title: Calpain 3 is a rapid-action, unidirectional proteolytic switch central to muscle remodeling.
abstract: Calpain 3 (CAPN3) is a cysteine protease that when mutated causes Limb Girdle Muscular Dystrophy 2A. It is thereby the only described Calpain family member that genetically causes a disease. Due to its inherent instability little is known of its substrates or its mechanism of activity and pathogenicity. In this investigation we define a primary sequence motif underlying CAPN3 substrate cleavage. This motif can transform non-related proteins into substrates, and identifies >300 new putative CAPN3 targets. Bioinformatic analyses of these targets demonstrate a critical role in muscle cytoskeletal remodeling and identify novel CAPN3 functions. Among the new CAPN3 substrates are three E3 SUMO ligases of the Protein Inhibitor of Activated Stats (PIAS) family. CAPN3 can cleave PIAS proteins and negatively regulates PIAS3 sumoylase activity. Consequently, SUMO2 is deregulated in patient muscle tissue. Our study thus uncovers unexpected crosstalk between CAPN3 proteolysis and protein sumoylation, with strong implications for muscle remodeling.
authors.affiliation: Center for Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Antoine
authors.initials: A
authors.lastname: de Morrée
authors.forename: David
authors.initials: D
authors.lastname: Lutje Hulsik
authors.forename: Antonietta
authors.initials: A
authors.lastname: Impagliazzo
authors.forename: Herman H H B M
authors.initials: HH
authors.lastname: van Haagen
authors.forename: Paula
authors.initials: P
authors.lastname: de Galan
authors.forename: Alexandra
authors.initials: A
authors.lastname: van Remoortere
authors.forename: Peter A C
authors.initials: PA
authors.lastname: 't Hoen
authors.forename: Gertjan B
authors.initials: GB
authors.lastname: van Ommen
authors.forename: Rune R
authors.initials: RR
authors.lastname: Frants
authors.forename: Silvère M
authors.initials: SM
authors.lastname: van der Maarel
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D002154:Calpain / Q000737:chemistry / Q000378:metabolism*; D019295:Computational Biology; D016384:Consensus Sequence; D003599:Cytoskeleton / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D009132:Muscles / Q000166:cytology / Q000378:metabolism*
chemical_list: D002154:Calpain