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The talin protein (large, involved in combinatorial control of synaptic memory). Could it be highly affected by aging b/c of its large size?

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Ben Goult presentations are the best!!





https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8697387/ (with the POSTER)




Binding of talin to the integrin β-tail disrupts the autoinhibitory association between the integrin α- and β-tails and promotes a conformational transition in the integrin structure that increases its affinity for extracellular ligands (Kim et al., 2011). Talin also links to actin filaments via the two actin-binding sites (ABS2 and ABS3) within the talin rod (Atherton et al., 2015) and by recruiting additional actin-binding proteins (Critchley, 2009; Goult et al., 2018; Klapholz and Brown, 2017) (see poster). We note that an additional actin-binding site ABS1 in the talin head also provides additional cytoskeletal linkages (Ciobanasu et al., 2018; Hemmings et al., 1996), but its function is not well understood. Of these, vinculin is best characterized and can bind to the 11 vinculin binding sites (VBSs) distributed throughout the talin rod (Gingras et al., 2005). In Drosophila at least, talin is essential for the recruitment of the remainder of the integrin-associated proteins, either directly or indirectly (Klapholz and Brown, 2017). This has led to the idea that talin forms a ‘platform’ for the assembly of an integrin adhesion complex. This design ensures that high-affinity ECM binding and connection to the cytoskeleton are functionally linked.

Once talin links integrins and actin, it transmits both cell-generated contractile forces and forces derived from externally applied strains between these components. Measured forces across talin range from a few to above 11 piconewtons (Austen et al., 2015; Driscoll et al., 2020; Kumar et al., 2016). The responses of talin to forces have four features with important consequences. First, forces stabilise the extended conformation of talin (Khan and Goult, 2019) as the head and tail are held apart by the tension, thus limiting autoinhibition mediated by head–tail interactions. Second, the binding of talin to actin and integrin shows catch-bond behaviour, that is the binding becomes stronger under moderate forces (Owen et al., 2020 preprint), which further stabilizes the activated, engaged state. Third, force unfolds the helix bundles of the talin rod domain; this simultaneously disrupts binding of proteins that bind the folded state and exposes binding sites for others (see poster and discussion below). Finally, talin rod domain unfolding exhibits hysteresis such that the force required for unfolding is higher than the force at which it refolds. For example, if a rod domain unfolds in response to a force of 10 pN it will not immediately refold when the force drops to just below 10 pN. Instead, refolding requires tension that is substantially lower (e.g. ∼1–3 pN; Yao et al., 2016). Thus, the basal physiological forces (∼5 pN) on talin within adhesions (Kumar et al., 2016) stabilise the patterns of folded and unfolded talin rod domains (Yao et al., 2016). Together, these features endow the talin molecule with mechanical memory (see poster and discussion below).



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  • InquilineKea changed the title to The talin protein (large, involved in combinatorial control of synaptic memory). Could it be highly affected by aging b/c of its large size?

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