PMID:11679592

Citation	Fallon, L, Moreau, F, Croft, BG, Labib, N, Gu, WJ and Fon, EA (2002) Parkin and CASK/LIN-2 associate via a PDZ-mediated interaction and are co-localized in lipid rafts and postsynaptic densities in brain. J. Biol. Chem. 277:486-91
Abstract	Mutations in the gene encoding parkin cause an autosomal recessive juvenile-onset form of Parkinson's disease. Parkin functions as a RING-type E3 ubiquitin-ligase, coordinating the transfer of ubiquitin to substrate proteins and thereby targeting them for degradation by the proteasome. We now report that the extreme C terminus of parkin, which is selectively truncated by a Parkinson's disease-causing mutation, functions as a class II PDZ-binding motif that binds CASK, the mammalian homolog of Caenorhabditis elegans Lin-2, but not other PDZ proteins in brain extracts. Importantly, parkin co-localizes with CASK at synapses in cultured cortical neurons as well as in postsynaptic densities and lipid rafts in brain. Further, parkin associates not only with CASK but also with other postsynaptic proteins in the N-methyl d-aspartate (NMDA) receptor-signaling complex, in rat brain in vivo. Finally, despite exhibiting E2-dependent ubiquitin ligase activity, rat brain parkin does not ubiquitinate CASK, suggesting that CASK may function in targeting or scaffolding parkin within the postsynaptic complex rather than as a direct substrate for parkin-mediated ubiquitination. These data implicate for the first time a PDZ-mediated interaction between parkin and CASK in neurodegeneration and possibly in ubiquitination of proteins involved in synaptic transmission and plasticity.
Links	PubMed Online version:10.1074/jbc.M109806200
Keywords	Animals; Brain Chemistry; Calcium-Calmodulin-Dependent Protein Kinases; Guanylate Kinases; Ligases/analysis; Ligases/metabolism; Membrane Microdomains/chemistry; Mice; Neurons/chemistry; Nucleoside-Phosphate Kinase/analysis; Nucleoside-Phosphate Kinase/metabolism; Rats; Synapses/chemistry; Synaptic Transmission; Ubiquitin/metabolism; Ubiquitin-Protein Ligases
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
RAT:CSKP	part_of	GO:0014069: postsynaptic density	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete
RAT:CSKP	part_of	GO:0045121: membrane raft	ECO:0000314: direct assay evidence used in manual assertion		C		Seeded From UniProt	complete

References

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