Parkin directly modulates 26S proteasome activity.
Parkinson's disease (PD) is a common neurodegenerative disease that involves the deterioration of dopaminergic neurons in the substantia nigra pars compacta. Although the etiology of PD remains poorly understood, recent genetic, postmortem, and experimental evidence shows that abnormal protein accumulation and subsequent aggregate formation are prominent features of both sporadic and familial PD. While proteasome dysfunction is observed in PD, diverse mutations in the parkin gene are linked to early-onset autosomal-recessive forms of familial PD. We demonstrate that parkin, an E3 ubiquitin ligase, activates the 26S proteasome in an E3 ligase activity-independent manner. Furthermore, an N-terminal ubiquitin-like domain within parkin is critical for the activation of the 26S proteasome through enhancing the interaction between 19S proteasomal subunits, whereas the PD-linked R42P mutant abolishes this action. The current findings point to a novel role for parkin for 26S proteasome assembly and suggest that parkin mutations contribute to the proteasomal dysfunction in PD.
Um
Ji Won
JW
Department of Biology, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea.
Im
Eunju
E
Lee
Hyun Jung
HJ
Min
Boram
B
Yoo
Lang
L
Yoo
Jiho
J
Lübbert
Hermann
H
Stichel-Gunkel
Christine
C
Cho
Hyun-Soo
HS
Yoon
Jong Bok
JB
Chung
Kwang Chul
KC
D000818:Animals; D030801:Animals, Genetically Modified; D004330:Drosophila / Q000235:genetics; D029721:Drosophila Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D004789:Enzyme Activation / Q000235:genetics; D005808:Genes, Recessive; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D029721:Drosophila Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; C487430:park protein, Drosophila
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