How the headpiece hinge angle is opened: new insights into the dynamics of integrin activation
Autor: | Mu Gao, Klaus Schulten, Viola Vogel, Eileen Puklin-Faucher |
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Jazyk: | angličtina |
Rok vydání: | 2006 |
Předmět: |
Models
Molecular Protein Conformation Integrin Allosteric regulation Hinge Plasma protein binding Crystallography X-Ray Ligands Article 03 medical and health sciences Molecular dynamics 0302 clinical medicine Protein structure Allosteric Regulation Humans Computer Simulation Research Articles 030304 developmental biology 0303 health sciences Integrin alphaVbeta3 Binding Sites biology Molecular Structure Cell Biology Fibronectins Biochemistry Helix biology.protein Biophysics Oligopeptides 030217 neurology & neurosurgery Protein Binding Signal Transduction |
Zdroj: | The Journal of Cell Biology |
ISSN: | 1540-8140 0021-9525 |
Popis: | 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. |
Databáze: | OpenAIRE |
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