14-3-3eta is a novel regulator of parkin ubiquitin ligase.
Mutation of the parkin gene, which encodes an E3 ubiquitin-protein ligase, is the major cause of autosomal recessive juvenile parkinsonism (ARJP). Although various substrates for parkin have been identified, the mechanisms that regulate the ubiquitin ligase activity of parkin are poorly understood. Here we report that 14-3-3eta, a chaperone-like protein present abundantly in neurons, could bind to parkin and negatively regulate its ubiquitin ligase activity. Furthermore, 14-3-3eta could bind to the linker region of parkin but not parkin with ARJP-causing R42P, K161N, and T240R mutations. Intriguingly, alpha-synuclein (alpha-SN), another familial Parkinson's disease (PD) gene product, abrogated the 14-3-3eta-induced suppression of parkin activity. alpha-SN could bind tightly to 14-3-3eta and consequently sequester it from the parkin-14-3-3eta complex. PD-causing A30P and A53T mutants of alpha-SN could not bind 14-3-3eta, and failed to activate parkin. Our findings indicate that 14-3-3eta is a regulator that functionally links parkin and alpha-SN. The alpha-SN-positive and 14-3-3eta-negative control of parkin activity sheds new light on the pathophysiological roles of parkin.
Sato
Shigeto
S
Department of Neurology, Juntendo University School of Medicine, Bunkyo, Tokyo, Japan.
Chiba
Tomoki
T
Sakata
Eri
E
Kato
Koichi
K
Mizuno
Yoshikuni
Y
Hattori
Nobutaka
N
Tanaka
Keiji
K
D048948:14-3-3 Proteins / Q000032:analysis / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation; D006801:Humans; D051379:Mice; D018832:Molecular Chaperones / Q000378:metabolism*; D009154:Mutation; D020734:Parkinsonian Disorders / Q000235:genetics / Q000378:metabolism*; D025941:Protein Interaction Mapping; D020033:Protein Isoforms / Q000032:analysis / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013378:Substantia Nigra / Q000737:chemistry / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein / Q000032:analysis / Q000378:metabolism
D048948:14-3-3 Proteins; D018832:Molecular Chaperones; D020033:Protein Isoforms; D051844:alpha-Synuclein; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein