Titin(S): Towards an Atomic Understanding of Mechanosensory Events in the Elastic Scaffolds of the Muscle Sarcomere

Abstract

The giant intra-sarcomeric filaments of the titin-like family are key orchestrators of stretch-sensing pathways that regulate muscle responses to mechanical load. Despite acute variations in the length and domain organization of these filamentous proteins across the animal biodiversity, they all comprise numerous Ig/FnIII domains linked in series and one or two kinase domains invariably located near their C-terminus. Combining the 3D-structural elucidation of multi-domain components at atomic level, in silico simulations, molecular engineering and in vivo transgenic muscle technologies, we are revealing the molecular events taking place during mechanosensing in titin-like proteins.Our findings show that the sensory role of titin is enabled by a subtle inter-domain order in the chain, imposed by short linkers that sterically govern domain packing and dynamics. This modular design is sensitive to mechanical deformations but affords a “chain memory” mechanism for molecular recovery. The local disruption of such domain arrangements by genetic mutation leads to human myopathy. Our data show that also the kinase domains of titin-like proteins undergo elastic deformations in their regulatory, flanking segments during muscle activity in vivo. Contrary to expectations, these kinases are catalytically-dispensable for muscle function and development. Instead, they act as regulated scaffolds for the recruitment of turnover/signaling proteins onto kinase-based signalosomes. This talk will provide a molecular perspective on the stretch-induced mechanics and signaling of titin-like proteins.Zacharchenkov T, et al. (2015). Biochem Soc Trans. In press.Bogomolovas J, et al. (2014). Open Biology. 4(5):140041.Von Castelmur E, et al. (2012). P.N.A.S. 109(34):13608-13.