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.
Highlights
We studied the implications of the R8 domain unfolding in the downstream activity of deleted in liver cancer 1 (DLC1), which binds the talin R8 domain and negatively regulates Ras homolog family member A (RhoA)
We propose a novel force-controlled molecular switch that refines the mechanism of talin-mediated focal adhesion activation, providing negative
We examined the stability of the R7-R8 domain using steered molecular dynamics (SMD) simulations, as well as investigating the effect of DLC1 binding (Fig 3A) on the stability of the R8 bundle
Summary
We used single-molecule techniques, combined with protein engineering and cellular biophysical approaches, to characterise how talin mechanotransduction through the interaction of the R8 domain with deleted in liver cancer 1 (DLC1) can regulate cell mechanics. One of the most studied mechanosensitive molecules, is a key protein in focal adhesions, where it simultaneously connects integrins in the cell membrane through its N-terminal head domain and the actin cytoskeleton using the C-terminal rod (Fig 1).
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