Molecular Investigations into the Mechanics of a Muscle Anchoring Complex

Abstract

The titin-telethonin complex, essential for anchoring filaments in the Z-disk of the sarcomere, is composed of immunoglobulin domains. Surprisingly, atomic force microscopy experiments showed that it resists forces much higher than the typical immunoglobulin domain and that the force distribution is unusually broad. To investigate the origin of this behavior, we developed a multiscale simulation approach, combining minimalist and atomistic models (SOP-AT). By following the mechanical response of the complex on experimental timescales, we found that the mechanical stability of titin-telethonin is modulated primarily by the strength of contacts between telethonin and the two titin chains, and secondarily by the timescales of conformational excursions inside telethonin and the pulled titin domains. Importantly, the conformational transitions executed by telethonin in simulations support its proposed role in mechanosensing. Our SOP-AT computational approach thus provides a powerful tool for the exploration of the link between conformational diversity and the broadness of the mechanical response, which can be applied to other multidomain complexes.

Empagliflozin Preserves Skeletal Muscle Function in a HFpEF Rat Model

“…One explanation would be the improvement of mitochondrial oxidative phosphorylation (discussion see below) and the increased expression of telethonin due to a modulation of the ubiquitin proteasome system (see Figure 4 ). Telethonin anchors the N-terminal region of titin in the Z-disk [ 37 ] and as an adapter protein it links myofibrillar components with the membranous beta-subunit of the I(Ks) channel [ 38 ]. In addition, telethonin knockdown leads to embryonic paralysis, myocyte defects and sarcomeric disruption [ 39 ].…”

Adaptability of protein structures to enable functional interactions and evolutionary implications

“…We present here a few recent studies supporting these concepts: Dima and coworkers showed that the conformational diversity attained via excursions on the conformational landscape underlie the mechanosensing functionality of a muscle anchoring complex observed in atomic force microscopy (AFM) [27]; Gur et al showed that the reconfiguration of adenylate kinase between its open and closed forms upon ligand binding takes place along such valleys of the conformational space [28]. Further, the conformational pathways described by a single mode starting from the open state were shown to successfully predict the closed state for a set of proteins that undergo large hinge-bending motions [29].…”