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

Texto completo
Autor(es):
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]
Número total de Autores: 9
Afiliação do(s) autor(es):
[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
Número total de Afiliações: 4
Tipo de documento: Artigo Científico
Fonte: PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS; v. 84, n. 5, p. 580-590, MAY 2016.
Citações Web of Science: 3
Resumo

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)

Processo FAPESP: 13/50355-0 - Structure and dynamics of proteins by high-resolution NMR spectroscopy, SAXS, and computation
Beneficiário:Roberto Kopke Salinas
Linha de fomento: Auxílio à Pesquisa - Regular
Processo FAPESP: 13/17883-2 - Estrutura e dinâmica do trocador Na+/Ca2+ de Drosophila melanogaster
Beneficiário:Roberto Kopke Salinas
Linha de fomento: Auxílio à Pesquisa - Regular
Processo FAPESP: 11/07777-5 - Sinalização por c-di-GMP e o sistema de secreção de macromoléculas do tipo IV em Xanthomonas citri
Beneficiário:Shaker Chuck Farah
Linha de fomento: Auxílio à Pesquisa - Temático