Mechanistic and functional diversity in the mechanosensory kinases of the titin-like family

Abstract

Abstract The giant cytoskeletal kinases of the titin-like family are emerging as key mediators of stretch-sensing in muscle. It is thought that their elastic conformational deformation during muscle function regulates both their catalysis and the recruitment of regulatory proteins to signalosomes that assemble in their vicinity. In the present article, we discuss the speciation of mechanosensory mechanisms in titin-like kinases, their scaffolding properties and the kinase/pseudokinase domain variations that define a rich functional diversity across the family. Titin-like kinases The cytoskeleton of muscle cells contains giant filamentous proteins of the titin-like family (0.7-4 MDa) that mediate the sensing and transduction of mechanical signals in the myofibril. Such mechanical signals drive the development and regulation of the tissue in adaptation to physical demands. Titin-like proteins are composed of numerous Iglike domains linked in series and contain one or two kinase domains invariably located near their C-termini. Members of this family include titin and obscurin in mammals; twitchin/UNC-22, the obscurin homologue UNC-89 and the small titin TTN-1 in nematodes; twitchin in molluscs; and projectin, UNC-89 and stretchin in insects Intrasteric regulation by kinase-flanking extensions The crystal structure of the Fn-linker-kinase-tail-Ig region of Caenorhabditis elegans twitchin (TwcKR) has been elucidated recentl