The N- and C-terminal autolytic fragments of CAPN3/p94/calpain-3 restore proteolytic activity by intermolecular complementation

Yasuko Ono, Mayumi Shindo, Naoko Doi, Fujiko Kitamura, Carol C. Gregorio, Hiroyuki Sorimachi

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

CAPN3/p94/calpain-3, a calpain protease family member predominantly expressed in skeletal muscle, possesses unusually rapid and exhaustive autolytic activity. Mutations in the human CAPN3 gene impairing its protease functions cause limb-girdle muscular dystrophy type 2A (LGMD2A); yet, the connection between CAPN3's autolytic activity and the enzyme's function in vivo remain unclear. Here, we demonstrated that CAPN3 protease activity was reconstituted by intermolecular complementation (iMOC) between its two autolytic fragments. Furthermore, the activity of full-length CAPN3 active-site mutants was surprisingly rescued through iMOC with autolytic fragments containing WT amino acid sequences. These results provide evidence that WT CAPN3 can be formed by the iMOC of two different complementary CAPN3 mutants. The finding of iMOC-mediated restoration of calpain activity indicates a novel mechanism for the genotype-phenotype links in LGMD2A.

Original languageEnglish (US)
Pages (from-to)E5527-E5536
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number51
DOIs
StatePublished - Dec 23 2014

Keywords

  • Calpain
  • Complementation
  • Muscular dystrophy
  • Protease
  • Skeletal muscle

ASJC Scopus subject areas

  • General

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