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PMID:16243356

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Citation

Kudryashova, E, Kudryashov, D, Kramerova, I and Spencer, MJ (2005) Trim32 is a ubiquitin ligase mutated in limb girdle muscular dystrophy type 2H that binds to skeletal muscle myosin and ubiquitinates actin. J. Mol. Biol. 354:413-24

Abstract

Trim32 belongs to the tripartite motif (TRIM) protein family, which is characterized by a common domain structure composed of a RING-finger, a B-box, and a coiled-coil motif. In addition to these motifs, Trim32 possesses six C-terminal NHL-domains. A point mutation in one NHL domain (D487N) has been linked to two forms of muscular dystrophy called limb girdle muscular dystrophy type 2H and sarcotubular myopathy. In the present study we demonstrate that Trim32 is an E3 ubiquitin ligase that acts in conjunction with ubiquitin-conjugating enzymes UbcH5a, UbcH5c, and UbcH6. Western blot analysis showed that Trim32 is expressed primarily in skeletal muscle, and revealed its differential expression from one muscle to another. The level of Trim32 expression was elevated significantly in muscle undergoing remodeling due to changes in weight bearing. Furthermore, expression of Trim32 was induced in myogenic differentiation. Thus, variability in Trim32 expression in different skeletal muscles could be due to induction of Trim32 expression upon changes in physiological conditions. We show that Trim32 associates with skeletal muscle thick filaments, interacting directly with the head and neck region of myosin. Our data indicate that myosin is not a substrate of Trim32; however, Trim32 was found to ubiquitinate actin in vitro and to cause a decrease in the level of endogenous actin when transfected into HEK293 cells. In conclusion, our results demonstrate that Trim32 is a ubiquitin ligase that is expressed in skeletal muscle, can be induced upon muscle unloading and reloading, associates with myofibrils and is able to ubiquitinate actin, suggesting its likely participation in myofibrillar protein turnover, especially during muscle adaptation.

Links

PubMed Online version:10.1016/j.jmb.2005.09.068

Keywords

Actins/metabolism; Animals; Blotting, Western; Cell Differentiation; Cells, Cultured; Hindlimb Suspension; Kidney/metabolism; Male; Mice; Muscle Proteins/genetics; Muscle Proteins/immunology; Muscle Proteins/metabolism; Muscle, Skeletal/metabolism; Muscular Dystrophies, Limb-Girdle; Mutation/genetics; Myofibrils/metabolism; Peptide Fragments/immunology; Protein Binding; Rabbits; Saccharomyces cerevisiae/genetics; Saccharomyces cerevisiae/growth & development; Saccharomyces cerevisiae/metabolism; Skeletal Muscle Myosins/metabolism; Subcellular Fractions; Two-Hybrid System Techniques; Ubiquitin/metabolism; Ubiquitin-Conjugating Enzymes/metabolism; Ubiquitin-Protein Ligases/genetics; Ubiquitin-Protein Ligases/immunology; Ubiquitin-Protein Ligases/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:TRI32

acts_upstream_of_or_within

GO:0016567: protein ubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TRI32

located_in

GO:0005863: striated muscle myosin thick filament

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:TRI32

acts_upstream_of_or_within

GO:0007014: actin ubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

  • occurs_in:(EMAPA:35988)

Seeded From UniProt

complete

MOUSE:TRI32

enables

GO:0017022: myosin binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:Q8VDD5

F

Seeded From UniProt

complete

MOUSE:TRI32

enables

GO:0031369: translation initiation factor binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:P10630

F

Seeded From UniProt

complete

MOUSE:TRI32

acts_upstream_of_or_within

GO:0045732: positive regulation of protein catabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:TRI32

enables

GO:0061630: ubiquitin protein ligase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete


See also

References

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