title: SH3 domains from a subset of BAR proteins define a Ubl-binding domain and implicate parkin in synaptic ubiquitination.
abstract: Mutations in the parkin gene are responsible for a common inherited form of Parkinson's disease (PD). Parkin is a RING-type E3 ubiquitin ligase with an N-terminal ubiquitin-like domain (Ubl). We report here that the parkin Ubl binds SH3 domains from endocytic BAR proteins such as endophilin-A with an affinity comparable to proline-rich domains (PRDs) from well-established SH3 partners. The NMR structure of the Ubl-SH3 complex identifies the PaRK extension, a unique C-terminal motif in the parkin Ubl required for SH3 binding and for parkin-mediated ubiquitination of endophilin-A in vitro. In nerve terminals, conditions that promote phosphorylation enhance the interaction between parkin and endophilin-A and increase the levels of ubiquitinated proteins within PRD-associated synaptic protein complexes in wild-type but not parkin knockout brain. The findings identify a pathway for the recruitment of synaptic substrates to parkin with the potential to explain the defects in synaptic transmission observed in recessive forms of PD.
authors.affiliation: Department of Biochemistry, McGill University, Montréal, Québec, Canada.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Trempe
authors.forename: Carol X-Q
authors.initials: CX
authors.lastname: Chen
authors.forename: Karl
authors.initials: K
authors.lastname: Grenier
authors.forename: Edna Matta
authors.initials: EM
authors.lastname: Camacho
authors.forename: Guennadi
authors.initials: G
authors.lastname: Kozlov
authors.forename: Peter S
authors.initials: PS
authors.lastname: McPherson
authors.forename: Kalle
authors.initials: K
authors.lastname: Gehring
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fon
mesh_terms: D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010300:Parkinson Disease / Q000235:genetics / Q000503:physiopathology; D011485:Protein Binding; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D013569:Synapses / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D018909:src Homology Domains
chemical_list: D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; D025801:Ubiquitin; D018698:Glutamic Acid; D000217:Acyltransferases; C018764:2-acylglycerophosphate acyltransferase; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein