How the headpiece hinge angle is opened: New insights into the dynamics of integrin activation

TitleHow the headpiece hinge angle is opened: New insights into the dynamics of integrin activation
Publication TypeJournal Article
Year of Publication2006
AuthorsPuklin-Faucher, E, Gao M, Schulten K, Vogel V
JournalThe Journal of cell biology
Volume175
Pagination349-60
Date Published2006 Oct 23
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.

Pub Med Link

http://www.ncbi.nlm.nih.gov/pubmed/17060501?dopt=Abstract

Alternate JournalJ. Cell Biol.
Citekey17060501