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

Jun Liao, Fabrizio Marinelli, Changkeun Lee, Yihe Huang, José D. Faraldo-Gómez, Youxing Jiang

Research output: Contribution to journalArticle

36 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)590-599
Number of pages10
JournalNature Structural and Molecular Biology
Volume23
Issue number6
DOIs
StatePublished - Jun 7 2016

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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