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doi: 10.1242/10.1242/jcs.00107

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The UCS family of myosin chaperones

¹ Departments of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX 77030, USA
² Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA

View larger version (30K): [in a new window]   Fig. 1. UCS-domain targets — type II and type V myosins. The common feature of all myosin classes is the myosin motor domain that contains the actin- and ATP-binding sites. The different classes are distinguished by their tails. Type II, or conventional myosin heavy chains possess coiled-coil tails that mediate dimerization and assembly into filamentous structures that function in processes such as cytokinesis and muscle contraction. Type V unconventional myosin heavy chains also dimerize through coiled coils but do not assemble into filaments and are implicated in intracellular transport of a variety of cargoes (Berg et al., 2001; Reck-Peterson et al., 2000; Sellers, 2000). Proteins X and Y represent myosin V tail-binding proteins that may mediate interactions with cargo (Reck-Peterson et al., 2000).

View larger version (19K): [in a new window]   Fig. 2. UCS domain-myosin interactions. Genetic analysis of UCS proteins from S. pombe (Rng3p), S. cerevisiae (She4p) and C. elegans (UNC-45) indicate functional interactions with type II and type V myosins.

View larger version (19K): [in a new window]   Fig. 3. The functions and interacting partners of UNC-45. The N-terminal TPR domain of UNC-45 binds directly to the C-terminal MEEVD motif of Hsp90. In addition to binding Hsp70, the central region and UCS domain of UNC-45 binds and has molecular chaperone activity on myosin S1 and the standard chaperone substrate citrate synthase (CS) (Barral et al., 2002).

View larger version (9K): [in a new window]   Fig. 4. The subfragments of myosin. Heavy meromyosin (HMM) and light meromyosin (LMM) can be obtained by proteolytic cleavage. Further cleavage at the neck of HMM separates the single-headed S1 fragments from the S2 fragment.

View larger version (146K): [in a new window]   Fig. 5. A multiple sequence alignment of invertebrate and vertebrate UNC-45 proteins. All show the same three-domain structure of a TPR domain (red), a unique central region (green) and a UCS domain (blue). Two isoforms are present in the bony fish Fugu rubripies as well as in mammals, suggesting that they diverged early in vertebrate radiation. Ag, Anopheles gambiae (coding sequence compiled from GenBank acc. no. AAAB01008844.1); Dm, Drosophila melanogaster (GenBank acc. no. AAK93568); Ce, Caenorhabditis elegans (GenBank acc. no. AAD01976); Cb, Caenorhabditis briggsae (GenBank acc. no. AAD01960); Dr, Danio rerio (GenBank acc. no. AAL57031); Fr, Fugu rubripies (SM, coding sequence compiled from JGI Fugu genome project scaffold 6404; GC, coding sequence compiled from JGI Fugu genome project scaffold 465); Mm, Mus musculus (SM, coding sequence compiled from AL603745; GC, GenBank acc. no. AAH04717); Hs, Homo sapiens (SM, coding sequence compiled from AC022916; GC, GenBank acc. nos. BAB20273, AAH06214); SM, striated muscle isoform; GC, general cell isoform.

View larger version (19K): [in a new window]   Fig. 6. A possible model for the function of UNC-45 in the folding and maturation of myosin motors based on the proposed mechanism of steroid receptor maturation (Kosano et al., 1998; Pratt and Toft, 1997). The interactions of UNC-45 with the molecular chaperones Hsp70 and Hsp90 may allow it to function as a co-chaperone that targets Hsp70 (1) and subsequently Hsp90 (2) to unfolded myosin. Under physiological conditions, Hsp70 may be complexed with Hsp40 and Hsp90 with p23 and an immunophilin such as FKBP52 (Kosano et al., 1998; Pratt and Toft, 1997). Myosin has already been shown to be associated with the eukaryotic chaperonin containing TCP-1 (CCT) (Srikakulam and Winkelmann, 1999) and may do so in an early step of its folding prior to the function of UNC-45. Upon acting on myosin, Hsp70 would leave the folding complex (3) and Hsp90 would further promote folding as it has been shown to associate with near-native folding intermediates (Jakob et al., 1995). Once the myosin motor has reached a mature state, UNC-45 and Hsp90 would dissociate (4) to begin another folding cycle.