Myosin chaperones

Abstract

The folding and assembly of myosin motor proteins is essential for most movement processes at the cellular, but also at the organism level. Importantly, myosins, which represent a very diverse family of proteins, require the activity of general and specialized folding factors to develop their full motor function. The activities of the myosin-specific UCS (UNC-45/Cro1/She4) chaperones range from assisting acto-myosin dependent transport processes to scaffolding multi-subunit chaperone complexes, which are required to assemble myofilaments. Recent structure-function studies revealed the structural organization of TPR (tetratricopeptide repeat)-containing and TPR-less UCS chaperones. The observed structural differences seem to reflect the specialized and remarkably versatile working mechanisms of myosin-directed chaperones, as will be discussed in this review.

Graphical abstract

Figure 1

Organization of myosin. (a) Structure of the myosin motor domain. Cartoon representation of the myosin V head domain (PDB code: 1w7i). The conserved domain structure of myosin proteins is indicated with the 50 kDa ATPase domain shown in green, the N-terminal (often SH3-like) domain in blue, the converter in magenta and the neck in yellow. The N-termini and C-termini of the molecule are labeled pointing to the highly intertwined tertiary structure of the myosin head domain. (b) Schematic representation of a sarcomeric unit. Actin filaments (grey) interdigitate with myosin II filaments (green). Myosin heads protrude as dimeric motifs from the filament backbone to interact with their actin counterparts. (c) Schematic representation of myosin mediated cargo transport in S. cerevisiae. Myosin V dimers (green), loaded with vesicular cargo, walk along actin filaments (grey).

Figure 2

Structures of UCS proteins. (a) Structure of C. elegans UNC-45 (PDB code: 4i2z). Upper panel: Cartoon representation of an UNC-45 protomer with the TPR, central, neck and UCS domains shown in green, orange, yellow and grey, respectively. Lower panel: UNC-45 chain (three protomers are shown) as observed in the crystal lattice. The co-crystallized Hsp90 peptide (magenta) marks the TPR interaction site for partner chaperones. Interaction of the UCS domain with the myosin substrate (blue) was modeled on the basis of the beta-catenin/E-cadherin co-crystal structure (PDB code: 1i7x). (b) Structure of S. cerevisiae She4 (PDB code: 3opb). Upper panel: Cartoon representation of a She4 molecule. Domain colors as in (a). Lower panel: The She4 dimer as observed in the crystal packing. The central and neck domains constitute the dimerization interface.

Figure 3

UCS proteins employ distinct mechanisms to exert their chaperone activity. Left panel: TPR-containing UCS chaperones function as oligomers in myosin folding and thick filament assembly. UNC-45 chains assemble a platform to foster myosin and partner chaperone (Hsp70, Hsp90) interactions. In parallel this assembly line should help to arrange myosin II head domains along thick filaments. Right panel: TPR-less UCS proteins work as dimers. In addition to promoting myosin folding, the She4 dimer can also interact with folded myosin, determining the step-size of myosin V when walking along actin filaments.