title: The atypical calpains: evolutionary analyses and roles in Caenorhabditis elegans cellular degeneration.
abstract: The calpains are physiologically important Ca(2+)-activated regulatory proteases, which are divided into typical or atypical sub-families based on constituent domains. Both sub-families are present in mammals, but our understanding of calpain function is based primarily on typical sub-family members. Here, we take advantage of the model organism Caenorhabditis elegans, which expresses only atypical calpains, to extend our knowledge of the phylogenetic evolution and function of calpains. We provide evidence that a typical human calpain protein with a penta EF hand, detected using custom profile hidden Markov models, is conserved in ancient metazoans and a divergent clade. These analyses also provide evidence for the lineage-specific loss of typical calpain genes in C. elegans and Ciona, and they reveal that many calpain-like genes lack an intact catalytic triad. Given the association between the dysregulation of typical calpains and human degenerative pathologies, we explored the phenotypes, expression profiles, and consequences of inappropriate reduction or activation of C. elegans atypical calpains. These studies show that the atypical calpain gene, clp-1, contributes to muscle degeneration and reveal that clp-1 activity is sensitive to genetic manipulation of [Ca(2+)](i). We show that CLP-1 localizes to sarcomeric sub-structures, but is excluded from dense bodies (Z-disks). We find that the muscle degeneration observed in a C. elegans model of dystrophin-based muscular dystrophy can be suppressed by clp-1 inactivation and that nemadipine-A inhibition of the EGL-19 calcium channel reveals that Ca(2+) dysfunction underlies the C. elegans MyoD model of myopathy. Taken together, our analyses highlight the roles of calcium dysregulation and CLP-1 in muscle myopathies and suggest that the atypical calpains could retain conserved roles in myofilament turnover.
authors.affiliation: School of Biochemistry, University of Bristol, Bristol, United Kingdom.
authors.forename: Peter I
authors.initials: PI
authors.lastname: Joyce
authors.forename: Rahul
authors.initials: R
authors.lastname: Satija
authors.forename: Maozi
authors.initials: M
authors.lastname: Chen
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Kuwabara
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics*; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D049028:Dystrophin-Associated Protein Complex / Q000235:genetics / Q000378:metabolism; D020832:EF Hand Motifs / Q000235:genetics; D019143:Evolution, Molecular; D005786:Gene Expression Regulation; D006801:Humans; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009136:Muscular Dystrophies / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010243:Paralysis / Q000235:genetics / Q000378:metabolism; D010770:Phosphotransferases / Q000235:genetics / Q000378:metabolism; D010802:Phylogeny; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D049028:Dystrophin-Associated Protein Complex; D009687:Nuclear Proteins; D014157:Transcription Factors; C520030:CLP1 protein, human; D010770:Phosphotransferases; D002154:Calpain; C484806:CAPN1 protein, human; D002118:Calcium