Structure-Dynamic Coupling Through Ca2+-Binding Regulatory Domains of Mammalian NCX Isoform/Splice Variants.
Adv Exp Med Biol
; 981: 41-58, 2017.
Article
em En
| MEDLINE
| ID: mdl-29594857
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 dynamics of Ca2+-bound CBDs in NCX1 and NCX3 variants, whereas the cassette exons control the stability of the interdomain linker. The combined effects of mutually exclusive and cassette exons permit a fine adjustment of two different regulatory pathways the Ca2+-dependent activation (controlled by CBD1) and the Ca2+-dependent alleviation of Na+-induced inactivation (controlled by CBD2). Exon-controlled dynamic features match with cell-specific regulatory requirements in a given variant.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Trocador de Sódio e Cálcio
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Adv Exp Med Biol
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Israel