期刊
NITRIC OXIDE-BIOLOGY AND CHEMISTRY
卷 86, 期 -, 页码 68-75出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.niox.2019.02.008
关键词
Ca2+/calmodulin-dependent protein kinase (CaMK); Phosphorylation; polysulfidation; reactive sulfur species (RSS); Redox regulation
资金
- Japan Society for the Promotion of Science (JSPS) [26111008, 18K11083, 18K14853, 15K18994]
- Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan [S1311012]
- Showa Pharmaceutical University [H27-3, H28-2, H23-2]
- Grants-in-Aid for Scientific Research [15K18994, 18K11083, 18K14853] Funding Source: KAKEN
Ca2+/calmodulin (CaM)-dependent protein kinase (CaMK) I is activated by the phosphorylation of a crucial activation loop Thr(177) by upstream kinases, CaMK kinase (CaMKK), and regulates axonal or dendritic extension and branching. Reactive sulfur species (RSS) modulate protein functions via polysulfidation of the reactive Cys residues. Here, we report that the activity of CaMKI was reversibly inhibited via its polysulfidation at Cys(179) by RSS. In vitro incubation of CaMKI with the exogenous RSS donor Na2S3 resulted in a dose -dependent inhibition of the phosphorylation at Thr(177) by CaMKK and inactivation of the enzymatic activity. Dithiothreitol (DTT), a small molecule reducing reagent, rescued these inhibitions. Conversely, mutated CaMKI (C179V) was resistant to the Na2S3-induced inactivation. In transfected cells expressing CaMKI, ionomycin-induced CaMKI activity was decreased upon treatment with Na2S4, whereas cells expressing mutant CaMKI (C179V) proved resistant to this treatment. A biotin-polyethylene glycol-conjugated maleimide capture assay revealed that CaMKI was a target for polysulfidation in cells. Furthermore, the polysulfidation of CaMKI protected Cys(179) from its irreversible modification, known as protein succination. Thus, we propose that CaMKI was reversibly inhibited via polysulfidation of Cys(179) by RSS, thereby protecting it from irreversible modification.
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