Structure-Dynamic Coupling Through Ca2+-Binding Regulatory Domains of Mammalian NCX Isoform/Splice Variants.

Structure-Dynamic Coupling Through Ca2+-Binding Regulatory Domains of Mammalian NCX Isoform/Splice Variants. Adv Exp Med Biol. 2017;981:41-58 Authors: Khananshvili D Abstract Mammalian Na+/Ca2+ exchangers (NCX1, NCX2, and NCX3) and their splice variants are expressed in a tissue-specific manner and are regulated by Ca2+ binding CBD1 and CBD2 domains. NCX2 does not undergo splicing, whereas in NCX1 and NCX3, the splicing segment (with mutually exclusive and cassette exons) is located in CBD2. Ca2+ binding to CBD1 results in Ca2+-dependent tethering of CBDs through the network of interdomain salt-bridges, which is associated with NCX activation, whereas a slow dissociation of "occluded" Ca2+ inactivates NCX. Although NCX variants share a common structural basis for Ca2+-dependent tethering of CBDs, the Ca2+ off-rates of occluded Ca2+ vary up to 50-fold, depending on the exons assembly. The Ca2+-dependent tethering of CBDs rigidifies the interdomain movements of CBDs without any significant changes in the CBDs' alignment; consequently, more constraining conformational states become more populated in the absence of global conformational changes. Although this Ca2+-dependent "population shift" is a common mechanism among NCX variants, the strength and span of backbone rigidification from the C-terminal of CBD1 to the C-terminal of CBD2 is exon dependent. The mutually exclusive exons differentially stabilize/destabilize the backbone dynami...
Source: Advances in Experimental Medicine and Biology - Category: Research Tags: Adv Exp Med Biol Source Type: research