SH3 domains from a subset of BAR proteins define a Ubl-binding domain and implicate parkin in synaptic ubiquitination.

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.
Mesh Terms:
Acyltransferases, Amino Acid Sequence, Animals, Cell Line, Glutamic Acid, Humans, Mice, Models, Molecular, Molecular Sequence Data, Parkinson Disease, Protein Binding, Protein Isoforms, Protein Structure, Tertiary, Recombinant Fusion Proteins, Sequence Alignment, Synapses, Synaptic Transmission, Ubiquitin, Ubiquitin-Protein Ligases, Ubiquitination, src Homology Domains
Mol. Cell
Date: Dec. 25, 2009
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