Structural Features of Ion Transport and Allosteric Regulation in Sodium-Calcium Exchanger (NCX) Proteins

@article{Giladi2016StructuralFO,
  title={Structural Features of Ion Transport and Allosteric Regulation in Sodium-Calcium Exchanger (NCX) Proteins},
  author={M. Giladi and Inbal Tal and D. Khananshvili},
  journal={Frontiers in Physiology},
  year={2016},
  volume={7}
}
Na+/Ca2+ exchanger (NCX) proteins extrude Ca2+ from the cell to maintain cellular homeostasis. Since NCX proteins contribute to numerous physiological and pathophysiological events, their pharmacological targeting has been desired for a long time. This intervention remains challenging owing to our poor understanding of the underlying structure-dynamic mechanisms. Recent structural studies have shed light on the structure-function relationships underlying the ion-transport and allosteric… Expand
Structure-Functional Basis of Ion Transport in Sodium–Calcium Exchanger (NCX) Proteins
TLDR
Determination of the crystal structure of an archaeal NCX (NCX_Mj) paved the way for a thorough and systematic investigation of ion transport mechanisms in NCX proteins, suggesting structure-dynamic preorganization of local structural entities in the apo protein predefines the status of ion-occlusion and transition states. Expand
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TLDR
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TLDR
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The superfamily of Calcium/Cation (Ca2+/CA) antiporters extrude Ca2+ from the cytosol or subcellular compartments in exchange with Na+, K+, H+, Li+, or Mg2+ and thereby provide a key mechanism forExpand
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Dynamic distinctions in the Na+/Ca2+ exchanger adopting the inward- and outward-facing conformational states
TLDR
Characteristic differences in the backbone dynamics were identified between apo NCX_Mj-WT and NCX-5L6–8, thereby underscoring specific conformational patterns owned by the OF and IF states. Expand
Structure-based dynamic arrays in regulatory domains of sodium-calcium exchanger (NCX) isoforms
TLDR
The unified model, according to which the Ca2+ binding to CBD12 shifts a dynamic equilibrium without generating new conformationalStates, and where more rigid conformational states become more populated without any global conformational changes, is revealed. Expand
Key residues controlling bidirectional ion movements in Na+/Ca2+ exchanger.
TLDR
The present mutational analysis highlights structural elements that differentially govern the intrinsic asymmetry and transport rates of NCX variants, including key residues, located at specific segments, which can affect the characteristic features of local backbone dynamics and thus, the conformational flexibility of ion-transporting helices contributing to critical conformational transitions. Expand
Modulation of the cardiac Na+-Ca2+ exchanger by cytoplasmic protons: Molecular mechanisms and physiological implications.
TLDR
This review summarizes the recent progress towards the understanding of the molecular mechanisms underlying the ionic regulation of the cardiac NCX with special emphasis on pH modulation and its physiological impact on the heart. Expand
Glycosylation controls sodium-calcium exchanger 3 sub-cellular localization during cell cycle.
TLDR
Results, obtained in transfected HEK293T and HeLa and confirmed endogenously in SH-SY5Y cells, suggest that cells can use a dynamic Ca2+ signaling toolkit in which the NCX3 sub-cellular localization changes in synchrony with the cell cycle. Expand
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References

SHOWING 1-10 OF 101 REFERENCES
Structural Insight into the Ion-Exchange Mechanism of the Sodium/Calcium Exchanger
TLDR
A structure model is proposed for the inward-facing NCX_Mj that clarifies the mechanism of ion exchange proteins and reveals the basis for the stoichiometry, cooperativity, and bidirectionality of the reaction. Expand
Sodium recognition by the Na+/Ca2+ exchanger in the outward-facing conformation
TLDR
The structural mechanism of Na+ recognition in a prokaryotic NCX homolog is established, using atomistic molecular-dynamics simulations based on recently reported crystallographic data, as well as experimental transport assays of wild-type and mutagenized exchangers, which imply that the ion exchange stoichiometry of NCX_Mj is 3:1 and that translocated Na+ across the membrane is electrogenic, whereas transport of Ca2+ is not. Expand
Structural Basis for Alternating Access of a Eukaryotic Calcium/Proton Exchanger
TLDR
Vcx1 is the first structure, to the authors' knowledge, within the CAX family, and it describes the key cytosol-facing conformation of the CaCA superfamily, providing the structural basis for a novel alternating access mechanism by which the Ca CA superfamily performs high-throughput Ca2+ transport across membranes. Expand
Structural Basis for the Counter-Transport Mechanism of a H+/Ca2+ Exchanger
TLDR
The structures and functional analyses provide insight into the mechanism of how the inward- to outward-facing state transition is triggered by the Ca2+ and H+ binding. Expand
Ca2+ Binding Alters the Interdomain Flexibility between the Two Cytoplasmic Calcium-binding Domains in the Na+/Ca2+ Exchanger*
TLDR
Solution NMR spectroscopy is used to study the interdomain dynamics of CBD12, a 32 kDa construct that contains both the CBD1 and CBD2 domains connected by a short linker, suggesting a molecular mechanism for the role of CBD 12 in the function of NCX. Expand
Sodium-calcium exchangers (NCX): molecular hallmarks underlying the tissue-specific and systemic functions
  • D. Khananshvili
  • Biology, Medicine
  • Pflügers Archiv - European Journal of Physiology
  • 2013
TLDR
The breakthrough discovery of the archaebacterial NCX structure may serve as a template for eukaryotic NCX, although the turnover rates of the transport cycle may differ ∼103-fold among NCX variants to fulfill the physiological demands for the Ca2+ flux rates. Expand
A Common Ca2+-Driven Interdomain Module Governs Eukaryotic NCX Regulation
TLDR
It is suggested that the Ca2+-driven interdomain switch described here represents a general mechanism for initial conduction of regulatory signals in NCX variants, which are nearly identical among eukaryotic NCXs, including CALX. Expand
Ca2+ regulation in the Na+/Ca2+ exchanger features a dual electrostatic switch mechanism
TLDR
A mechanism for NCX activation and inactivation based on data obtained using NMR, isothermal titration calorimetry (ITC) and small-angle X-ray scattering (SAXS) to propose that Ca2+-binding to CBD2 induces a second electrostatic switch, required to alleviate Na+-dependent inactivation of Na+/Ca2+ exchange. Expand
Ca 2 ! Binding Alters the Interdomain Flexibility between the Two Cytoplasmic Calcium-binding Domains in the Na ! / Ca 2 ! Exchanger *
The Na!/Ca2! exchanger (NCX) is a membrane protein, which catalyzes the counter transport of Na! and Ca2! ions across the plasma membrane, playing a key role in the maintenance of theExpand
Kinetic and Equilibrium Properties of Regulatory Calcium Sensors of NCX1 Protein*
TLDR
New experimental approaches for evaluating the kinetic and equilibrium properties of Ca2+ interaction with regulatory sites by using purified preparations of CBD1, CBD2, and CBD12 proteins are provided. Expand
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