Abstract
The activation of heterodimeric (α/β) integrin is crucial for regulating cell adhesion. Binding of talin to the cytoplasmic face of integrin activates the receptor, but how integrin is properly maintained in resting state to counterbalance its activation for regulating adhesion dynamics remains obscure. We report the structure of 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 where FLNa-Ig21 not only binds to previously predicted C-terminus of integrin β3 cytoplasmic tail (CT) 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 novel mechanism of filamin-mediated retention of inactive integrin, suggesting a new framework for understanding regulation of integrin activation and adhesion.
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