Dataset Information

NCX-DB: a unified resource for integrative analysis of the sodium calcium exchanger super-family.

ABSTRACT: Na⁺/Ca²⁺ exchangers are low-affinity high-capacity transporters that mediate Ca²⁺ extrusion by coupling Ca²⁺ efflux to the influx of Na⁺ ions. The Na⁺/Ca²⁺ exchangers form a super-family comprised of three branches each differing in ion-substrate selectivity: Na⁺/Ca²⁺ exchangers (NCX), Na⁺/Ca²⁺/K⁺ exchangers, and Ca²⁺/cation exchangers. Their primary function is to maintain Ca²⁺ homeostasis and play a particularly important role in excitable cells that experience transient Ca²⁺ fluxes. Research into the role and activity of Na⁺/Ca²⁺ exchangers has focused extensively on the cardio-vascular system, however, growing evidence suggests that Na⁺/Ca²⁺ exchangers play a key role in neuronal processes such as memory formation, learning, oligodendrocyte differentiation, neuroprotection during brain ischemia and axon guidance. They have also been implicated in pathologies such as Alzheimer's disease, Parkinson's disease, Multiple Sclerosis and Epilepsy, however, a clear understanding of their mechanism during disease is lacking. To date, there has never been a central resource or database for Na⁺/Ca²⁺ exchangers. With clear disease relevance and ever-increasing research on Na⁺/Ca²⁺ exchangers from both model and non-model species, a database that unifies the data on Na⁺/Ca²⁺ exchangers is needed for future research. NCX-DB is a publicly available database with a web interface that enables users to explore various Na⁺/Ca²⁺ exchangers, perform cross-species sequence comparison, identify new exchangers, and stay-up to date with recent literature. NCX-DB is available on the web via an interactive user interface with an intuitive design, which is applicable for the identification and comparison of Na⁺/Ca²⁺ exchanger proteins across diverse species.

SUBMITTER: Bode K

PROVIDER: S-EPMC5898058 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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NCX-DB: a unified resource for integrative analysis of the sodium calcium exchanger super-family.

Bode Katrin K O'Halloran Damien M DM

BMC neuroscience 20180413 1

Na+/Ca2+ exchangers are low-affinity high-capacity transporters that mediate Ca2+ extrusion by coupling Ca2+ efflux to the influx of Na+ ions. The Na+/Ca2+ exchangers form a super-family comprised of three branches each differing in ion-substrate selectivity: Na+/Ca2+ exchangers (NCX), Na+/Ca2+/K+ exchangers, and Ca2+/cation exchangers. Their primary func ...[more]

PMID: 29649983

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Project description:Na(+)/Ca(2+) exchanger (NCX) proteins extrude Ca(2+) from the cell to maintain cellular homeostasis. Since NCX proteins contribute to numerous physiological and pathophysiological events, their pharmacological targeting has been desired for a long time. This intervention remains challenging owing to our poor understanding of the underlying structure-dynamic mechanisms. Recent structural studies have shed light on the structure-function relationships underlying the ion-transport and allosteric regulation of NCX. The crystal structure of an archaeal NCX (NCX_Mj) along with molecular dynamics simulations and ion flux analyses, have assigned the ion binding sites for 3Na(+) and 1Ca(2+), which are being transported in separate steps. In contrast with NCX_Mj, eukaryotic NCXs contain the regulatory Ca(2+)-binding domains, CBD1 and CBD2, which affect the membrane embedded ion-transport domains over a distance of ~80 Å. The Ca(2+)-dependent regulation is ortholog, isoform, and splice-variant dependent to meet physiological requirements, exhibiting either a positive, negative, or no response to regulatory Ca(2+). The crystal structures of the two-domain (CBD12) tandem have revealed a common mechanism involving a Ca(2+)-driven tethering of CBDs in diverse NCX variants. However, dissociation kinetics of occluded Ca(2+) (entrapped at the two-domain interface) depends on the alternative-splicing segment (at CBD2), thereby representing splicing-dependent dynamic coupling of CBDs. The HDX-MS, SAXS, NMR, FRET, equilibrium (45)Ca(2+) binding and stopped-flow techniques provided insights into the dynamic mechanisms of CBDs. Ca(2+) binding to CBD1 results in a population shift, where more constraint conformational states become highly populated without global conformational changes in the alignment of CBDs. This mechanism is common among NCXs. Recent HDX-MS studies have demonstrated that the apo CBD1 and CBD2 are stabilized by interacting with each other, while Ca(2+) binding to CBD1 rigidifies local backbone segments of CBD2, but not of CBD1. The extent and strength of Ca(2+)-dependent rigidification at CBD2 is splice-variant dependent, showing clear correlations with phenotypes of matching NCX variants. Therefore, diverse NCX variants share a common mechanism for the initial decoding of the regulatory signal upon Ca(2+) binding at the interface of CBDs, whereas the allosteric message is shaped by CBD2, the dynamic features of which are dictated by the splicing segment.

Project description:BackgroundThe Na(+)/Ca(2+) Exchanger (NCX) protein family is a member of the Cation/Ca(2+) exchanger superfamily and its members play important roles in cellular Ca(2+) homeostasis. While the functions of NCX family of proteins is well understood in humans, not much is known about the total complement of Na(+)/Ca(2+) exchangers in plants and their role in various physiological and developmental processes. In the present study, we have identified all the NCX proteins encoded in the genomes of rice and Arabidopsis and studied their phylogeny, domain architecture and expression profiles across different tissues, at various developmental stages and under stress conditions.ResultsThrough whole genome investigation, we identified twenty-two NCX proteins encoded by fifteen genes in rice and sixteen NCX proteins encoded by thirteen genes in Arabidopsis. Based on phylogenetic reconstruction, these could be classified into five clades, members of most of which were found to possess distinct domain architecture. Expression profiling of the identified NCX genes using publicly available MPSS and microarray data showed differential expression patterns under abiotic stresses, and at various development stages. In rice, OsNCX1, OsNCX8, OsNCX9 and OsNCX15 were found to be highly expressed in all the plant parts and various developmental stages. qRT-PCR based expression analysis revealed that OsNCX3, OsNCX10 and OsNCX15 were highly induced by salt and dehydration stress. Besides, expression profiling showed differential regulation of rice NCX genes in response to calcium and EGTA. Interestingly, expression of none of the NCX genes was found to be co-regulated by NaCl and calcium.ConclusionsTogether, our results present insights into the potential role of NCX family of proteins in abiotic stresses and development. Findings of the present investigation should serve as a starting point for future studies aiming functional characterization of plant NCX family proteins.

Dataset Information

NCX-DB: a unified resource for integrative analysis of the sodium calcium exchanger super-family.

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NCX-DB: a unified resource for integrative analysis of the sodium calcium exchanger super-family.

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