ArticleProceedings of the National Academy of Sciences of the United States of America2009
Ca2+ regulation in the Na+/Ca2+ exchanger features a dual electrostatic switch mechanism.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed.
- Article
- Current Flow in Nerves and Mitochondria: An Electro-Osmotic Approach.Biomolecules · 2025Review
- Inhibition of forward and reverse transport of CaBiological research · 2024Article
- Structural dynamics of NaCommunications biology · 2024Article
- Structural insight into the allosteric inhibition of human sodium-calcium exchanger NCX1 by XIP and SEA0400.The EMBO journal · 2024Article
- Structural mechanisms of the human cardiac sodium-calcium exchanger NCX1.Nature communications · 2023Article
- Skeletal and cardiac muscle calcium transport regulation in health and disease.Bioscience reports · 2022Review
- Structure-Based Function and Regulation of NCX Variants: Updates and Challenges.International journal of molecular sciences · 2022Review
- Molecular insights on CALX-CBD12 interdomain dynamics from MD simulations, RDCs, and SAXS.Biophysical journal · 2021Article
- Modulation of the cardiac NaCell calcium · 2020Review
- Regulation of ion transport from within ion transit pathways.The Journal of general physiology · 2020Review
- Molecular determinants of pH regulation in the cardiac NaThe Journal of general physiology · 2018Article
- An amphipathic α-helix directs palmitoylation of the large intracellular loop of the sodium/calcium exchanger.The Journal of biological chemistry · 2017Article
- Structure-based dynamic arrays in regulatory domains of sodium-calcium exchanger (NCX) isoforms.Scientific reports · 2017Article
- Modeling NaJournal of molecular and cellular cardiology · 2016Article
- Development of a high-affinity peptide that prevents phospholemman (PLM) inhibition of the sodium/calcium exchanger 1 (NCX1).The Biochemical journal · 2016Article
- Structural Features of Ion Transport and Allosteric Regulation in Sodium-Calcium Exchanger (NCX) Proteins.Frontiers in physiology · 2016Review
- Palmitoylation of the Na/Ca exchanger cytoplasmic loop controls its inactivation and internalization during stress signaling.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2015Article
- Article
- Uniqueness of models from small-angle scattering data: the impact of a hydration shell and complementary NMR restraints.Acta crystallographica. Section D, Biological crystallography · 2015Article
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5 authors.
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No grant is acknowledged in the PubMed record.
Abstract
Regulation of ion-transport in the Na(+)/Ca(2+) exchanger (NCX) occurs via its cytoplasmic Ca(2+)-binding domains, CBD1 and CBD2. Here, we present a mechanism for NCX activation and inactivation based on data obtained using NMR, isothermal titration calorimetry (ITC) and small-angle X-ray scattering (SAXS). We initially determined the structure of the Ca(2+)-free form of CBD2-AD and the structure of CBD2-BD that represent the two major splice variant classes in NCX1. Although the apo-form of CBD2-AD displays partially disordered Ca(2+)-binding sites, those of CBD2-BD are entirely unstructured even in an excess of Ca(2+). Striking differences in the electrostatic potential between the Ca(2+)-bound and -free forms strongly suggest that Ca(2+)-binding sites in CBD1 and CBD2 form electrostatic switches analogous to C(2)-domains. SAXS analysis of a construct containing CBD1 and CBD2 reveals a conformational change mediated by Ca(2+)-binding to CBD1. We propose that the electrostatic switch in CBD1 and the associated conformational change are necessary for exchanger activation. The response of the CBD1 switch to intracellular Ca(2+) is influenced by the closely located cassette exons. We further propose that Ca(2+)-binding to CBD2 induces a second electrostatic switch, required to alleviate Na(+)-dependent inactivation of Na(+)/Ca(2+) exchange. In contrast to CBD1, the electrostatic switch in CBD2 is isoform- and splice variant-specific and allows for tailored exchange activities.
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