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Int. J. Mol. Sci. 2016, 17(11), 1949;

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

Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 699780, Israel
Tel-Aviv Sourasky Medical Center, Tel-Aviv 6423906, Israel
Authors to whom correspondence should be addressed.
Academic Editor: Masatoshi Maki
Received: 29 September 2016 / Revised: 13 November 2016 / Accepted: 14 November 2016 / Published: 22 November 2016
(This article belongs to the Special Issue Metalloproteins 2017)
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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. View Full-Text
Keywords: alternating access; NCX (sodium–calcium exchanger); antiporter; transporter; occlusion; catalysis; selectivity; HDX-MS (hydrogen–deuterium exchange mass-spectrometry) alternating access; NCX (sodium–calcium exchanger); antiporter; transporter; occlusion; catalysis; selectivity; HDX-MS (hydrogen–deuterium exchange mass-spectrometry)

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Giladi, M.; Shor, R.; Lisnyansky, M.; Khananshvili, D. Structure-Functional Basis of Ion Transport in Sodium–Calcium Exchanger (NCX) Proteins. Int. J. Mol. Sci. 2016, 17, 1949.

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