Muscle Giants Create Order from Chaos with Force

Abstract

Titin and nebulin possess perhaps the longest span of intrinsically disordered protein segments in the human proteome. We have implemented an integrated platform of nanomechanics to investigate the elasticity of intrinsically disordered segments and its functional manifestations. Our titin studies have indicated that the titin PEVK region is an elastic spring, with charge pairing as a new mechanism of creating diversity and modulating molecular elasticity. Significantly, PEVK also serves a dual role as a giant scaffold for SH3-containing signaling proteins. Many novel hybrid and overlapping motifs for SH3 domains are embedded in the seemingly random proline-rich sequences throughout the titin molecule. We now propose that titin PEVK directly couples the force sensing and response, by controlling the accessibility of SH3 receptor proteins via the opening and closing the access to binding sites upon mechanical stress, reversibly and elastically. In other words, titin's elastic PEVK appears to act both as an analog force sensor and as a transducer that converts the force input directly into biochemical signals of the SH3 pathways. Our nebulin studies indicated that native full length nebulin and nebulin modules are intrinsically disordered and elastic. We proposed that that nebulin is an “elastic or adjustable ruler” that has to be stretched and lengthened properly to interact and stabilize actin filaments. The continued presence of compressive force exerted by stretched nebulin may well be a requirement for thin filament assembly, integrity and maintenance. Additionally, since skeletal muscle thin filaments is thought to be “dually-regulated” where calcium activates contraction by targeting both troponin and nebulin-bound calcium sensor proteins (Root and Wang 1994), we envisage that nebulin tethers elastically myosin heads to actin in the inactivated state and then releases and de-inhibits myosin heads upon calcium activation.