Molecular stretching modulates mechanosensing pathways

Abstract

For individual cells in tissues to create the diverse forms of biological organisms, it is necessary that they must reliably sense and generate the correct forces over the correct distances and directions. There is considerable evidence that the mechanical aspects of the cellular microenvironment provide critical physical parameters to be sensed. How proteins sense forces and cellular geometry to create the correct morphology is not understood in detail but protein unfolding appears to be a major component in force and displacement sensing. Thus, the crystallographic structure of a protein domain provides only a starting point to then analyze what will be the effects of physiological forces through domain unfolding or catch-bond formation. In this review, we will discuss the recent studies of cytoskeletal and adhesion proteins that describe protein domain dynamics. Forces applied to proteins can activate or inhibit enzymes, increase or decrease protein-protein interactions, activate or inhibit protein substrates, induce catch bonds and regulate interactions with membranes or nucleic acids. Further, the dynamics of stretch-relaxation can average forces or movements to reliably regulate morphogenic movements. In the few cases where single molecule mechanics are studied under physiological conditions such as titin and talin, there are rapid cycles of stretch-relaxation that produce mechanosensing signals. Fortunately, the development of new single molecule and super-resolution imaging methods enable the analysis of single molecule mechanics in physiologically relevant conditions. Thus, we feel that stereotypical changes in cell and tissue shape involve mechanosensing that can be analyzed at the nanometer level to determine the molecular mechanisms involved.

The plakin domain of C. elegans VAB-10/plectin acts as a hub in a mechanotransduction pathway to promote morphogenesis

“…The paradigm for mechanosensing is largely based on talin and α-catenin, the two best-characterized mechanosensors. In both cases, it requires the unfolding of talin and α-catenin internal domains following their interaction with a junction receptor and with actin through terminal domains (del Rio et al, 2009;Hu et al, 2017;le Duc et al, 2010;Yao et al, 2016;Yao et al, 2014;Yonemura et al, 2010). There are two intriguing similarities between talin and plakins.…”

Statistical Mechanics of an Elastically Pinned Membrane: Static Profile and Correlations

“…Similarly, inside the cell, for example on the nuclear envelope, the cytoskeleton again couples to the external nuclear membrane by nesprins, while toward the interior, protein p58 serves as a membrane attachment site for the nuclear lamina by acting as a specific receptor for lamin B (5). All these couplings regulate the mechanical state of the cell, which in turn affects the cell motility, division rate, proliferation, mechanosensitivity, and a number of other processes (4). Hence, understanding the principles of protein-mediated interactions between membranes and the surrounding scaffolds is one of the key problems in mechanobiology.…”

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

“…In both cases, it occurs when talin and α-catenin interact with a junction receptor (integrin or ß-catenin bound to E-cadherin, respectively) and with actin through specific domains (del Rio et al, 2009;le Duc et al, 2010;Yao et al, 2016;Yao et al, 2014;Yonemura et al, 2010). Receptor activation combined with increased intracellular tension stretches talin or α-catenin to reveal vinculin-binding regions (Hu et al, 2017). How would the VAB-10 based mechanosensing process operate in comparison to talin and α-catenin?…”

“…Whereas mechanosensing events occurring at focal adhesions and adherens junctions have now been well characterized (Hu et al, 2017), hemidesmosomes represent another mechanosensitive junction about which much less is known. In vertebrates, there is evidence that plectin, a core component of vertebrate hemidesmosomes, can mediate the mechanical response of lung epithelial cell when combined with dystroglycan, or can regulate nuclear mechanotransduction in keratinocytes (Almeida et al, 2015;Takawira et al, 2011).…”