title: Pathogenic mutations inactivate parkin by distinct mechanisms.
abstract: Loss of parkin function is the major cause of autosomal recessive Parkinson's disease (ARPD). A wide variety of parkin mutations have been identified in patients; however, the pathophysiological mechanisms leading to the inactivation of mutant parkin are poorly understood. In this study we characterized pathogenic C- and N-terminal parkin mutants and found distinct pathways of parkin inactivation. Deletion of the C terminus abrogated the association of parkin with cellular membranes and induced rapid misfolding and aggregation. Four N-terminal missense mutations, located within the ubiquitin-like domain (UBL), decrease the stability of parkin; as a consequence, these mutants are rapidly degraded by the proteasome. Furthermore, we present evidence that a smaller parkin species of 42 kDa, which is present in extracts prepared from human brain and cultured cells, originates from an internal start site and lacks the N-terminal UBL domain.
authors.affiliation: Department of Cellular Biochemistry, Max Planck Institute for Biochemistry, Martinsried, Germany.
authors.forename: Iris H
authors.initials: IH
authors.lastname: Henn
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Gostner
authors.forename: Peter
authors.initials: P
authors.lastname: Lackner
authors.forename: Jörg
authors.initials: J
authors.lastname: Tatzelt
authors.forename: Konstanze F
authors.initials: KF
authors.lastname: Winklhofer
mesh_terms: D000595:Amino Acid Sequence; D045744:Cell Line, Tumor; D020868:Gene Silencing; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism*; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017510:Protein Folding; D017434:Protein Structure, Tertiary / Q000235:genetics; D017384:Sequence Deletion; D024363:Transcription Initiation Site; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*
chemical_list: D010446:Peptide Fragments; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D046988:Proteasome Endopeptidase Complex