Abiko, Layara Akemi
Vitale, Phelipe M.
Favaro, Denize C.
Salinas, Roberto K.
[3, 2, 4]
Total Authors: 9
 Univ Sao Paulo, Inst Chem, BR-05508000 Sao Paulo, SP - Brazil
 Ohio State Univ, Campus Chem Instrument Ctr, Columbus, OH 43210 - USA
 Ohio State Univ, Dept Chem & Biochem, Columbus, OH 43210 - USA
 Ohio State Univ, Dept Biol Chem & Pharmacol, Columbus, OH 43210 - USA
Total Affiliations: 4
PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS;
Web of Science Citations:
The Na+/Ca2+ exchanger provides a major Ca2+ extrusion pathway in excitable cells and plays a key role in the control of intracellular Ca2+ concentrations. In Canis familiaris, Na+/Ca2+ exchanger (NCX) activity is regulated by the binding of Ca2+ to two cytosolic Ca2+-binding domains, CBD1 and CBD2, such that Ca2+-binding activates the exchanger. Despite its physiological importance, little is known about the exchanger's global structure, and the mechanism of allosteric Ca2+-regulation remains unclear. It was found previously that for NCX in the absence of Ca2+ the two domains CBD1 and CBD2 of the cytosolic loop are flexibly linked, while after Ca2+-binding they adopt a rigid arrangement that is slightly tilted. A realistic model for the mechanism of the exchanger's allosteric regulation should not only address this property, but also it should explain the distinctive behavior of Drosophila melanogaster's sodium/calcium exchanger, CALX, for which Ca2+-binding to CBD1 inhibits Ca2+ exchange. Here, NMR spin relaxation and residual dipolar couplings were used to show that Ca2+ modulates CBD1 and CBD2 interdomain flexibility of CALX in an analogous way as for NCX. A mechanistic model for the allosteric Ca2+ regulation of the Na+/Ca2+ exchanger is proposed. In this model, the intracellular loop acts as an entropic spring whose strength is modulated by Ca2+-binding to CBD1 controlling ion transport across the plasma membrane. (C) 2016 Wiley Periodicals, Inc. (AU)