title: Interaction between RING1 (R1) and the Ubiquitin-like (UBL) Domains Is Critical for the Regulation of Parkin Activity.
abstract: Parkin is an E3 ligase that contains a ubiquitin-like (UBL) domain in the N terminus and an R1-in-between-ring-RING2 motif in the C terminus. We showed that the UBL domain specifically interacts with the R1 domain and negatively regulates Parkin E3 ligase activity, Parkin-dependent mitophagy, and Parkin translocation to the mitochondria. The binding between the UBL domain and the R1 domain was suppressed by carbonyl cyanide m-chlorophenyl hydrazone treatment or by expression of PTEN-induced putative kinase 1 (PINK1), an upstream kinase that phosphorylates Parkin at the Ser-65 residue of the UBL domain. Moreover, we demonstrated that phosphorylation of the UBL domain at Ser-65 prevents its binding to the R1 domain and promotes Parkin activities. We further showed that mitochondrial translocation of Parkin, which depends on phosphorylation at Ser-65, and interaction between the R1 domain and a mitochondrial outer membrane protein, VDAC1, are suppressed by binding of the UBL domain to the R1 domain. Interestingly, Parkin with missense mutations associated with Parkinson disease (PD) in the UBL domain, such as K27N, R33Q, and A46P, did not translocate to the mitochondria and induce E3 ligase activity by m-chlorophenyl hydrazone treatment, which correlated with the interaction between the R1 domain and the UBL domain with those PD mutations. These findings provide a molecular mechanism of how Parkin recruitment to the mitochondria and Parkin activation as an E3 ubiquitin ligase are regulated by PINK1 and explain the previously unknown mechanism of how Parkin mutations in the UBL domain cause PD pathogenesis.
authors.affiliation: From the Interdisciplinary Graduate Program in Genetic Engineering,; National Creative Research Initiatives Center for Energy Homeostasis Regulation,; Institute of Molecular Biology and Genetics, and.
authors.forename: Su Jin
authors.initials: SJ
authors.lastname: Ham
authors.affiliation: National Creative Research Initiatives Center for Energy Homeostasis Regulation,; Institute of Molecular Biology and Genetics, and.
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Lee
authors.affiliation: National Creative Research Initiatives Center for Energy Homeostasis Regulation,; Institute of Molecular Biology and Genetics, and.
authors.forename: Saera
authors.initials: S
authors.lastname: Song
authors.affiliation: School of Biological Sciences, Seoul National University, Seoul 51-742, Republic of Korea.
authors.forename: Ju-Ryung
authors.initials: JR
authors.lastname: Chung
authors.affiliation: National Creative Research Initiatives Center for Energy Homeostasis Regulation,; Institute of Molecular Biology and Genetics, and.
authors.forename: Sekyu
authors.initials: S
authors.lastname: Choi
authors.affiliation: From the Interdisciplinary Graduate Program in Genetic Engineering,; National Creative Research Initiatives Center for Energy Homeostasis Regulation,; Institute of Molecular Biology and Genetics, and; School of Biological Sciences, Seoul National University, Seoul 51-742, Republic of Korea. Electronic address: jkc@snu.ac.kr.
authors.forename: Jongkyeong
authors.initials: J
authors.lastname: Chung
mesh_terms: D020816:Amino Acid Motifs; D006801:Humans; D008928:Mitochondria / Q000201:enzymology; D010300:Parkinson Disease / Q000201:enzymology* / Q000235:genetics; D010766:Phosphorylation; D063150:Polycomb Repressive Complex 1 / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D000099202:PTEN-Induced Putative Kinase
chemical_list: D063150:Polycomb Repressive Complex 1; D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C080355:RING1 protein, human; C111567:parkin protein
keywords: PTEN-induced putative kinase 1 (PINK1); Parkinson disease; mitochondria; mitophagy; parkin; voltage-dependent anion channel (VDAC)