Structural basis for the autoinhibition of talin in regulating integrin activation.
Activation of heterodimeric (alpha/beta) integrin transmembrane receptors by the 270 kDa cytoskeletal protein talin is essential for many important cell adhesive and physiological responses. A key step in this process involves interaction of phosphotyrosine-binding (PTB) domain in the N-terminal head of talin (talin-H) with integrin beta membrane-proximal cytoplasmic tails (beta-MP-CTs). Compared to talin-H, intact talin exhibits low potency in inducing integrin activation. Using NMR spectroscopy, we show that the large C-terminal rod domain of talin (talin-R) interacts with talin-H and allosterically restrains talin in a closed conformation. We further demonstrate that talin-R specifically masks a region in talin-PTB where integrin beta-MP-CT binds and competes with it for binding to talin-PTB. The inhibitory interaction is disrupted by a constitutively activating mutation (M319A) or by phosphatidylinositol 4,5-bisphosphate, a known talin activator. These data define a distinct autoinhibition mechanism for talin and suggest how it controls integrin activation and cell adhesion.
Goksoy
Esen
E
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
Ma
Yan-Qing
YQ
Wang
Xiaoxia
X
Kong
Xiangming
X
Perera
Dhanuja
D
Plow
Edward F
EF
Qin
Jun
J
D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D039641:Integrin beta Chains / Q000737:chemistry / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D016608:Talin / Q000037:antagonists & inhibitors* / Q000737:chemistry*
D039641:Integrin beta Chains; D019269:Phosphatidylinositol 4,5-Diphosphate; D016608:Talin