Getting folded: chaperone proteins in muscle development, maintenance and disease

Abstract

Chaperone proteins are critical for protein folding and stability, and hence are necessary for normal cellular organization and function. Recent studies have begun to interrogate the role of this specialized class of proteins in muscle biology. During development, chaperone-mediated folding of client proteins enables their integration into nascent functional sarcomeres. In addition to assisting with muscle differentiation, chaperones play a key role in the maintenance of muscle tissues. Furthermore, disruption of the chaperone network can result in neuromuscular disease. In this review, we discuss how chaperones are involved in myofibrillogenesis, sarcomere maintenance, and muscle disorders. We also consider the possibilities of therapeutically targeting chaperones to treat muscle disease.

Keywords: chaperones; contractile proteins; myofibril; protein folding; sarcomere.

Figure 1

Representation of a simplified sarcomeric unit. Muscle fibers contain myofibrils with repeating sarcomeric units, the boundaries of which are defined by the Z-disk. The actin thin filaments are bound to the Z-disk and extend toward the middle of the sarcomere where they interact with the myosin motor domains of the thick filament. The I-bands are the region composed only of thin filaments whereas the A-band includes the region where the thick filaments interact with the thin filaments.

Figure 2

Chaperones with their respective client proteins during development and in the mature sarcomere. The chaperones Hsp90 and UNC-45 are responsible for myosin motor domain folding; myosin molecules are then incorporated into the thick filament (pink arrow). After sarcomere assembly, Hsp90 and UNC-45 appear to migrate to the Z-disk (blue, green arrows). The proposed UNC-45 activity modulator SmyD1 has been shown to interact with UNC-45 and is required for normal sarcomere development. It moves to the M-line following sarcomere assembly (purple arrow). The CCT (chaperonin) and GimC (prefoldin) complex is responsible for efficient folding of actin prior to incorporation into the thin filaments (yellow arrow), though Hsp25/27 and αB-crystallin have also been shown to facilitate actin folding. αB-crystallin assists in folding of titin and several intermediate filament proteins including desmin. Finally, N-RAP has been shown to assist in folding of the α-actinin protein that is incorporated into the Z-disk (orange arrows).

Figure 3

Localization and movement of chaperones in response to stress in vertebrate sarcomeric structures. Myosin chaperones Hsp90 and UNC-45 are held in reserve in the Z-disk until cellular stress induces rapid localization to the A-band. Similarly, the intermediate filament chaperones αB-crystallin and Hsp25/27 are located in the cytosol and localize to titin near the Z-disk upon stress to the sarcomere.