Calpain 3: a key regulator of the sarcomere?
Calpain 3 is a 94-kDa calcium-dependent cysteine protease mainly expressed in skeletal muscle. In this tissue, it localizes at several regions of the sarcomere through binding to the giant protein, titin. Loss-of-function mutations in the calpain 3 gene have been associated with limb-girdle muscular dystrophy type 2A (LGMD2A), a common form of muscular dystrophy found world wide. Recently, significant progress has been made in understanding the mode of regulation and the possible function of calpain 3 in muscle. It is now well accepted that it has an unusual zymogenic activation and that cytoskeletal proteins are one class of its substrates. Through the absence of cleavage of these substrates, calpain 3 deficiency leads to abnormal sarcomeres, impairment of muscle contractile capacity, and death of the muscle fibers. These data indicate a role for calpain 3 as a chef d'orchestre in sarcomere remodeling and suggest a new category of LGMD2 pathological mechanisms.
Duguez
Stéphanie
S
Généthon, CNRS UMR8115, Evry, France.
Bartoli
Marc
M
Richard
Isabelle
I
D000818:Animals; D002154:Calpain / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D015870:Gene Expression; D006801:Humans; D006868:Hydrolysis; D015394:Molecular Structure; D009124:Muscle Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D012518:Sarcomeres / Q000502:physiology*; D013347:Subcellular Fractions / Q000201:enzymology; D013379:Substrate Specificity
D009124:Muscle Proteins; C105884:CAPN3 protein, human; D002154:Calpain