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Mechanism of extracellular ion exchange and binding-site occlusion in a sodium/calcium exchanger.

Liao J, Marinelli F, Lee C, Huang Y, Faraldo-Gómez JD, Jiang Y
Nat Struct Mol Biol 23 590-599 (2016)
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Cited: 35 times
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Abstract

Na(+)/Ca(2+) exchangers use the Na(+) electrochemical gradient across the plasma membrane to extrude intracellular Ca(2+) and play a central role in Ca(2+) homeostasis. Here, we elucidate their mechanisms of extracellular ion recognition and exchange through a structural analysis of the exchanger from Methanococcus jannaschii (NCX_Mj) bound to Na(+), Ca(2+) or Sr(2+) in various occupancies and in an apo state. This analysis defines the binding mode and relative affinity of these ions, establishes the structural basis for the anticipated 3:1 Na(+)/Ca(2+)-exchange stoichiometry and reveals the conformational changes at the onset of the alternating-access transport mechanism. An independent analysis of the dynamics and conformational free-energy landscape of NCX_Mj in different ion-occupancy states, based on enhanced-sampling molecular dynamics simulations, demonstrates that the crystal structures reflect mechanistically relevant, interconverting conformations. These calculations also reveal the mechanism by which the outward-to-inward transition is controlled by the ion occupancy, thereby explaining the emergence of strictly coupled Na(+)/Ca(2+) antiport.

Reviews - 5hxr mentioned but not cited (1)

  1. Structure-Functional Basis of Ion Transport in Sodium-Calcium Exchanger (NCX) Proteins. Giladi M, Shor R, Lisnyansky M, Khananshvili D. Int J Mol Sci 17 E1949 (2016)

Articles - 5hxr mentioned but not cited (4)

  1. Mechanism of extracellular ion exchange and binding-site occlusion in a sodium/calcium exchanger. Liao J, Marinelli F, Lee C, Huang Y, Faraldo-Gómez JD, Jiang Y. Nat Struct Mol Biol 23 590-599 (2016)
  2. Dynamic distinctions in the Na+/Ca2+ exchanger adopting the inward- and outward-facing conformational states. Giladi M, van Dijk L, Refaeli B, Almagor L, Hiller R, Man P, Forest E, Khananshvili D. J Biol Chem 292 12311-12323 (2017)
  3. New Insights into the Structure-Activity Relationship and Neuroprotective Profile of Benzodiazepinone Derivatives of Neurounina-1 as Modulators of the Na+/Ca2+ Exchanger Isoforms. Magli E, Fattorusso C, Persico M, Corvino A, Esposito G, Fiorino F, Luciano P, Perissutti E, Santagada V, Severino B, Tedeschi V, Pannaccione A, Pignataro G, Caliendo G, Annunziato L, Secondo A, Frecentese F. J Med Chem 64 17901-17919 (2021)
  4. research-article Conformational free-energy landscapes of a Na+/Ca2+ exchanger explain its alternating-access mechanism and functional specificity. Marinelli F, Faraldo-Gómez JD. bioRxiv 2023.01.20.524959 (2023)


Reviews citing this publication (7)

  1. Hydrogen-Deuterium Exchange Mass-Spectrometry of Secondary Active Transporters: From Structural Dynamics to Molecular Mechanisms. Giladi M, Khananshvili D. Front Pharmacol 11 70 (2020)
  2. Sequence Features of Mitochondrial Transporter Protein Families. Gyimesi G, Hediger MA. Biomolecules 10 E1611 (2020)
  3. The Cardiac Na+ -Ca2+ Exchanger: From Structure to Function. Ottolia M, John S, Hazan A, Goldhaber JI. Compr Physiol 12 2681-2717 (2021)
  4. The Archaeal Na+/Ca2+ Exchanger (NCX_Mj) as a Model of Ion Transport for the Superfamily of Ca2+/CA Antiporters. Khananshvili D. Front Chem 9 722336 (2021)
  5. Modulation of the cardiac Na+-Ca2+ exchanger by cytoplasmic protons: Molecular mechanisms and physiological implications. Scranton K, John S, Escobar A, Goldhaber JI, Ottolia M. Cell Calcium 87 102140 (2020)
  6. Sodium-Calcium Exchangers of the SLC8 Family in Oligodendrocytes: Functional Properties in Health and Disease. Spencer SA, Suárez-Pozos E, Escalante M, Myo YP, Fuss B. Neurochem Res 45 1287-1297 (2020)
  7. Structure-Based Function and Regulation of NCX Variants: Updates and Challenges. Khananshvili D. Int J Mol Sci 24 61 (2022)

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  3. Broadly conserved Na+-binding site in the N-lobe of prokaryotic multidrug MATE transporters. Ficici E, Zhou W, Castellano S, Faraldo-Gómez JD. Proc Natl Acad Sci U S A 115 E6172-E6181 (2018)
  4. Dynamic Palmitoylation of the Sodium-Calcium Exchanger Modulates Its Structure, Affinity for Lipid-Ordered Domains, and Inhibition by XIP. Gök C, Plain F, Robertson AD, Howie J, Baillie GS, Fraser NJ, Fuller W. Cell Rep 31 107697 (2020)
  5. The prokaryotic Na+/Ca2+ exchanger NCX_Mj transports Na+ and Ca2+ in a 3:1 stoichiometry. Shlosman I, Marinelli F, Faraldo-Gómez JD, Mindell JA. J Gen Physiol 150 51-65 (2018)
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  7. Key residues controlling bidirectional ion movements in Na+/Ca2+ exchanger. van Dijk L, Giladi M, Refaeli B, Hiller R, Cheng MH, Bahar I, Khananshvili D. Cell Calcium 76 10-22 (2018)
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  9. A K+/Na+ co-binding state: Simultaneous versus competitive binding of K+ and Na+ to glutamate transporters. Wang J, Zielewicz L, Grewer C. J Biol Chem 294 12180-12190 (2019)
  10. Sulfation and Calcium Favor Compact Conformations of Chondroitin in Aqueous Solutions. Guvench O, Whitmore EK. ACS Omega 6 13204-13217 (2021)
  11. Interpretation of spectroscopic data using molecular simulations for the secondary active transporter BetP. Leone V, Waclawska I, Kossmann K, Koshy C, Sharma M, Prisner TF, Ziegler C, Endeward B, Forrest LR. J Gen Physiol 151 381-394 (2019)
  12. Exploring the Li+ transporting mutant of NCX_Mj for assigning ion binding sites of mitochondrial NCLX. Giladi M, Mitra S, Simhaev L, Hiller R, Refaeli B, Strauss T, Baiz CR, Khananshvili D. Cell Calcium 107 102651 (2022)
  13. Calcium dysregulation potentiates wild-type myocilin misfolding: implications for glaucoma pathogenesis. Saccuzzo EG, Martin MD, Hill KR, Ma MT, Ku Y, Lieberman RL. J Biol Inorg Chem 27 553-564 (2022)
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  15. On the Role of a Conserved Methionine in the Na+-Coupling Mechanism of a Neurotransmitter Transporter Homolog. Zhou W, Trinco G, Slotboom DJ, Forrest LR, Faraldo-Gómez JD. Neurochem Res 47 163-175 (2022)
  16. Proton-modulated interactions of ions with transport sites of prokaryotic and eukaryotic NCX prototypes. Refaeli B, Liu S, Hiller R, Giladi M, Baiz CR, Khananshvili D. Cell Calcium 99 102476 (2021)
  17. Quantitative Proteomic Profiling of Fungal Growth, Development, and Ochratoxin A Production in Aspergillus ochraceus on High- and Low-NaCl Cultures. Wang Y, Guan Y, Lin W, Yan H, Neng J, Sun P. Toxins (Basel) 13 51 (2021)
  18. Ca2+ efflux facilitated by co-transport of inorganic phosphate anion in the H+/Ca2+ antiporter YfkE. Niu W, Zhou W, Lu S, Vu T, Jayaraman V, Faraldo-Gómez JD, Zheng L. Commun Biol 6 573 (2023)
  19. Interrogating the conformational dynamics of BetP transport. Robertson JL. J Gen Physiol 151 279-281 (2019)
  20. Investigation of toxicity effect of TiCN coated on 304 SS and 410 SS substrates in rat fibroblasts and B-lymphocytes. Naserzadeh P, Razmi A, Yesildal R, Ashtari B. Toxicol Res (Camb) 11 286-298 (2022)
  21. Markov state modelling reveals heterogeneous drug-inhibition mechanism of Calmodulin. Westerlund AM, Sridhar A, Dahl L, Andersson A, Bodnar AY, Delemotte L. PLoS Comput Biol 18 e1010583 (2022)
  22. Structural insight into the allosteric inhibition of human sodium-calcium exchanger NCX1 by XIP and SEA0400. Dong Y, Yu Z, Li Y, Huang B, Bai Q, Gao Y, Chen Q, Li N, He L, Zhao Y. EMBO J 43 14-31 (2024)
  23. Structural mechanisms of the human cardiac sodium-calcium exchanger NCX1. Xue J, Zeng W, Han Y, John S, Ottolia M, Jiang Y. Nat Commun 14 6181 (2023)


Related citations provided by authors (1)

  1. Structural insight into the ion-exchange mechanism of the sodium/calcium exchanger.. Liao J, Li H, Zeng W, Sauer DB, Belmares R, Jiang Y Science 335 686-90 (2012)

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