title: Structural mechanism of integrin inactivation by filamin.
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.
authors: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors: Jianmin
authors: J
authors: Liu
authors: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors: Mitali
authors: M
authors: Das
authors: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors: Jun
authors: J
authors: Yang
authors: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors: Sujay Subbayya
authors: SS
authors: Ithychanda
authors: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors: Valentin P
authors: VP
authors: Yakubenko
authors: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors: Edward F
authors: EF
authors: Plow
authors: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
authors: Jun
authors: J
authors: Qin
mesh_terms: D002448:Cell Adhesion / Q000502:physiology; D018360:Crystallography, X-Ray; D064448:Filamins / Q000378:metabolism* / Q000648:ultrastructure*; D006801:Humans; D019906:Nuclear Magnetic Resonance, Biomolecular; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000648:ultrastructure*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D020349:Surface Plasmon Resonance; D016608:Talin / Q000378:metabolism
chemical_list: C578663:FLNA protein, human; D064448:Filamins; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D016608:Talin