Faculty Collaboration Database

Mechanism of extracellular ion exchange and binding-site occlusion in a sodium/calcium exchanger. Nat Struct Mol Biol 2016 Jun;23(6):590-599

Date

05/18/2016

Pubmed ID

27183196

Pubmed Central ID

PMC4918766

DOI

10.1038/nsmb.3230

Scopus ID

2-s2.0-84968658964 (requires institutional sign-in at Scopus site)   81 Citations

Abstract

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.

Author List

Liao J, Marinelli F, Lee C, Huang Y, Faraldo-Gómez JD, Jiang Y

Author

Fabrizio Marinelli PhD Associate Professor in the Biophysics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Archaeal Proteins
Binding Sites
Calcium
Crystallography, X-Ray
Ion Exchange
Methanocaldococcus
Molecular Docking Simulation
Molecular Dynamics Simulation
Protein Conformation
Sodium
Sodium-Calcium Exchanger
Strontium