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Structural mechanisms of extracellular ion exchange and induced binding-site occlusion in the sodium-calcium exchangerNCX_Mj soaked with 150 mM Na+ and nominal Ca2+Structural mechanisms of extracellular ion exchange and induced binding-site occlusion in the sodium-calcium exchangerNCX_Mj soaked with 150 mM Na+ and nominal Ca2+
Structural highlights
FunctionPublication Abstract from PubMedNa+/Ca2+ exchangers use the Na+ electrochemical gradient across the plasma membrane to extrude intracellular Ca2+ and play a central role in Ca2+ homeostasis. Here, we elucidate their mechanisms of extracellular ion recognition and exchange through a structural analysis of the exchanger from Methanococcus jannaschii (NCX_Mj) bound to Na+, Ca2+ or Sr2+ in various occupancies and in an apo state. This analysis defines the binding mode and relative affinity of these ions, establishes the structural basis for the anticipated 3:1 Na+/Ca2+-exchange stoichiometry and reveals the conformational changes at the onset of the alternating-access transport mechanism. An independent analysis of the dynamics and conformational free-energy landscape of NCX_Mj in different ion-occupancy states, based on enhanced-sampling molecular dynamics simulations, demonstrates that the crystal structures reflect mechanistically relevant, interconverting conformations. These calculations also reveal the mechanism by which the outward-to-inward transition is controlled by the ion occupancy, thereby explaining the emergence of strictly coupled Na+/Ca2+ antiport. Mechanism of extracellular ion exchange and binding-site occlusion in a sodium/calcium exchanger.,Liao J, Marinelli F, Lee C, Huang Y, Faraldo-Gomez JD, Jiang Y Nat Struct Mol Biol. 2016 May 16. doi: 10.1038/nsmb.3230. PMID:27183196[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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