TY - JOUR
T1 - Mechanism of extracellular ion exchange and binding-site occlusion in a sodium/calcium exchanger
AU - Liao, Jun
AU - Marinelli, Fabrizio
AU - Lee, Changkeun
AU - Huang, Yihe
AU - Faraldo-Gómez, José D.
AU - Jiang, Youxing
N1 - Publisher Copyright:
© 2016 Nature America, Inc. All rights reserved.
PY - 2016/6/7
Y1 - 2016/6/7
N2 - Na + /Ca 2+ exchangers use the Na + electrochemical gradient across the plasma membrane to extrude intracellular Ca 2+ and play a central role in Ca 2+ 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 +, Ca 2+ or Sr 2+ 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 + /Ca 2+ -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 + /Ca 2+ antiport.
AB - Na + /Ca 2+ exchangers use the Na + electrochemical gradient across the plasma membrane to extrude intracellular Ca 2+ and play a central role in Ca 2+ 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 +, Ca 2+ or Sr 2+ 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 + /Ca 2+ -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 + /Ca 2+ antiport.
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U2 - 10.1038/nsmb.3230
DO - 10.1038/nsmb.3230
M3 - Article
C2 - 27183196
AN - SCOPUS:84968658964
SN - 1545-9993
VL - 23
SP - 590
EP - 599
JO - Nature Structural and Molecular Biology
JF - Nature Structural and Molecular Biology
IS - 6
ER -