Asymmetric Preorganization of Inverted Pair Residues in the Sodium-Calcium Exchanger

Scientific Reports
Moshe GiladiDaniel Khananshvili

Abstract

In analogy with many other proteins, Na(+)/Ca(2+) exchangers (NCX) adapt an inverted twofold symmetry of repeated structural elements, while exhibiting a functional asymmetry by stabilizing an outward-facing conformation. Here, structure-based mutant analyses of the Methanococcus jannaschii Na(+)/Ca(2+) exchanger (NCX_Mj) were performed in conjunction with HDX-MS (hydrogen/deuterium exchange mass spectrometry) to identify the structure-dynamic determinants of functional asymmetry. HDX-MS identified hallmark differences in backbone dynamics at ion-coordinating residues of apo-NCX_Mj, whereas Na(+)or Ca(2+) binding to the respective sites induced relatively small, but specific, changes in backbone dynamics. Mutant analysis identified ion-coordinating residues affecting the catalytic capacity (kcat/Km), but not the stability of the outward-facing conformation. In contrast, distinct "noncatalytic" residues (adjacent to the ion-coordinating residues) control the stability of the outward-facing conformation, but not the catalytic capacity. The helix-breaking signature sequences (GTSLPE) on the α1 and α2 repeats (at the ion-binding core) differ in their folding/unfolding dynamics, while providing asymmetric contributions to transport ...Continue Reading

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Citations

Nov 24, 2016·International Journal of Molecular Sciences·Moshe GiladiDaniel Khananshvili
Feb 23, 2017·Proceedings of the National Academy of Sciences of the United States of America·Suraj AdhikarySatinder K Singh
Jan 29, 2017·Biochimica Et Biophysica Acta. Molecular Cell Research·Soumitra RoyIsrael Sekler
Apr 7, 2017·Journal of Applied Crystallography·Ai Woon YeeV Trevor Forsyth
Jun 3, 2017·The Journal of Biological Chemistry·Moshe GiladiDaniel Khananshvili
May 18, 2016·Nature Structural & Molecular Biology·Jun LiaoYouxing Jiang
May 23, 2020·Scientific Reports·Charline FagnenCatherine Vénien-Bryan
Jan 14, 2020·Cell Calcium·Ali H JalloulPaul P M Schnetkamp
Feb 13, 2021·Protein Science : a Publication of the Protein Society·Qi-Tong LinPeter B Stathopulos
Feb 28, 2020·Biophysical Journal·Richard T BradshawLucy R Forrest

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