Format

Send to

Choose Destination
Int J Mol Sci. 2016 Nov 22;17(11). pii: E1949.

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

Author information

1
Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 699780, Israel. moshegil@post.tau.ac.il.
2
Tel-Aviv Sourasky Medical Center, Tel-Aviv 6423906, Israel. moshegil@post.tau.ac.il.
3
Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 699780, Israel. reutshor@gmail.com.
4
Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 699780, Israel. michallis505@gmail.com.
5
Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 699780, Israel. dhanan@post.tau.ac.il.

Abstract

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

PMID:
27879668
PMCID:
PMC5133943
DOI:
10.3390/ijms17111949
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Multidisciplinary Digital Publishing Institute (MDPI) Icon for PubMed Central
Loading ...
Support Center