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PMID:18676612

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Citation

Kramerova, I, Kudryashova, E, Wu, B, Ottenheijm, C, Granzier, H and Spencer, MJ (2008) Novel role of calpain-3 in the triad-associated protein complex regulating calcium release in skeletal muscle. Hum. Mol. Genet. 17:3271-80

Abstract

Calpain-3 (CAPN3) is a non-lysosomal cysteine protease that is necessary for normal muscle function, as mutations in CAPN3 result in an autosomal recessive form of limb girdle muscular dystrophy type 2A. To elucidate the biological roles of CAPN3 in skeletal muscle, we performed a search for potential substrates and interacting partners. By yeast-two-hybrid analysis we identified the glycolytic enzyme aldolase A (AldoA) as a binding partner of CAPN3. In co-expression studies CAPN3 degraded AldoA; however, no accumulation of AldoA was observed in total extracts from CAPN3-deficient muscles suggesting that AldoA is not an in vivo substrate of CAPN3. Instead, we found CAPN3 to be necessary for recruitment of AldoA to one specific location, namely the triads, which are structural components of muscle responsible for calcium transport and excitation-contraction coupling. Both aldolase and CAPN3 are present in the triad-enriched fraction and are able to interact with ryanodine receptors (RyR) that form major calcium release channels. Levels of triad-associated AldoA and RyR were decreased in CAPN3-deficient muscles compared with wild-type. Consistent with these observations we found calcium release to be significantly reduced in fibers from CAPN3-deficient muscles. Together, these data suggest that CAPN3 is necessary for the structural integrity of the triad-associated protein complex and that impairment of calcium transport is a phenotypic feature of CAPN3-deficient muscle.

Links

PubMed PMC2566524 Online version:10.1093/hmg/ddn223

Keywords

Animals; Calcium/metabolism; Calpain/genetics; Calpain/metabolism; Cell Line; Fructose-Bisphosphate Aldolase/metabolism; Humans; Mice; Muscle Proteins/genetics; Muscle Proteins/metabolism; Muscle, Skeletal/enzymology; Muscle, Skeletal/metabolism; Protein Transport/physiology; Ryanodine Receptor Calcium Release Channel/metabolism

Significance

Annotations

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

MOUSE:ALDOA

located_in

GO:0016020: membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:ALDOA

located_in

GO:0030018: Z disc

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(UBERON:0004057)

Seeded From UniProt

complete

RAT:CAN3

involved_in

GO:0097264: self proteolysis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:CAN3

involved_in

GO:0006508: proteolysis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:CAN3

enables

GO:0019899: enzyme binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P05064

F

Seeded From UniProt

complete

RAT:CAN3

enables

GO:0005102: signaling receptor binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:E9PZQ0

F

Seeded From UniProt

complete

MOUSE:CAN3

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(UBERON:0002385)

Seeded From UniProt

complete

MOUSE:CAN3

part_of

GO:0032991: protein-containing complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:CAN3

located_in

GO:0005829: cytosol

ECO:0000314: direct assay evidence used in manual assertion

C

  • part_of:(UBERON:0002385)

Seeded From UniProt

complete

MOUSE:CAN3

enables

GO:0008307: structural constituent of muscle

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:CAN3

involved_in

GO:0051281: positive regulation of release of sequestered calcium ion into cytosol

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • occurs_in:(UBERON:0001134)

Seeded From UniProt

complete

MOUSE:CAN3

involved_in

GO:0061061: muscle structure development

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:CAN3

involved_in

GO:0065003: protein-containing complex assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:CAN3

involved_in

GO:0072657: protein localization to membrane

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:P05064)
  • occurs_in:(UBERON:0004057)

Seeded From UniProt

complete

MOUSE:CAN3

enables

GO:0060090: molecular adaptor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:ALDOA

enables

GO:0002020: protease binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P16259

F

Seeded From UniProt

complete

MOUSE:ALDOA

part_of

GO:0016020: membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:ALDOA

part_of

GO:0030018: Z disc

ECO:0000314: direct assay evidence used in manual assertion

C

part_of:(UBERON:0004057)

Seeded From UniProt

complete

MOUSE:ALDOA

part_of

GO:0032991: protein-containing complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:RYR1

enables

GO:0002020: protease binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P16259

F

Seeded From UniProt

complete

MOUSE:RYR1

part_of

GO:0032991: protein-containing complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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