Abstract
In cell-extracellular matrix junctions (focal adhesions), the cytoskeletal protein talin is central to the connection of integrins to the actin cytoskeleton. Talin is thought to mediate this connection via its two integrin, (at least) three actin, and several vinculin binding sites. The binding sites are cryptic in the head-to-rod autoinhibited cytoplasmic form of the protein and require (stepwise) conformational activation. This activation process, however, remains poorly understood, and there are contradictory models with respect to the determinants of adhesion site localization. Here, we report turnover rates and protein-protein interactions in a range of talin rod domain constructs varying in helix bundle structure. We conclude that several bundles of the C terminus cooperate to regulate targeting and concomitantly tailor high affinity interactions of the talin rod in cell adhesions. Intrinsic control of ligand binding activities is essential for the coordination of adhesion site function of talin.
Highlights
In cell-extracellular matrix junctions, the cytoskeletal protein talin is central to the connection of integrins to the actin cytoskeleton
All three talin rod constructs targeted to focal adhesions (FAs), albeit with different efficiency (Fig. 1, A and B), indicating that active binding sites for either vinculin or -integrins suffice to mediate some sort of localization
FA targeting of a core IBS-2A four-helix bundle (H47– 50, the proposed minimal integrin binding site) has been reported by Kieffer and co-workers [19]
Summary
The binding sites are cryptic in the head-to-rod autoinhibited cytoplasmic form of the protein and require (stepwise) conformational activation. This activation process, remains poorly understood, and there are contradictory models with respect to the determinants of adhesion site localization. The C-terminal part of talin rod, talinC (H47-H62), comprising the IBS-2A/B and the ABS-3/DS domain, contains important binding sites and regulatory elements that convey essential aspects of talin function in cells. Our data provide evidence for interdependent binding site activities in IBS-2 and ABS-3, a key characteristic of talinC, allowing control of targeting to and residency times in FAs. TalinC, establishes a tightly regulated connection between talin and the actin cytoskeleton
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