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- 题目:
- A neurostimulant para-chloroamphetamine inhibits the arginylation branch of the N-end rule pathway.
- 作者:
- Jiang(Yanxialei),Choi(Won Hoon),Lee(Jung Hoon),Han(Dong Hoon),Kim(Ji Hyeon),Chung(Young-Shin),Kim(Se Hyun),Lee(Min Jae)
- 状态:
- 发布时间2014-09-12 , 更新时间 2014-09-12
- 期刊:
- Sci Rep
- 摘要:
- In the arginylation branch of the N-end rule pathway, unacetylated N-terminal destabilizing residues function as essential determinants of protein degradation signals (N-degron). Here, we show that a neurostimulant, para-chloroamphetamine (PCA), specifically inhibits the Arg/N-end rule pathway, delaying the degradation of its artificial and physiological substrates, including regulators of G protein signaling 4 (RGS4), in vitro and in cultured cells. In silico computational analysis indicated that PCA strongly interacts with both UBR box and ClpS box, which bind to type 1 and type 2 N-degrons, respectively. Moreover, intraperitoneal injection of PCA significantly stabilized endogenous RGS4 proteins in the whole mouse brain and, particularly, in the frontal cortex and hippocampus. Consistent with the role of RGS4 in G protein signaling, treatment with PCA impaired the activations of GPCR downstream effectors in N2A cells, phenocopying ATE1-null mutants. In addition, levels of pathological C-terminal fragments of TDP43 bearing N-degrons (Arg208-TDP25) were significantly elevated in the presence of PCA. Thus, our study identifies PCA as a potential tool to understand and modulate various pathological processes regulated by the Arg/N-end rule pathway, including neurodegenerative processes in FTLD-U and ALS.
- 语言:
- eng
- DOI:
DataTable pData
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