Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 10 August 2007:
Vol. 317. no. 5839, pp. 799 - 803
DOI: 10.1126/science.1142824
Prev | Table of Contents | Next

Reports

Mechanism of Na+/H+ Antiporting

Isaiah T. Arkin,1* Huafeng Xu,1 Morten Ø. Jensen,1 Eyal Arbely,2 Estelle R. Bennett,2 Kevin J. Bowers,1 Edmond Chow,1 Ron O. Dror,1 Michael P. Eastwood,1 Ravenna Flitman-Tene,2 Brent A. Gregersen,1 John L. Klepeis,1 István Kolossváry,1 Yibing Shan,1 David E. Shaw1,3{dagger}

Na+/H+ antiporters are central to cellular salt and pH homeostasis. The structure of Escherichia coli NhaA was recently determined, but its mechanisms of transport and pH regulation remain elusive. We performed molecular dynamics simulations of NhaA that, with existing experimental data, enabled us to propose an atomically detailed model of antiporter function. Three conserved aspartates are key to our proposed mechanism: Asp164 (D164) is the Na+-binding site, D163 controls the alternating accessibility of this binding site to the cytoplasm or periplasm, and D133 is crucial for pH regulation. Consistent with experimental stoichiometry, two protons are required to transport a single Na+ ion: D163 protonates to reveal the Na+-binding site to the periplasm, and subsequent protonation of D164 releases Na+. Additional mutagenesis experiments further validated the model.

1 D. E. Shaw Research, New York, NY 10036, USA.
2 The Hebrew University of Jerusalem, Department of Biological Chemistry, Jerusalem 91904, Israel.
3 Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10032, USA.

* On sabbatical leave from The Hebrew University of Jerusalem, Department of Biological Chemistry, Jerusalem, 91904, Israel.

{dagger} To whom correspondence should be addressed. E-mail: david{at}deshaw.com

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Features of Subunit NuoM (ND4) in Escherichia coli NDH-1: TOPOLOGY AND IMPLICATION OF CONSERVED GLU144 FOR COUPLING SITE 1.
J. Torres-Bacete, P. K. Sinha, N. Castro-Guerrero, A. Matsuno-Yagi, and T. Yagi (2009)
J. Biol. Chem. 284, 33062-33069
   Abstract »    Full Text »    PDF »
Substrate Binding Tunes Conformational Flexibility and Kinetic Stability of an Amino Acid Antiporter.
C. A. Bippes, A. Zeltina, F. Casagrande, M. Ratera, M. Palacin, D. J. Muller, and D. Fotiadis (2009)
J. Biol. Chem. 284, 18651-18663
   Abstract »    Full Text »    PDF »
NhaA crystal structure: functional-structural insights.
E. Padan, L. Kozachkov, K. Herz, and A. Rimon (2009)
J. Exp. Biol. 212, 1593-1603
   Abstract »    Full Text »    PDF »
Structural and Functional Analysis of Transmembrane XI of the NHE1 Isoform of the Na+/H+ Exchanger.
B. L. Lee, X. Li, Y. Liu, B. D. Sykes, and L. Fliegel (2009)
J. Biol. Chem. 284, 11546-11556
   Abstract »    Full Text »    PDF »
Two Snapshots of Electron Transport across the Membrane: INSIGHTS INTO THE STRUCTURE AND FUNCTION OF DsbD.
S.-H. Cho and J. Beckwith (2009)
J. Biol. Chem. 284, 11416-11424
   Abstract »    Full Text »    PDF »
G-Protein-Coupled Receptor Kinase Interacting Protein-1 Is Required for Pulmonary Vascular Development.
J. Pang, R. Hoefen, G. S. Pryhuber, J. Wang, G. Yin, R. J. White, X. Xu, M. R. O'Dell, A. Mohan, H. Michaloski, et al. (2009)
Circulation 119, 1524-1532
   Abstract »    Full Text »    PDF »
A provisional transport mechanism for a chloride channel-type Cl-/H+ exchanger.
C. Miller and W. Nguitragool (2009)
Phil Trans R Soc B 364, 175-180
   Abstract »    Full Text »    PDF »
Steady-state Function of the Ubiquitous Mammalian Na/H Exchanger (NHE1) in Relation to Dimer Coupling Models with 2Na/2H Stoichiometry.
D. Fuster, O. W. Moe, and D. W. Hilgemann (2008)
J. Gen. Physiol. 132, 465-480
   Abstract »    Full Text »    PDF »
Ion binding and selectivity of the rotor ring of the Na+-transporting V-ATPase.
T. Murata, I. Yamato, Y. Kakinuma, M. Shirouzu, J. E. Walker, S. Yokoyama, and S. Iwata (2008)
PNAS 105, 8607-8612
   Abstract »    Full Text »    PDF »
Complete Genome Sequence of Nitrobacter hamburgensis X14 and Comparative Genomic Analysis of Species within the Genus Nitrobacter.
S. R. Starkenburg, F. W. Larimer, L. Y. Stein, M. G. Klotz, P. S. G. Chain, L. A. Sayavedra-Soto, A. T. Poret-Peterson, M. E. Gentry, D. J. Arp, B. Ward, et al. (2008)
Appl. Envir. Microbiol. 74, 2852-2863
   Abstract »    Full Text »    PDF »
Cationic pathway of pH regulation in larvae of Anopheles gambiae.
B. A. Okech, D. Y. Boudko, P. J. Linser, and W. R. Harvey (2008)
J. Exp. Biol. 211, 957-968
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)