TCB Publications - Abstract

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.

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