Structure of giant muscle proteins

Abstract

Giant muscle proteins (e.g., titin, nebulin, and obscurin) play a seminal role in muscle elasticity, stretch response, and sarcomeric organization. Each giant protein consists of multiple tandem structural domains, usually arranged in a modular fashion spanning 500 kDa to 4 MDa. Although many of the domains are similar in structure, subtle differences create a unique function of each domain. Recent high and low resolution structural and dynamic studies now suggest more nuanced overall protein structures than previously realized. These findings show that atomic structure, interactions between tandem domains, and intrasarcomeric environment all influence the shape, motion, and therefore function of giant proteins. In this article we will review the current understanding of titin, obscurin, and nebulin structure, from the atomic level through the molecular level. Titin, obscurin, and nebulin are all giant muscle-specific proteins that play key roles in sarcomere organization, strength, and development. The size (all >500 kDa) and apparent flexibility of these molecules has hindered traditional structure determination. However, through the integration and creative use of multiple structural elucidation tools including crystallography, nuclear magnetic resonance (NMR), small angle x-ray scattering (SAXS), and electron microscopy (EM), a concerted effort to describe fully the structure and dynamics of these systems is underway. Here, we review the current understanding of giant muscle protein structure. Titin and obscurin are primarily composed of related but distinct modular domains, while nebulin has a more repetitive and simple repeating structure. © 2013 Meyer and Wright.