TCB Publications - Abstract

Eileen Puklin-Faucher, Mu Gao, Klaus Schulten, and Viola Vogel. How the headpiece hinge angle is opened: new insights into the dynamics of integrin activation. Journal of Cell Biology, 175:349-360, 2006. (PMC: 2064575)

PUKL2006 How the integrin headpiece transitions to the high affinity conformation is debated. While experiments link activation with the opening of the hinge angle between the $\beta$A and hybrid domains in the ligand-binding headpiece, this hinge is closed in the liganded $\alpha_V\beta_3$-integrin crystal structure. Here, we replaced the RGD-peptide ligand of this structure with the 10th type III fibronectin module (FnIII$_{10}$) and discovered through molecular dynamics (MD) equilibrations that when the conformational constraints of the leg domains are lifted, the $\beta$A/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 $\alpha$1-helix to the $\beta$A/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.

Download Full Text

The manuscripts available on our site are provided for your personal use only and may not be retransmitted or redistributed without written permissions from the paper's publisher and author. You may not upload any of this site's material to any public server, on-line service, network, or bulletin board without prior written permission from the publisher and author. You may not make copies for any commercial purpose. Reproduction or storage of materials retrieved from this web site is subject to the U.S. Copyright Act of 1976, Title 17 U.S.C.

Download full text: PDF ( 3.0MB)