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Structural mechanism of integrin inactivation by filamin.

ABSTRACT: Activation of heterodimeric (??) 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 ?IIb?3 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 ?3 cytoplasmic tail (CT), as previously predicted, but also engages N-terminal helices of ?IIb and ?3 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.

SUBMITTER: Liu J

PROVIDER: S-EPMC4424056 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Structural mechanism of integrin inactivation by filamin.

Liu Jianmin J Das Mitali M Yang Jun J Ithychanda Sujay Subbayya SS Yakubenko Valentin P VP Plow Edward F EF Qin Jun J

Nature structural & molecular biology 20150406 5

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 on ...[more]

PMID: 25849143

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