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Published 23 October 2006. doi:10.1083/jcb.200602071
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 175, Number 2, 349-360
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Article

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



Eileen Puklin-Faucher1,2, Mu Gao3,4, Klaus Schulten3,4, and Viola Vogel1

1 Department of Materials, Swiss Federal Institute of Technology in Zurich (ETH Zurich), CH-8093 Zurich, Switzerland
2 Department of Chemistry, University of Washington, Seattle, Washington 98195
3 Beckman Institute and 4 Department of Physics, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801

Correspondence to Viola Vogel: viola.vogel{at}mat.ethz.ch

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 ßA and hybrid domains in the ligand-binding headpiece, this hinge is closed in the liganded {alpha}vß3 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 ßA/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 ßA/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.

M. Gao's present address is the Center for the Study of Systems Biology, School of Biology, Georgia Institute of Technology, Atlanta, GA.

Abbreviations used in this paper: ADMIDAS, adjacent to the MIDAS; LIMBS, ligand-induced metal-binding site; MIDAS, metal ion–dependent adhesion site; MD, molecular dynamics; SMD, steered molecular dynamics.


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