Date of Award

2009

Degree Type

Dissertation

Department

Biological, Geological and Environmental Sciences

First Advisor

Qin, Jun

Subject Headings

Integrins, Integrins -- Structure-activity relationships, Cytoskeletal proteins, Phosphoinositides, Biochemistry, Talin, Integrin, Integrin activation, PIP2

Abstract

Activation of heterodimeric (alpha/beta) integrin transmembrane receptors by the cytoskeletal protein talin is essential for many important cell adhesive responses including cell-extracellular matrix contact, cell motility and survival. A key step in this process involves interaction of phosphotyrosine-binding (PTB) domain in the N-terminal head of talin (talin-H) with integrin beta3membrane-proximal cytoplasmic tails (beta-MP-CTs). Compared to talin-H, intact talin exhibits low potency in inducing integrin activation. Using TROSY NMR spectroscopy, we found that the large C-terminal rod domain of talin (talin-R) interacts with talin-H and allosterically restrains talin in a closed conformation. Structural, mutational, and biochemical analyses demonstrate that talin-R specifically masks a region in talin-PTB where integrin beta3-MP-CT binds and competes with it for binding to talin-PTB. The inhibitory interaction is disrupted by a constitutively activating mutation (M319A) or phosphatidylinositol 4,5-bisphosphate - a known talin activator. These data define a distinct autoinhibition mechanism for talin and suggest how it controls the dynamics of integrin activation and cell adhesion

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