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Review
. 2018 Nov 5;217(11):3776-3784.
doi: 10.1083/jcb.201808061. Epub 2018 Sep 25.

Talin as a mechanosensitive signaling hub

Benjamin T Goult  1 , Jie Yan  2   3   4 , Martin A Schwartz  5   6
Affiliations
Review

Talin as a mechanosensitive signaling hub

Benjamin T Goult et al. J Cell Biol. .

Abstract

Cell adhesion to the extracellular matrix (ECM), mediated by transmembrane receptors of the integrin family, is exquisitely sensitive to biochemical, structural, and mechanical features of the ECM. Talin is a cytoplasmic protein consisting of a globular head domain and a series of α-helical bundles that form its long rod domain. Talin binds to the cytoplasmic domain of integrin β-subunits, activates integrins, couples them to the actin cytoskeleton, and regulates integrin signaling. Recent evidence suggests switch-like behavior of the helix bundles that make up the talin rod domains, where individual domains open at different tension levels, exerting positive or negative effects on different protein interactions. These results lead us to propose that talin functions as a mechanosensitive signaling hub that integrates multiple extracellular and intracellular inputs to define a major axis of adhesion signaling.

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Figures

Figure 1.
Figure 1.
Talin domain organization and interactions. (A) Talin contains an N-terminal FERM domain (F0–F3) connected via an 80-aa unstructured linker to the 13 talin rod domains R1–R13. 9 of the 13 rod domains contain VBSs (red). (B) Major binding sites for folded talin domains (black boxes) and unfolded domains (white boxes).
Figure 2.
Figure 2.
Talin rod domains as mechanochemical switches. (A–C) Each talin rod domain can adopt a number of conformations under different force regimes. (A) Folded bundle at low force. (B) Unfolded string of helices at forces above the mechanical threshold. (C) A fully unfolded polypeptide at high forces. Force-induced domain unfolding leads to a switch in the ligand binding profile of that domain. Complete unfolding at high force will result in a linear polypeptide unable to bind folded-domain ligands or helix-binding ligands. While no ligands for this form have been identified so far, many proteins bind linear peptide motifs.
Figure 3.
Figure 3.
Talin as an MSH. Talin contains multiple linkages to the actin cytoskeleton and also links to microtubules (Bouchet et al., 2016; Sun et al., 2016b) and intermediate filaments (Sun et al., 2008). Depending on the cytoskeletal linkages engaged, different domains will be under tension, resulting in different sets of bound ligands and different signaling outputs.
Figure 4.
Figure 4.
Talin as a series of mechanochemical switches. (A) The force-induced unfolding of the 13 talin rod domains R1–R13. Six force-extension curves are shown (at a loading rate of 3.8 pN/s), and each step in the profile corresponds with a single domain unfolding independently and undergoing mechanical switching. Adapted with permission from Yao et al. (2016). (B–D) Schematic diagram representing mechanochemical switches I–IV. (B) In the absence of mechanical force, the four domains are folded, and multiple ligands can bind simultaneously. (C) Mechanical force causes one domain (in this figure, domain II) to unfold, which drives a switch in binding partners on that domain. The other three domains remain folded and bound to their ligands. (D) Higher mechanical force causes a second domain (in this figure, domain IV) to unfold, switch binding partner, and further alter the signaling complex on that talin. Talin has 13 rod domains that exhibit this switch-like behavior, so multiple permutations of switch states and MSH complexes are possible on a single talin.
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