title: A neurostimulant para-chloroamphetamine inhibits the arginylation branch of the N-end rule pathway.
abstract: 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.
authors.affiliation: 1] Department of Applied Chemistry, College of Applied Sciences, Kyung Hee University, Yongin 446-701, Republic of Korea [2].
authors.forename: Yanxialei
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: 1] Department of Applied Chemistry, College of Applied Sciences, Kyung Hee University, Yongin 446-701, Republic of Korea [2].
authors.forename: Won Hoon
authors.initials: WH
authors.lastname: Choi
authors.affiliation: Department of Applied Chemistry, College of Applied Sciences, Kyung Hee University, Yongin 446-701, Republic of Korea.
authors.forename: Jung Hoon
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Applied Chemistry, College of Applied Sciences, Kyung Hee University, Yongin 446-701, Republic of Korea.
authors.forename: Dong Hoon
authors.initials: DH
authors.lastname: Han
authors.affiliation: Department of Applied Chemistry, College of Applied Sciences, Kyung Hee University, Yongin 446-701, Republic of Korea.
authors.forename: Ji Hyeon
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Department of Biotechnology, Hoseo University, Asan 336-795, Republic of Korea.
authors.forename: Young-Shin
authors.initials: YS
authors.lastname: Chung
authors.affiliation: Department of Neuropsychiatry, Dongguk University International Hospital, Goyang 410-773, Republic of Korea.
authors.forename: Se Hyun
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Applied Chemistry, College of Applied Sciences, Kyung Hee University, Yongin 446-701, Republic of Korea.
authors.forename: Min Jae
authors.initials: MJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D001120:Arginine / Q000378:metabolism*; D045744:Cell Line, Tumor; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D006367:HeLa Cells; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D059748:Proteolysis / Q000187:drug effects*; D020710:RGS Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D010133:p-Chloroamphetamine / Q000494:pharmacology*
chemical_list: D020710:RGS Proteins; C098799:RGS4 protein; D010133:p-Chloroamphetamine; D001120:Arginine; D019204:GTP-Binding Proteins