Journal
CELL CALCIUM
Volume 51, Issue 6, Pages 478-485Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.ceca.2012.04.007
Keywords
NCX; Ca2+ occlusion; Allosteric sensor; Regulation; Splice variants
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Funding
- Israeli Ministry of Health [2010-3-6266]
- USA-Israeli Binational Research Grant [2009-334]
- Israel Science Foundation [23/10]
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The Na+-Ca2+ exchanger (NCX) mediated Ca2+ fluxes are essential for handling Ca2+ homeostasis in many cell-types. Eukaryotic NCX variants contain regulatory CBD1 and CBD2 domains, whereas in distinct variants the Ca2+ binding to Ca3-Ca4 sites of CBD1 results either in sustained activation, inhibition or no effect. CBD2 contains an alternatively spliced segment, which is expressed in a tissue-specific manner although its impact on allosteric regulation remains unclear. Recent studies revealed that the Ca2+ binding to Ca3-Ca4 sites results in interdomain tethering of CBDs, which rigidifies CBDs movements with accompanied slow dissociation of occluded Ca2+. Here we investigate the effects of CBD2 variants on Ca2+ occlusion in the two-domain construct (CBD12). Mutational studies revealed that both sites (Ca3 and Ca4) contribute to Ca2+ occlusion, whereas after dissociation of the first Ca2+ ion the second Ca2+ ion becomes occluded. This mechanism is common for the brain, kidney and cardiac splice variants of CBD12, although the occluded Ca2+ exhibits 20-50-fold difference in off-rates among the tested variants. Therefore, the spliced exons on CBD2 affect the rate-limiting step of the occluded Ca2+ dissociation at the primary regulatory sensor to shape dynamic features of allosteric regulation in NCX variants. (C) 2012 Elsevier Ltd. All rights reserved.
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