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

Moshe Giladi,Reut Shor,Daniel Khananshvili,Michal Lisnyansky

doi:10.3390/ijms17111949

Moshe Giladi, Reut Shor + Show 2 more

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https://doi.org/10.3390/ijms17111949

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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.

Highlights

A cascade of biological events at the cellular, organ, and systemic levels requires the direct or indirect contribution of distinct cations, such as H+, Na+, K+, Ca2+, and Mg2+, where protein structures can somehow manage the selective recognition of specific cations to couple the mechanical, catalytic, and transport activities possessed by a given protein [1,2,3]
Physiological concentrations of important cations in the extracellular, cytosolic, and subcellular compartments are tightly controlled by membrane-intercalated proteins, channels, transporters and pumps, which can dynamically generate, retain, and modify ion homeostasis in time and space in accordance with the physiological demands of a given cell type [4,5,6]
A thorough understanding of ligand-coupled alternating-access mechanisms remains challenging mainly because the dynamic features of transient intermediates throughout the transport cycle are incompletely resolved even for proteins with known crystal structures [9,10,11,12,13,14]. This is especially true for antiporter systems, where ligand interactions with proteins is “mandatory” for alternating between the outward-facing and inward-facing states [7,8,9,10,11]

Summary

Introduction

A cascade of biological events at the cellular, organ, and systemic levels requires the direct or indirect contribution of distinct cations, such as H+, Na+, K+, Ca2+, and Mg2+, where protein structures can somehow manage the selective recognition of specific cations to couple the mechanical, catalytic, and transport activities possessed by a given protein [1,2,3]. A thorough understanding of ligand-coupled alternating-access mechanisms remains challenging mainly because the dynamic features of transient intermediates throughout the transport cycle are incompletely resolved even for proteins with known crystal structures [9,10,11,12,13,14].

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