S-nitrosylation of parkin regulates ubiquitination and compromises parkin's protective function.
Parkin is an E3 ubiquitin ligase involved in the ubiquitination of proteins that are important in the survival of dopamine neurons in Parkinson's disease (PD). We show that parkin is S-nitrosylated in vitro, as well as in vivo in a mouse model of PD and in brains of patients with PD and diffuse Lewy body disease. Moreover, S-nitrosylation inhibits parkin's ubiquitin E3 ligase activity and its protective function. The inhibition of parkin's ubiquitin E3 ligase activity by S-nitrosylation could contribute to the degenerative process in these disorders by impairing the ubiquitination of parkin substrates.
Chung
Kenny K K
KK
Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Thomas
Bobby
B
Li
Xiaojie
X
Pletnikova
Olga
O
Troncoso
Juan C
JC
Marsh
Laura
L
Dawson
Valina L
VL
Dawson
Ted M
TM
D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D020134:Catalytic Domain; D016923:Cell Death; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D020961:Lewy Body Disease / Q000378:metabolism; D020267:MPTP Poisoning / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism; D010300:Parkinson Disease / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D051843:Synucleins; D014162:Transfection; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D002352:Carrier Proteins; D015853:Cysteine Proteinase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D020030:Nitric Oxide Donors; D011994:Recombinant Proteins; C118958:SNCAIP protein, human; C498464:Sncaip protein, mouse; D051843:Synucleins; D025801:Ubiquitin; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein