Key result
X-ray crystallographic structure of CBD2 and mutational analysis revealed the crucial role of one of the two bound Ca2+ ions in regulating the mammalian cardiac Na+-Ca2+ exchanger.
This study provides structural insights into the mechanism by which intracellular Ca2+ regulates the mammalian cardiac Na+-Ca2+ exchanger via the CBD2 domain.
Informs NCX modulator design; leaves open validation in human cardiac models before any therapeutic consideration.
Spatial and temporal regulation of intracellular Ca2+ concentrations is a fundamental requirement for life. The mammalian cardiac Na+-Ca2+ exchanger serves as the main mechanism for Ca2+ efflux after heart contraction. Exchange activity is highly regulated by intracellular Ca2+, which binds two regulatory domains (CBD1 and CBD2) and triggers the full activity of the exchanger. We solved the X-ray crystallographic structure of CBD2 in the presence and absence of Ca2+. Together with mutational analysis of the Ca2+ binding sites, this study reveals the crucial role of one of the two bound Ca2+ ions and helps propose hypotheses on the mechanism of regulation of the exchanger.
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Chaptal et al. (2007) studied this question. X-ray crystallography and mutational analysis was evaluated on Structure and regulatory mechanism of CBD2. X-ray crystallographic structure of CBD2 and mutational analysis revealed the crucial role of one of the two bound Ca2+ ions in regulating the mammalian cardiac Na+-Ca2+ exchanger.
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