Activation of heterodimeric (α/β) 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 β membrane-proximal cytoplasmic tails (β-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 aclosed conformation. We further demonstrate that talin-R specifically masks a region in talin-PTB where integrin β-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. © 2008 Elsevier Inc. All rights reserved.
Goksoy, E., Ma, Y. Q., Wang, X., Kong, X., Perera, D., Plow, E. F., & Qin, J. (2008). Structural Basis for the Autoinhibition of Talin in Regulating Integrin Activation. Molecular Cell, 31(1), 124–133. https://doi.org/10.1016/j.molcel.2008.06.011