Calcium Ion Induced Structural Changes Promote Dimerization of Secretagogin, Which Is Required for Its Insulin Secretory Function

Abstract Secretagogin (SCGN), a hexa EF-hand calcium binding protein, plays key roles in insulin secretion in pancreatic β-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 d...

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Autores principales:	Jae-Jin Lee, Seo-Yun Yang, Jimin Park, James E. Ferrell, Dong-Hae Shin, Kong-Joo Lee
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ce36b1a0499a4abe9aeb1be8098e29ca
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spelling	oai:doaj.org-article:ce36b1a0499a4abe9aeb1be8098e29ca2021-12-02T12:32:56ZCalcium Ion Induced Structural Changes Promote Dimerization of Secretagogin, Which Is Required for Its Insulin Secretory Function10.1038/s41598-017-07072-42045-2322https://doaj.org/article/ce36b1a0499a4abe9aeb1be8098e29ca2017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-07072-4https://doaj.org/toc/2045-2322Abstract Secretagogin (SCGN), a hexa EF-hand calcium binding protein, plays key roles in insulin secretion in pancreatic β-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 β 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.Jae-Jin LeeSeo-Yun YangJimin ParkJames E. FerrellDong-Hae ShinKong-Joo LeeNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Jae-Jin Lee Seo-Yun Yang Jimin Park James E. Ferrell Dong-Hae Shin Kong-Joo Lee Calcium Ion Induced Structural Changes Promote Dimerization of Secretagogin, Which Is Required for Its Insulin Secretory Function
description	Abstract Secretagogin (SCGN), a hexa EF-hand calcium binding protein, plays key roles in insulin secretion in pancreatic β-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 β 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.
format	article
author	Jae-Jin Lee Seo-Yun Yang Jimin Park James E. Ferrell Dong-Hae Shin Kong-Joo Lee
author_facet	Jae-Jin Lee Seo-Yun Yang Jimin Park James E. Ferrell Dong-Hae Shin Kong-Joo Lee
author_sort	Jae-Jin Lee
title	Calcium Ion Induced Structural Changes Promote Dimerization of Secretagogin, Which Is Required for Its Insulin Secretory Function
title_short	Calcium Ion Induced Structural Changes Promote Dimerization of Secretagogin, Which Is Required for Its Insulin Secretory Function
title_full	Calcium Ion Induced Structural Changes Promote Dimerization of Secretagogin, Which Is Required for Its Insulin Secretory Function
title_fullStr	Calcium Ion Induced Structural Changes Promote Dimerization of Secretagogin, Which Is Required for Its Insulin Secretory Function
title_full_unstemmed	Calcium Ion Induced Structural Changes Promote Dimerization of Secretagogin, Which Is Required for Its Insulin Secretory Function
title_sort	calcium ion induced structural changes promote dimerization of secretagogin, which is required for its insulin secretory function
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/ce36b1a0499a4abe9aeb1be8098e29ca
work_keys_str_mv	AT jaejinlee calciumioninducedstructuralchangespromotedimerizationofsecretagoginwhichisrequiredforitsinsulinsecretoryfunction AT seoyunyang calciumioninducedstructuralchangespromotedimerizationofsecretagoginwhichisrequiredforitsinsulinsecretoryfunction AT jiminpark calciumioninducedstructuralchangespromotedimerizationofsecretagoginwhichisrequiredforitsinsulinsecretoryfunction AT jameseferrell calciumioninducedstructuralchangespromotedimerizationofsecretagoginwhichisrequiredforitsinsulinsecretoryfunction AT donghaeshin calciumioninducedstructuralchangespromotedimerizationofsecretagoginwhichisrequiredforitsinsulinsecretoryfunction AT kongjoolee calciumioninducedstructuralchangespromotedimerizationofsecretagoginwhichisrequiredforitsinsulinsecretoryfunction
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Calcium Ion Induced Structural Changes Promote Dimerization of Secretagogin, Which Is Required for Its Insulin Secretory Function

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