Structure-based dynamic arrays in regulatory domains of sodium-calcium exchanger (NCX) isoforms

Abstract Mammalian Na+/Ca2+ exchangers, NCX1 and NCX3, generate splice variants, whereas NCX2 does not. The CBD1 and CBD2 domains form a regulatory tandem (CBD12), where Ca2+ binding to CBD1 activates and Ca2+ binding to CBD2 (bearing the splicing segment) alleviates the Na+-induced inactivation. He...

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Autores principales:	Moshe Giladi, Su Youn Lee, Yarden Ariely, Yotam Teldan, Rotem Granit, Roi Strulovich, Yoni Haitin, Ka Young Chung, Daniel Khananshvili
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e36e68f88afb4f2581ecb244352f12a3
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spelling	oai:doaj.org-article:e36e68f88afb4f2581ecb244352f12a32021-12-02T11:52:25ZStructure-based dynamic arrays in regulatory domains of sodium-calcium exchanger (NCX) isoforms10.1038/s41598-017-01102-x2045-2322https://doaj.org/article/e36e68f88afb4f2581ecb244352f12a32017-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01102-xhttps://doaj.org/toc/2045-2322Abstract Mammalian Na+/Ca2+ exchangers, NCX1 and NCX3, generate splice variants, whereas NCX2 does not. The CBD1 and CBD2 domains form a regulatory tandem (CBD12), where Ca2+ binding to CBD1 activates and Ca2+ binding to CBD2 (bearing the splicing segment) alleviates the Na+-induced inactivation. Here, the NCX2-CBD12, NCX3-CBD12-B, and NCX3-CBD12-AC proteins were analyzed by small-angle X-ray scattering (SAXS) and hydrogen-deuterium exchange mass-spectrometry (HDX-MS) to resolve regulatory variances in the NCX2 and NCX3 variants. SAXS revealed the unified model, according to which the Ca2+ binding to CBD12 shifts a dynamic equilibrium without generating new conformational states, and where more rigid conformational states become more populated without any global conformational changes. HDX-MS revealed the differential effects of the B and AC exons on the folding stability of apo CBD1 in NCX3-CBD12, where the dynamic differences become less noticeable in the Ca2+-bound state. Therefore, the apo forms predefine incremental changes in backbone dynamics upon Ca2+ binding. These observations may account for slower inactivation (caused by slower dissociation of occluded Ca2+ from CBD12) in the skeletal vs the brain-expressed NCX2 and NCX3 variants. This may have physiological relevance, since NCX must extrude much higher amounts of Ca2+ from the skeletal cell than from the neuron.Moshe GiladiSu Youn LeeYarden ArielyYotam TeldanRotem GranitRoi StrulovichYoni HaitinKa Young ChungDaniel KhananshviliNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-12 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Moshe Giladi Su Youn Lee Yarden Ariely Yotam Teldan Rotem Granit Roi Strulovich Yoni Haitin Ka Young Chung Daniel Khananshvili Structure-based dynamic arrays in regulatory domains of sodium-calcium exchanger (NCX) isoforms
description	Abstract Mammalian Na+/Ca2+ exchangers, NCX1 and NCX3, generate splice variants, whereas NCX2 does not. The CBD1 and CBD2 domains form a regulatory tandem (CBD12), where Ca2+ binding to CBD1 activates and Ca2+ binding to CBD2 (bearing the splicing segment) alleviates the Na+-induced inactivation. Here, the NCX2-CBD12, NCX3-CBD12-B, and NCX3-CBD12-AC proteins were analyzed by small-angle X-ray scattering (SAXS) and hydrogen-deuterium exchange mass-spectrometry (HDX-MS) to resolve regulatory variances in the NCX2 and NCX3 variants. SAXS revealed the unified model, according to which the Ca2+ binding to CBD12 shifts a dynamic equilibrium without generating new conformational states, and where more rigid conformational states become more populated without any global conformational changes. HDX-MS revealed the differential effects of the B and AC exons on the folding stability of apo CBD1 in NCX3-CBD12, where the dynamic differences become less noticeable in the Ca2+-bound state. Therefore, the apo forms predefine incremental changes in backbone dynamics upon Ca2+ binding. These observations may account for slower inactivation (caused by slower dissociation of occluded Ca2+ from CBD12) in the skeletal vs the brain-expressed NCX2 and NCX3 variants. This may have physiological relevance, since NCX must extrude much higher amounts of Ca2+ from the skeletal cell than from the neuron.
format	article
author	Moshe Giladi Su Youn Lee Yarden Ariely Yotam Teldan Rotem Granit Roi Strulovich Yoni Haitin Ka Young Chung Daniel Khananshvili
author_facet	Moshe Giladi Su Youn Lee Yarden Ariely Yotam Teldan Rotem Granit Roi Strulovich Yoni Haitin Ka Young Chung Daniel Khananshvili
author_sort	Moshe Giladi
title	Structure-based dynamic arrays in regulatory domains of sodium-calcium exchanger (NCX) isoforms
title_short	Structure-based dynamic arrays in regulatory domains of sodium-calcium exchanger (NCX) isoforms
title_full	Structure-based dynamic arrays in regulatory domains of sodium-calcium exchanger (NCX) isoforms
title_fullStr	Structure-based dynamic arrays in regulatory domains of sodium-calcium exchanger (NCX) isoforms
title_full_unstemmed	Structure-based dynamic arrays in regulatory domains of sodium-calcium exchanger (NCX) isoforms
title_sort	structure-based dynamic arrays in regulatory domains of sodium-calcium exchanger (ncx) isoforms
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/e36e68f88afb4f2581ecb244352f12a3
work_keys_str_mv	AT moshegiladi structurebaseddynamicarraysinregulatorydomainsofsodiumcalciumexchangerncxisoforms AT suyounlee structurebaseddynamicarraysinregulatorydomainsofsodiumcalciumexchangerncxisoforms AT yardenariely structurebaseddynamicarraysinregulatorydomainsofsodiumcalciumexchangerncxisoforms AT yotamteldan structurebaseddynamicarraysinregulatorydomainsofsodiumcalciumexchangerncxisoforms AT rotemgranit structurebaseddynamicarraysinregulatorydomainsofsodiumcalciumexchangerncxisoforms AT roistrulovich structurebaseddynamicarraysinregulatorydomainsofsodiumcalciumexchangerncxisoforms AT yonihaitin structurebaseddynamicarraysinregulatorydomainsofsodiumcalciumexchangerncxisoforms AT kayoungchung structurebaseddynamicarraysinregulatorydomainsofsodiumcalciumexchangerncxisoforms AT danielkhananshvili structurebaseddynamicarraysinregulatorydomainsofsodiumcalciumexchangerncxisoforms
_version_	1718395077348294656

Structure-based dynamic arrays in regulatory domains of sodium-calcium exchanger (NCX) isoforms

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