title: How the headpiece hinge angle is opened: New insights into the dynamics of integrin activation.
abstract: How the integrin head transitions to the high-affinity conformation is debated. Although experiments link activation with the opening of the hinge angle between the betaA and hybrid domains in the ligand-binding headpiece, this hinge is closed in the liganded alpha(v)beta3 integrin crystal structure. We replaced the RGD peptide ligand of this structure with the 10th type III fibronectin module (FnIII10) and discovered through molecular dynamics (MD) equilibrations that when the conformational constraints of the leg domains are lifted, the betaA/hybrid hinge opens spontaneously. Together with additional equilibrations on the same nanosecond timescale in which small structural variations impeded hinge-angle opening, these simulations allowed us to identify the allosteric pathway along which ligand-induced strain propagates via elastic distortions of the alpha1 helix to the betaA/hybrid domain hinge. Finally, we show with steered MD how force accelerates hinge-angle opening along the same allosteric pathway. Together with available experimental data, these predictions provide a novel framework for understanding integrin activation.
authors.affiliation: Department of Materials, Swiss Federal Institute of Technology in Zurich (ETH Zurich), CH-8093 Zurich, Switzerland.
authors.forename: Eileen
authors.initials: E
authors.lastname: Puklin-Faucher
authors.forename: Mu
authors.initials: M
authors.lastname: Gao
authors.forename: Klaus
authors.initials: K
authors.lastname: Schulten
authors.forename: Viola
authors.initials: V
authors.lastname: Vogel
mesh_terms: D000494:Allosteric Regulation; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D005353:Fibronectins / Q000737:chemistry; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000737:chemistry* / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009842:Oligopeptides / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D015398:Signal Transduction
chemical_list: D005353:Fibronectins; D039302:Integrin alphaVbeta3; D008024:Ligands; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid