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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Model for the allosteric regulation of the Na+/Ca2+ exchanger NCX

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Abiko, Layara Akemi [1] ; Vitale, Phelipe M. [1] ; Favaro, Denize C. [1] ; Hauk, Pricila [1] ; Li, Da-Wei [2] ; Yuan, Jiaqi [3] ; Bruschweiler-Li, Lei [2] ; Salinas, Roberto K. [1] ; Bruschweiler, Rafael [3, 2, 4]
Total Authors: 9
[1] Univ Sao Paulo, Inst Chem, BR-05508000 Sao Paulo, SP - Brazil
[2] Ohio State Univ, Campus Chem Instrument Ctr, Columbus, OH 43210 - USA
[3] Ohio State Univ, Dept Chem & Biochem, Columbus, OH 43210 - USA
[4] Ohio State Univ, Dept Biol Chem & Pharmacol, Columbus, OH 43210 - USA
Total Affiliations: 4
Document type: Journal article
Web of Science Citations: 3

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)

FAPESP's process: 13/50355-0 - Structure and dynamics of proteins by high-resolution NMR spectroscopy, SAXS, and computation
Grantee:Roberto Kopke Salinas
Support type: Regular Research Grants
FAPESP's process: 13/17883-2 - Structure and dynamics of the Na+/Ca2+ exchanger from Drosophila melanogaster
Grantee:Roberto Kopke Salinas
Support type: Regular Research Grants
FAPESP's process: 11/07777-5 - Cyclic di-GMP signaling and the Type IV macromolecule secretion system in Xanthomonas citri
Grantee:Shaker Chuck Farah
Support type: Research Projects - Thematic Grants