Talin in mechanotransduction and mechanomemory at a glance

Abstract

Talins are cytoskeletal linker proteins that consist of an N-terminal head domain, a flexible neck region and a C-terminal rod domain made of 13 helical bundles. The head domain binds integrin β-subunit cytoplasmic tails, which triggers integrin conformational activation to increase affinity for extracellular matrix proteins. The rod domain links to actin filaments inside the cell to transmit mechanical loads and serves as a mechanosensitive signalling hub for the recruitment of many other proteins. The α-helical bundles function as force-dependent switches – proteins that interact with folded bundles are displaced when force induces unfolding, exposing previously cryptic binding sites for other ligands. This leads to the notion of a talin code. In this Cell Science at a Glance article and the accompanying poster, we propose that the multiple switches within the talin rod function to process and store time- and force-dependent mechanical and chemical information.

The MeshCODE to scale – Visualising synaptic binary information

“…The spatial organisation of enzymatic activity can be achieved via scaffold, anchoring and adapter proteins 50 . Many talin ligands are enzymes, or known enzyme substrates 27,44,45 , and there are many enzymes linked to IACs 46 and located in dendritic spines 47 . Some of these, such as receptor-linked kinases are membrane bound, some are freely diffusing and some specifically engage the talin switches.…”

“…The talin molecules anchored around the periphery of the active zone/PSD, would be acting in synchrony as springs, connecting the force generation machinery to the active zone. Each talin would be serving as a mechanosensitive signalling hub 21,27 and as the binary patterns change, molecules engaged to the MeshCODE would be (re)positioned at quantised distances relative to the active zone/PSD. If all the talins within a spine have similar binary patterns it would have the implication that molecules engaging the MeshCODE would be stratified in the z-dimension relative to the active zone/PSD ( Fig.6C-D ).…”

“…These switch domains are helical bundles that open and close in response to mechanical signals 26 . The switches coordinate signalling outputs by recruiting and displacing different signalling molecules as a function of their state 21,27 . When in the open, 1 state, 9 of the 13 talin switches expose binding sites for vinculin 28 .…”

A subpopulation of Talin 1 resides in the nucleus and regulates gene expression

“…The LINC complex connects the nuclear envelope with the contractile cytoskeleton, and this physical connection mediates the transmission of force to proteins in the inner periphery of the nuclear envelope including nuclear lamins (Miroshnikova et al , 2019; Khilan et al , 2021). Curiously, the rod domain of TLN1 is composed of 13 α-helical bundles that function as mechanosensitive switches, which change their conformation to expose binding sites for different interacting partners (Goult et al , 2021). Thus, one can hypothesize that TLN1 acts as a nuclear mechanosensitive signaling hub.…”

“…To achieve its function at the FAs, TLN1 has a particular domain structure that is composed of an N-terminal FERM (4.1 protein, ezrin, radixin, moesin) domain, known as the head domain, which is coupled to a flexible rod domain comprised of 13 helical bundles (Goult et al , 2013b). The head domain interacts with the cytoplasmic tails of β-integrin subunits, whereas the rod domain binds to actin filaments and acts as a mechanosensitive signaling hub (Goult et al , 2021) (Fig 1A, left panel). Dysregulation of TLN1 is associated with different diseases, such as cancer, cardiovascular malfunction, and hematologic disorders, which makes TLN1 a relevant protein in the context of therapeutics and diagnostics (Azizi et al , 2021; Li et al , 2021; Haining et al , 2016).…”