14-3-3η is a novel regulator of parkin ubiquitin ligase

被引:97
作者
Sato, S
Chiba, T
Sakata, E
Kato, K
Mizuno, Y
Hattori, N
Tanaka, K
机构
[1] Tokyo Metropolitan Inst Med Sci, Dept Mol Oncol, Bunkyo Ku, Tokyo 1138613, Japan
[2] Juntendo Univ, Sch Med, Dept Neurol, Tokyo 113, Japan
[3] Nagoya City Univ, Dept Struct Biol & Biomol Engn, Grad Sch Pharmaceut Sci, Nagoya, Aichi, Japan
关键词
alpha-synuclein; 14-3-3; eta; parkin; Parkinson's disease; ubiquitin ligase;
D O I
10.1038/sj.emboj.7600774
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 14-3-3 eta, a chaperone-like protein present abundantly in neurons, could bind to parkin and negatively regulate its ubiquitin ligase activity. Furthermore, 14-3-3 eta 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 14-3-3 eta-induced suppression of parkin activity. alpha-SN could bind tightly to 14-3-3 eta and consequently sequester it from the parkin -14-3-3 eta complex. PD-causing A30P and A53T mutants of alpha-SN could not bind 14-3-3 eta, and failed to activate parkin. Our findings indicate that 14-3-3 eta is a regulator that functionally links parkin and alpha-SN. The alpha-SN-positive and 14-3-3 eta-negative control of parkin activity sheds new light on the pathophysiological roles of parkin.
引用
收藏
页码:211 / 221
页数:11
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