154:Mutation; D040201:Platelet Membrane Glycoprotein IIb / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D016608:Talin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D019012:Integrin beta1; D008051:Lipid Bilayers; D008563:Membrane Lipids; D046912:Multiprotein Complexes; D040201:Platelet Membrane Glycoprotein IIb; D016608:Talin