Migfilin, a Molecular Switch in Regulation of Integrin Activation

Jun Qin,Mitali Das,Keyang Ding,Yan-Qing Ma,Sudhiranjan Gupta,Edward F Plow,Sujay Subbayya Ithychanda,Xiaoxia Wang,Chuanyue Wu

doi:10.1074/jbc.m807719200

Jun Qin, Mitali Das + Show 7 more

Open Access

https://doi.org/10.1074/jbc.m807719200

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Abstract

The linkage of heterodimeric (alpha/beta) integrin receptors with their extracellular matrix ligands and intracellular actin cytoskeleton is a fundamental step for controlling cell adhesion and migration. Binding of the actin-linking protein, talin, to integrin beta cytoplasmic tails (CTs) induces high affinity ligand binding (integrin activation), whereas binding of another actin-linking protein, filamin, to the integrin beta CTs negatively regulates this process by blocking the talin-integrin interaction. Here we show structurally that migfilin, a novel cytoskeletal adaptor highly enriched in the integrin adhesion sites, strongly interacts with the same region in filamin where integrin beta CTs bind. We further demonstrate that the migfilin interaction dissociates filamin from integrin and promotes the talin/integrin binding and integrin activation. Migfilin thus acts as a molecular switch to disconnect filamin from integrin for regulating integrin activation and dynamics of extracellular matrix-actin linkage.

Highlights

Cells reside in a protein network, the extracellular matrix (ECM).4 Cell-ECM contact is crucial for many physiological and pathophysiological processes and is primarily mediated by heterodimeric (␣/␤) transmembrane receptors, the integrins [1]
More significant chemical shift changes of IgFLN21 occurred upon binding to migfilin-N than to ␤7 cytoplasmic tails (CTs), suggesting that the filamin-migfilin interaction is stronger than the filamin-integrin interaction
We performed the Isothermal Titration Calorimetry (ITC) experiments, which revealed that the affinity of migfilin-N/IgFLNa21 was an order of magnitude higher than that for integrin ␤7/IgFLNa21 (Fig. 2)

Summary

Introduction

Cells reside in a protein network, the extracellular matrix (ECM).4 Cell-ECM contact is crucial for many physiological and pathophysiological processes and is primarily mediated by heterodimeric (␣/␤) transmembrane receptors, the integrins [1]. We further demonstrate that the migfilin interaction dissociates filamin from integrin and promotes the talin/integrin binding and integrin activation.

Results

Conclusion