期刊
SCIENTIFIC REPORTS
卷 7, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-017-07072-4
关键词
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资金
- Global Research Lab Program [2012K1A1A2045441]
- National Research Foundation of Korea [2015M3C7A1028373]
- Brain Korea 21 Plus (BK21 Plus) Project
- [2015R1D1A4A01019646]
- National Research Foundation of Korea [2015M3C7A1028373] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Secretagogin (SCGN), a hexa EF-hand calcium binding protein, plays key roles in insulin secretion in pancreatic beta-cells. It is not yet understood how the binding of Ca2+ to human SCGN (hSCGN) promotes secretion. Here we have addressed this question, using mass spectrometry combined with a disulfide searching algorithm DBond. We found that the binding of Ca2+ to hSCGN promotes the dimerization of hSCGN via the formation of a Cys193-Cys193 disulfide bond. Hydrogen/deuterium exchange mass spectrometry (HDX-MS) and molecular dynamics studies revealed that Ca2+ binding to the EF-hands of hSCGN induces significant structural changes that affect the solvent exposure of N-terminal region, and hence the redox sensitivity of the Cys193 residue. These redox sensitivity changes were confirmed using biotinylated methyl-3-nitro-4-(piperidin-1-ylsulfonyl) benzoate (NPSB-B), a chemical probe that specifically labels reactive cysteine sulfhydryls. Furthermore, we found that wild type hSCGN overexpression promotes insulin secretion in pancreatic beta cells, while C193S-hSCGN inhibits it. These findings suggest that insulin secretion in pancreatic cells is regulated by Ca2+ and ROS signaling through Ca2+-induced structural changes promoting dimerization of hSCGN.
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