Regulation of the Myosin-Directed Chaperone UNC-45 by a Novel E3/E4-Multiubiquitylation Complex in C. elegans

@article{Hoppe2004RegulationOT,
  title={Regulation of the Myosin-Directed Chaperone UNC-45 by a Novel E3/E4-Multiubiquitylation Complex in C. elegans},
  author={Thorsten Hoppe and Giuseppe Cassata and José Moreno Barral and Wolfdieter Springer and Alex H. Hutagalung and Henry F. Epstein and Ralf Baumeister},
  journal={Cell},
  year={2004},
  volume={118},
  pages={337-349}
}
The organization of the motor protein myosin into motile cellular structures requires precise temporal and spatial control. Caenorhabditis elegans UNC-45 facilitates this by functioning both as a chaperone and as a Hsp90 cochaperone for myosin during thick filament assembly. Consequently, mutations in C. elegans unc-45 result in paralyzed animals with severe myofibril disorganization in striated body wall muscles. Here, we report a new E3/E4 complex, formed by CHN-1, the C. elegans ortholog of… Expand
The Myosin Chaperone UNC-45 Is Organized in Tandem Modules to Support Myofilament Formation in C. elegans
TLDR
In vivo analyses reveal the elongated canyon of the UCS domain as a myosin-binding site and show that multimeric UNC-45 chains support organization of sarcomeric repeats. Expand
The ubiquitin-selective chaperone CDC-48/p97 links myosin assembly to human myopathy
TLDR
A key role is identified for CDC-48/p97 in the process of myofibre differentiation and maintenance, which is abolished during pathological conditions leading to protein aggregation and inclusion-body formation in human skeletal muscle. Expand
The myosin-binding UCS domain but not the Hsp90-binding TPR domain of the UNC-45 chaperone is essential for function in Caenorhabditis elegans
TLDR
It is shown that the myosin-binding UCS domain of UNC-45 alone is sufficient to rescue lethal unc-45 null mutants arrested in embryonic muscle development and temperature-sensitive loss-of-functionunc-45 mutants defective in worm A-band assembly. Expand
UNC-45: A Chaperone for Myosin and a Co-Chaperone for Hsp90
UNC-45 is a prototype of the protein family characterized by the presence of the C-terminal UCS (UNC-45/CR01/She4p) domain. These proteins function in various important actin- and myosin-dependentExpand
Less is more: how protein degradation regulates muscle development.
  • T. Hoppe
  • Biology, Medicine
  • Ernst Schering Foundation symposium proceedings
  • 2008
TLDR
It is suggested that functional muscle formation in Caenorhabditis elegans is linked to ubiquitin-dependent UNC-45 turnover, regulated by the E3 enzymes UFD-2 and CHN-1 in cooperation with the ubiquitIn-selective chaperone CDC-48 (also known as p97 in human). Expand
The UNC-45 chaperone mediates sarcomere assembly through myosin degradation in Caenorhabditis elegans
TLDR
It is found that loss-of-function mutations in Caenorhabditis elegans UNC-45 lead to decreased muscle myosin accumulation and defective thick filament assembly, resulting in paralyzed animals, and that the reduction is the result of degradation through the ubiquitin/proteasome system. Expand
Mutations in conserved residues of the myosin chaperone UNC‐45 result in both reduced stability and chaperoning activity
TLDR
Interestingly, the biophysical assays performed on purified proteins show that all of the mutations result in reduced myosin chaperone activity but not overall protein stability, suggesting that these mutations only cause protein instability in the in vivo setting and that these conserved regions may be involved in UNC-45 protein stability/regulation via post translational modifications, protein-protein interactions, or some other unknown mechanism. Expand
UFD-2 is an adaptor-assisted E3 ligase targeting unfolded proteins
TLDR
In vitro and in vivo experiments are performed and it is shown that UFD-2 has E3 ligase activity and that it ubiquitinates unfolded myos in muscle cells using the C. elegans myosin chaperone UNC-45 as an adaptor protein. Expand
UNC-45A Is a Nonmuscle Myosin IIA Chaperone Required for NK Cell Cytotoxicity via Control of Lytic Granule Secretion
TLDR
It is shown that, in human NK cells, UNC-45A localize at the NK cell immunological synapse of activated NK cells and is part of the multiprotein complex formed during NK cell activation, suggesting that UNC- 45A is a crucial component in regulating human NK cell cytoskeletal dynamics via promoting the formation of actomyosin complexes. Expand
Chaperoning myosin assembly in muscle formation and aging
TLDR
Recent findings on the dynamic regulation of UNC-45 structure and stability in the context of muscle regeneration mechanisms that are affected in myopathic diseases and during aging are discussed. Expand
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