Mechanotransduction in talin through the interaction of the R8 domain with DLC1

Abstract

The mechanical unfolding of proteins is a cellular mechanism for force transduction with potentially broad implications in cell fate. Despite this, the mechanism by which protein unfolding elicits differential downstream signalling pathways remains poorly understood. Here, we used protein engineering, atomic force microscopy, and biophysical tools to delineate how protein unfolding controls cell mechanics. Deleted in liver cancer 1 (DLC1) is a negative regulator of Ras homolog family member A (RhoA) and cell contractility that regulates cell behaviour when localised to focal adhesions bound to folded talin. Using a talin mutant resistant to force-induced unfolding of R8 domain, we show that talin unfolding determines DLC1 downstream signalling and, consequently, cell mechanics. We propose that this new mechanism of mechanotransduction may have implications for a wide variety of associated cellular processes.

Principal mode of Syndecan‐4 mechanotransduction for the endothelial glycocalyx is a scissor‐like dimer motion

“…Mechanotransduction, which involves biomolecules sensing mechanical signals (flow shear stress being of interest in this work) and transducing these physical cues into the intracellular biomolecules, is a hallmark function of the EG. The transmitted signals can cause oxidant production, and the resulting redox signals initiate inflammation signalling pathways which in turn can compromise vascular health.…”

“…4 For example, the disintegration of EG occurs very early in the course of sepsis and its prevention improves the survival of mice with sepsis, and pharmacological acceleration of EG restoration can be achieved using sulodexide. 9 Mechanotransduction, [11][12][13] which involves biomolecules sensing mechanical signals [14][15][16] (flow shear stress 17 being of interest in this work) and transducing these physical cues into the intracellular biomolecules, is a hallmark function of the EG. The transmitted signals can cause oxidant production, and the resulting redox signals initiate inflammation signalling pathways which in turn can compromise vascular health.…”

The plakin domain ofC. elegansVAB-10/plectin acts as a hub in a mechanotransduction pathway to promote morphogenesis

“…There is an intriguing similarity between talin and plakins in that among the 13 alpha helix bundles composing the talin central region, the central one (R8) loops out of the preceding R7 and unfolds with it (Yao et al, 2016), which is partially reminiscent of the SH3 domain being inserted within the central SR5 domain of the plakin domain. Moreover, the Rho GTPase Activating Protein DLC1 (Deleted in Colorectal Cancer1) is active when bound to the folded R8 but becomes inactive and unbound when R8 is unfolded (Haining et al, 2018).…”

DLC1 is a direct target of activated YAP/TAZ that drives collective migration and sprouting angiogenesis

“…DLC1 has been shown to interact with the integrin-related proteins Talin, focal adhesion kinase (FAK) and Tensin (Qian et al, 2007;Liao and Lo, 2008;Li et al, 2011;Zacharchenko et al, 2016). Interestingly, tension-induced conformational unfolding of Talin, a key mechanosensor for integrins, inhibits the interaction between DLC1 and Talin and prevents downstream inhibition of myosin phosphorylation (Haining et al, 2018). Thus DLC1's interaction with Talin might regulate myosin-driven turnover of focal adhesions to favor migration.…”