Structure-functional basis of ion transport in sodium–calcium exchanger (NCX) proteins

Moshe Giladi*, Reut Shor, Michal Lisnyansky, Daniel Khananshvili

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review


The membrane-bound sodium–calcium exchanger (NCX) proteins shape Ca2+ homeostasis in many cell types, thus participating in a wide range of physiological and pathological processes. 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. Here, we review the data gathered from the X-ray crystallography, molecular dynamics simulations, hydrogen–deuterium exchange mass-spectrometry (HDX-MS), and ion-flux analyses of mutants. Strikingly, the apo NCX_Mj protein exhibits characteristic patterns in the local backbone dynamics at particular helix segments, thereby possessing characteristic HDX profiles, suggesting structure-dynamic preorganization (geometric arrangements of catalytic residues before the transition state) of conserved α1 and α2 repeats at ion-coordinating residues involved in transport activities. Moreover, dynamic preorganization of local structural entities in the apo protein predefines the status of ion-occlusion and transition states, even though Na+ or Ca2+ binding modifies the preceding backbone dynamics nearby functionally important residues. Future challenges include resolving the structural-dynamic determinants governing the ion selectivity, functional asymmetry and ion-induced alternating access. Taking into account the structural similarities of NCX_Mj with the other proteins belonging to the Ca2+/cation exchanger superfamily, the recent findings can significantly improve our understanding of ion transport mechanisms in NCX and similar proteins.

Original languageEnglish
Article number1949
JournalInternational Journal of Molecular Sciences
Issue number11
StatePublished - 22 Nov 2016


  • Alternating access
  • Antiporter
  • Catalysis
  • HDX-MS (hydrogen–deuterium exchange mass-spectrometry)
  • NCX (sodium–calcium exchanger)
  • Occlusion
  • Selectivity
  • Transporter


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