title: Structure-Functional Basis of Ion Transport in Sodium-Calcium Exchanger (NCX) Proteins.
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.
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 699780, Israel. moshegil@post.tau.ac.il.|Tel-Aviv Sourasky Medical Center, Tel-Aviv 6423906, Israel. moshegil@post.tau.ac.il.
authors.forename: Moshe
authors.initials: M
authors.lastname: Giladi
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 699780, Israel. reutshor@gmail.com.
authors.forename: Reut
authors.initials: R
authors.lastname: Shor
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 699780, Israel. michallis505@gmail.com.
authors.forename: Michal
authors.initials: M
authors.lastname: Lisnyansky
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 699780, Israel. dhanan@post.tau.ac.il.
authors.forename: Daniel
authors.initials: D
authors.lastname: Khananshvili
mesh_terms: D000595:Amino Acid Sequence; D001105:Archaea / Q000737:chemistry / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D018360:Crystallography, X-Ray; D041961:Deuterium Exchange Measurement; D015870:Gene Expression; D006706:Homeostasis; D006801:Humans; D017136:Ion Transport; D056004:Molecular Dynamics Simulation; D009154:Mutation; D000072417:Protein Domains; D020033:Protein Isoforms / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017433:Protein Structure, Secondary; D012964:Sodium / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D020033:Protein Isoforms; D019831:Sodium-Calcium Exchanger; D012964:Sodium; D002118:Calcium
keywords: HDX-MS (hydrogen–deuterium exchange mass-spectrometry); NCX (sodium–calcium exchanger); alternating access; antiporter; catalysis; occlusion; selectivity; transporter