The Archaeal Na+/Ca2+ Exchanger (NCX_Mj) as a Model of Ion Transport for the Superfamily of Ca2+/CA Antiporters.

Daniel Khananshvili

doi:10.3389/fchem.2021.722336

Abstract

The superfamily of Calcium/Cation (Ca2+/CA) antiporters extrude Ca2+ from the cytosol or subcellular compartments in exchange with Na+, K+, H+, Li+, or Mg2+ and thereby provide a key mechanism for Ca2+ signaling and ion homeostasis in biological systems ranging from bacteria to humans. The structure-dynamic determinants of ion selectivity and transport rates remain unclear, although this is of primary physiological significance. Despite wide variances in the ion selectivity and transport rates, the Ca2+/CA proteins share structural motifs, although it remains unclear how the ion recognition/binding is coupled to the ion translocation events. Here, the archaeal Na+/Ca2+ exchanger (NCX_Mj) is considered as a structure-based model that can help to resolve the ion transport mechanisms by using X-ray, HDX-MS, ATR-FTIR, and computational approaches in conjunction with functional analyses of mutants. Accumulating data reveal that the local backbone dynamics at ion-coordinating residues is characteristically constrained in apo NCX_Mj, which may predefine the affinity and stability of ion-bound species in the ground and transition states. The 3Na+ or 1Ca2+ binding to respective sites of NCX_Mj rigidify the backbone dynamics at specific segments, where the ion-dependent compression of the ion-permeating four-helix bundle (TM2, TM3, TM7, and TM8) induces the sliding of the two-helix cluster (TM1/TM6) on the protein surface to switch the OF (outward-facing) and IF (inward-facing) conformations. Taking into account the common structural elements shared by Ca2+/CAs, NCX_Mj may serve as a model for studying the structure-dynamic and functional determinants of ion-coupled alternating access, transport catalysis, and ion selectivity in Ca2+/CA proteins.

Highlights

Membrane-bound ion transport proteins can selectively recognize and transport physiologically important cations such as H+, Na+, K+, Ca2+, and Mg2+ in accordance with the physiological requirements of a given cell type and thereby control the vast majority of biochemical reactions in nearly every living cell (Carafoli, 1987; Berridge et al, 2003; Bers 2008; Forrest et al, 2011; Keller et al, 2014)
A systematic replacement of differing ion-coordinating residues in Na+/Ca2+ exchanger protein derived from Methanococcus jannaschii (NCX_Mj) cannot recapitulate the high turnover rates of those possessed by prokaryotic sodium-calcium exchanger (NCX) (Almagor et al, 2014; van Dijk et al, 2018; Iwaki et al, 2020)
A systematic application of multidisciplinary approaches, which included structural (X-ray crystallography), computational, biophysical (HDX-MS, ATR-FITR), and biochemical techniques, shed light on the ion transport mechanisms operating in the Ca2+/ CA proteins

Summary

Daniel Khananshvili *

Model of Ion Transport for the Superfamily of Ca2+/CA Antiporters. The structure-dynamic determinants of ion selectivity and transport rates remain unclear, this is of primary physiological significance. Despite wide variances in the ion selectivity and transport rates, the Ca2+/CA proteins share structural motifs, it remains unclear how the ion recognition/binding is coupled to the ion translocation events. The archaeal Na+/Ca2+ exchanger (NCX_Mj) is considered as a structure-based model that can help to resolve the ion transport mechanisms by using X-ray, HDX-MS, ATR-FTIR, and computational approaches in conjunction with functional analyses of mutants. Taking into account the common structural elements shared by Ca2+/CAs, NCX_Mj may serve as a model for studying the structure-dynamic and functional determinants of ion-coupled alternating access, transport catalysis, and ion selectivity in Ca2+/CA proteins

INTRODUCTION

Since the crystal structures of the NCKX and mitochondrial

With Ion Occlusion

CONCLUDING REMARKS AND PERSPECTIVE