Article | Published:

Structural mechanism of integrin inactivation by filamin

Nature Structural & Molecular Biology volume 22, pages 383389 (2015) | Download Citation

Abstract

Activation of heterodimeric (αβ) integrin is crucial for regulating cell adhesion. Binding of talin to the cytoplasmic face of integrin activates the receptor, but how integrin is maintained in a resting state to counterbalance its activation has remained obscure. Here, we report the structure of the cytoplasmic domain of human integrin αIIbβ3 bound to its inhibitor, the immunoglobin repeat 21 of filamin A (FLNa-Ig21). The structure reveals an unexpected ternary complex in which FLNa-Ig21 not only binds to the C terminus of the integrin β3 cytoplasmic tail (CT), as previously predicted, but also engages N-terminal helices of αIIb and β3 CTs to stabilize an inter-CT clasp that helps restrain the integrin in a resting state. Combined with functional data, the structure reveals a new mechanism of filamin-mediated retention of inactive integrin, suggesting a new framework for understanding regulation of integrin activation and adhesion.

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Acknowledgements

We wish to thank X. Zhang, Y.-Q. Ma, J.-H. Ma and S. Misra for useful discussions and technical assistance. This work was supported by US National Institutes of Health grants to J.Q. (GM062823), V.P.Y. (DK102020) and E.F.P. (HL073311).

Author information

Author notes

    • Jianmin Liu
    •  & Mitali Das

    These authors contributed equally to this work.

Affiliations

  1. Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.

    • Jianmin Liu
    • , Mitali Das
    • , Jun Yang
    • , Sujay Subbayya Ithychanda
    • , Valentin P Yakubenko
    • , Edward F Plow
    •  & Jun Qin

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Contributions

J.L. and J.Q. conceived the study. J.L. performed all NMR and biochemical studies with the assistance of J.Y. and S.S.I. M.D. performed all functional experiments. All authors were involved in data interpretation and discussion. J.L. and J.Q. wrote the manuscript with contributions from all other authors.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Edward F Plow or Jun Qin.

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https://doi.org/10.1038/nsmb.2999

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