ArticleThe Journal of biological chemistry2009
Structure and functional analysis of a Ca2+ sensor mutant of the Na+/Ca2+ exchanger.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed.
- Identification of a magnesium-binding site at the primary allosteric calcium sensor of the sodium-calcium exchanger: Implications for physiological regulation.Protein science : a publication of the Protein Society · 2024Article
- Proton-modulated interactions of ions with transport sites of prokaryotic and eukaryotic NCX prototypes.Cell calcium · 2021Article
- Modulation of the cardiac NaCell calcium · 2020Review
- Molecular determinants of pH regulation in the cardiac NaThe Journal of general physiology · 2018Article
- The Role of Sodium in Diabetic Cardiomyopathy.Frontiers in physiology · 2018Review
- An amphipathic α-helix directs palmitoylation of the large intracellular loop of the sodium/calcium exchanger.The Journal of biological chemistry · 2017Article
- Sodium-calcium exchangers (NCX): molecular hallmarks underlying the tissue-specific and systemic functions.Pflugers Archiv : European journal of physiology · 2014Review
- Population shift underlies Ca2+-induced regulatory transitions in the sodium-calcium exchanger (NCX).The Journal of biological chemistry · 2013Article
- Ca2+ regulation of ion transport in the Na+/Ca2+ exchanger.The Journal of biological chemistry · 2012Review
- Article
- Ca2+ binding alters the interdomain flexibility between the two cytoplasmic calcium-binding domains in the Na+/Ca2+ exchanger.The Journal of biological chemistry · 2011Article
- Proton-sensing Ca2+ binding domains regulate the cardiac Na+/Ca2+ exchanger.The Journal of biological chemistry · 2011Article
- Ca2+-dependent structural rearrangements within Na+-Ca2+ exchanger dimers.Proceedings of the National Academy of Sciences of the United States of America · 2011Article
- Essential role of the CBD1-CBD2 linker in slow dissociation of Ca2+ from the regulatory two-domain tandem of NCX1.The Journal of biological chemistry · 2010Article
- Roles of two Ca2+-binding domains in regulation of the cardiac Na+-Ca2+ exchanger.The Journal of biological chemistry · 2009Article
Corrections and comments
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Authors and funding
6 authors.
Funding
Abstract
The mammalian Na(+)/Ca(2+) exchanger, NCX1.1, serves as the main mechanism for Ca(2+) efflux across the sarcolemma following cardiac contraction. In addition to transporting Ca(2+), NCX1.1 activity is also strongly regulated by Ca(2+) binding to two intracellular regulatory domains, CBD1 and CBD2. The structures of both of these domains have been solved by NMR spectroscopy and x-ray crystallography, greatly enhancing our understanding of Ca(2+) regulation. Nevertheless, the mechanisms by which Ca(2+) regulates the exchanger remain incompletely understood. The initial NMR study showed that the first regulatory domain, CBD1, unfolds in the absence of regulatory Ca(2+). It was further demonstrated that a mutation of an acidic residue involved in Ca(2+) binding, E454K, prevents this structural unfolding. A contradictory result was recently obtained in a second NMR study in which Ca(2+) removal merely triggered local rearrangements of CBD1. To address this issue, we solved the crystal structure of the E454K-CBD1 mutant and performed electrophysiological analyses of the full-length exchanger with mutations at position 454. We show that the lysine substitution replaces the Ca(2+) ion at position 1 of the CBD1 Ca(2+) binding site and participates in a charge compensation mechanism. Electrophysiological analyses show that mutations of residue Glu-454 have no impact on Ca(2+) regulation of NCX1.1. Together, structural and mutational analyses indicate that only two of the four Ca(2+) ions that bind to CBD1 are important for regulating exchanger activity.
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