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Calpain 3 cleaves filamin C and regulates its ability to interact with gamma- and delta-sarcoglycans.

Calpain 3 (C3) is the only muscle-specific member of the calcium-dependent protease family. Although neither its physiological function nor its in vivo substrates are known, C3 must be an important protein for normal muscle function as mutations in the C3 gene result in limb-girdle muscular dystrophy type 2A. Previous reports have shown that the ubiquitous calpains (mu and m) proteolyze filamins in nonmuscle cells. This observation suggests that the muscle-specific filamin C (FLNC) is a good candidate substrate for C3. Binding studies using recombinant proteins establish that recombinant C3 and native FLNC can interact. When these two proteins are translated in vitro and incubated together, C3 cleaves the C-terminal portion of FLNC. Cleavage is specific as C3 fails to cleave FLNC lacking its C-terminal hinge and putative dimerization domains. Cotransfection experiments in COS-7 cells confirm that C3 can cleave the C-terminus of FLNC in live cells. The C-terminus of FLNC has been shown to bind the cytoplasmic domains of both delta- and gamma-sarcoglycan. Removal of the last 127 amino acids from FLNC, a protein that mimics FLNC after C3 cleavage, abolishes this interaction with the sarcoglycans. These studies confirm that C3 can cleave FLNC in vitro and suggest that FLNC may be an in vivo substrate for C3, functioning to regulate protein-protein interactions with the sarcoglycans. Thus, calpain-mediated remodeling of cytoskeletal-membrane interactions, such as those that occur during myoblast fusion and muscle repair, may involve regulation of FLNC-sarcoglycan interactions.

Pubmed ID: 14506720

Authors

  • Guyon JR
  • Kudryashova E
  • Potts A
  • Dalkilic I
  • Brosius MA
  • Thompson TG
  • Beckmann JS
  • Kunkel LM
  • Spencer MJ

Journal

Muscle & nerve

Publication Data

October 24, 2003

Associated Grants

  • Agency: NINDS NIH HHS, Id: P01 NS040828
  • Agency: NINDS NIH HHS, Id: P01 NS40828
  • Agency: NIAMS NIH HHS, Id: R01 AR48177
  • Agency: NIAMS NIH HHS, Id: R03 AR45838

Mesh Terms

  • Animals
  • COS Cells
  • Calpain
  • Cercopithecus aethiops
  • Contractile Proteins
  • Cytoskeletal Proteins
  • Filamins
  • Isoenzymes
  • Membrane Glycoproteins
  • Microfilament Proteins
  • Muscle Proteins
  • Rats
  • Recombinant Proteins
  • Sarcoglycans
  • Transfection