Parkin and CASK/LIN-2 associate via a PDZ-mediated interaction and are co-localized in lipid rafts and postsynaptic densities in brain.
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.
Fallon
Lara
L
Centre for Neuronal Survival, Montreal Neurological Institute, McGill University, Montreal, Quebec H3A 2B4, Canada.
Moreau
France
F
Croft
Benjamin G
BG
Labib
Noura
N
Gu
Wen-Jie
WJ
Fon
Edward A
EA
D000818:Animals; D001923:Brain Chemistry; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D051528:Guanylate Kinases; D008025:Ligases / Q000032:analysis* / Q000378:metabolism; D021962:Membrane Microdomains / Q000737:chemistry*; D051379:Mice; D009474:Neurons / Q000737:chemistry; D009703:Nucleoside-Phosphate Kinase / Q000032:analysis* / Q000378:metabolism; D051381:Rats; D013569:Synapses / Q000737:chemistry*; D009435:Synaptic Transmission; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; C106868:CASK kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D009703:Nucleoside-Phosphate Kinase; D051528:Guanylate Kinases; D008025:Ligases