Affiliation:
1. Généthon, CNRS UMR-8115, 91000 Evry, France
Abstract
ABSTRACT
Calpain
3 (Capn3) is known as the skeletal muscle-specific member of the
calpains, a family of intracellular nonlysosomal cysteine
proteases. This enigmatic protease has many unique features among the
calpain family and, importantly, mutations in Capn3 have been shown to
be responsible for limb girdle muscular dystrophy type 2A. Here we
demonstrate that the Capn3 activation mechanism is similar to the
universal activation of caspases and corresponds to an autolysis within
the active site of the protease. We undertook a search for substrates
in immature muscle cells, as several lines of evidence suggest that
Capn3 is mostly in an inactive state in muscle and needs a signal to be
activated. In this model, Capn3 proteolytic activity leads to
disruption of the actin cytoskeleton and disorganization of focal
adhesions through cleavage of several endogenous proteins. In addition,
we show that titin, a previously identified Capn3 partner, and filamin
C are further substrates of Capn3. Finally, we report that Capn3
colocalizes in vivo with its substrates at various sites along
cytoskeletal structures. We propose that Capn3-mediated cleavage
produces an adaptive response of muscle cells to external and/or
internal stimuli, establishing Capn3 as a muscle cytoskeleton
regulator.
Publisher
American Society for Microbiology
Subject
Cell Biology,Molecular Biology
Cited by
131 articles.
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