title: Dentatorubral pallidoluysian atrophy (DRPLA) protein is cleaved by caspase-3 during apoptosis.
abstract: Dentatorubral pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder. It is associated with an abnormal CAG repeat expansion resulting in formation of a protein with an elongated polyglutamine stretch. However, neither the physiological roles of the DRPLA gene product nor molecular mechanisms of its pathogenesis have yet been elucidated. Here we report that the DRPLA protein is cleaved at a site near the N terminus during apoptosis induced by VP-16, staurosporine, or glucocorticoid. Moreover, the in vitro translated DRPLA protein is cleaved by recombinant caspase-3, a member of the cysteine protease family, which is thought to be a main executioner of apoptosis. Using mutant DRPLA proteins, the cleavage site was identified as 106DSLDG110. The cleavage, however, was not modulated by the length of the polyglutamine stretch. These findings suggest that the DRPLA protein is one of the physiological substrates of caspase-3, and its cleavage may result in structural and biochemical alterations associated with apoptosis.
authors.affiliation: Department of Genetics, National Children's Medical Research Center, 3-35-31, Taishido, Setagaya, Tokyo 154, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Miyashita
authors.forename: Y
authors.initials: Y
authors.lastname: Okamura-Oho
authors.forename: Y
authors.initials: Y
authors.lastname: Mito
authors.forename: S
authors.initials: S
authors.lastname: Nagafuchi
authors.forename: M
authors.initials: M
authors.lastname: Yamada
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000378:metabolism; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured
chemical_list: D009419:Nerve Tissue Proteins; D010455:Peptides; C095278:atrophin-1; C097188:polyglutamine; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D003546:Cysteine Endopeptidases