Structure-Functional Basis of Ion Transport in Sodium-Calcium Exchanger (NCX) Proteins

Int J Mol Sci. 2016 Nov 22;17(11):1949. doi: 10.3390/ijms17111949.


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.

Keywords: HDX-MS (hydrogen–deuterium exchange mass-spectrometry); NCX (sodium–calcium exchanger); alternating access; antiporter; catalysis; occlusion; selectivity; transporter.

Publication types

  • Review

MeSH terms

  • Amino Acid Sequence
  • Archaea / chemistry
  • Archaea / metabolism
  • Calcium / metabolism*
  • Crystallography, X-Ray
  • Deuterium Exchange Measurement
  • Gene Expression
  • Homeostasis
  • Humans
  • Ion Transport
  • Molecular Dynamics Simulation
  • Mutation
  • Protein Domains
  • Protein Isoforms / chemistry*
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Structure, Secondary
  • Sodium / metabolism*
  • Sodium-Calcium Exchanger / chemistry*
  • Sodium-Calcium Exchanger / genetics
  • Sodium-Calcium Exchanger / metabolism
  • Structure-Activity Relationship


  • Protein Isoforms
  • Sodium-Calcium Exchanger
  • Sodium
  • Calcium