NhaA family

Na+/H+ antiporter 1
Identifiers
Symbol Na_H_antiport_1
Pfam PF06965
InterPro IPR004670
TCDB 2.A.36
OPM superfamily 346
OPM protein 1zcd

Na+/H+ antiporter A (NhaA) family (TC# 2.A.33) contains a number of bacterial sodium-proton antiporter (SPAP) proteins. These are integral membrane proteins that catalyse the exchange of H+ for Na+ in a manner that is highly pH dependent. Homologues have been sequenced from a number of bacteria and archaea. Prokaryotes possess multiple paralogues. A representative list of the proteins that belong to the NhaA family can be found in the Transporter Classification Database.

Structure

Proteins of the NhaA family are of 300-700 amino acyl residues in length. NhaA of E. coli is a homeodimer, each subunit consisting of a bundle of 12 tilted transmembrane α-helices (TMSs).[1][2][3][4][5]

Molecular dynamics simulations of NhaA enabled proposal of an atomically detailed model of antiporter function.[6] Three conserved aspartate residues are key to this 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.[6][7][8]

Function

Na+-H+ antiporters are integral membrane proteins that exchange Na+ for H+ across the cytoplasmic membrane and many intracellular membranes. They are essential for Na+, pH, and volume homeostasis, which are processes crucial for cell viability.[8][9] The E. coli protein probably functions in the regulation of the internal pH when the external pH is alkaline, and the protein effectively functions as a pH sensor.[7] It also uses the H+ gradient to expel Na+ from the cell. Its activity is highly pH dependent.[3][10]

The NhaA crystal structure has provided insight into the pH-regulated mechanism of antiporter action and revealed transmembrane segments, which are interrupted by extended mid-membrane chains that have since been found with variations in other ion-transport proteins. This novel structural fold creates a delicately balance electrostatic environment in the middle of the membrane, which might be essential for ion binding and translocation.[3]

The generalized transport reaction catalyzed by NhaA is:[6][11]

Na+ (in) + 2H+ (out) ⇌ Na+ (out) + 2H+ (in).

Crystal Structures

PDB: 1ZCD​, 3FI1​, 4ATV​, 4AU5​

See also

Further reading

References

  1. ↑ Williams, K. A.; Geldmacher-Kaufer, U.; Padan, E.; Schuldiner, S.; Kühlbrandt, W. (1999-07-01). "Projection structure of NhaA, a secondary transporter from Escherichia coli, at 4.0 A resolution". The EMBO journal 18 (13): 3558–3563. doi:10.1093/emboj/18.13.3558. ISSN 0261-4189. PMC 1171434. PMID 10393172.
  2. ↑ Williams, K. A. (2000-01-06). "Three-dimensional structure of the ion-coupled transport protein NhaA". Nature 403 (6765): 112–115. doi:10.1038/47534. ISSN 0028-0836. PMID 10638764.
  3. 1 2 3 Hunte, Carola; Screpanti, Emanuela; Venturi, Miro; Rimon, Abraham; Padan, Etana; Michel, Hartmut (2005-06-30). "Structure of a Na+/H+ antiporter and insights into mechanism of action and regulation by pH". Nature 435 (7046): 1197–1202. doi:10.1038/nature03692. ISSN 1476-4687. PMID 15988517.
  4. ↑ Olkhova, Elena; Hunte, Carola; Screpanti, Emanuela; Padan, Etana; Michel, Hartmut (2006-02-21). "Multiconformation continuum electrostatics analysis of the NhaA Na+/H+ antiporter of Escherichia coli with functional implications". Proceedings of the National Academy of Sciences of the United States of America 103 (8): 2629–2634. doi:10.1073/pnas.0510914103. ISSN 0027-8424. PMC 1413810. PMID 16477015.
  5. ↑ Screpanti, Emanuela; Padan, Etana; Rimon, Abraham; Michel, Hartmut; Hunte, Carola (2006-09-15). "Crucial steps in the structure determination of the Na+/H+ antiporter NhaA in its native conformation". Journal of Molecular Biology 362 (2): 192–202. doi:10.1016/j.jmb.2006.07.019. ISSN 0022-2836. PMID 16919297.
  6. 1 2 3 Arkin, Isaiah T.; Xu, Huafeng; Jensen, Morten Ø; Arbely, Eyal; Bennett, Estelle R.; Bowers, Kevin J.; Chow, Edmond; Dror, Ron O.; Eastwood, Michael P. (2007-08-10). "Mechanism of Na+/H+ antiporting". Science (New York, N.Y.) 317 (5839): 799–803. doi:10.1126/science.1142824. ISSN 1095-9203. PMID 17690293.
  7. 1 2 Gerchman, Y.; Olami, Y.; Rimon, A.; Taglicht, D.; Schuldiner, S.; Padan, E. (1993-02-15). "Histidine-226 is part of the pH sensor of NhaA, a Na+/H+ antiporter in Escherichia coli". Proceedings of the National Academy of Sciences of the United States of America 90 (4): 1212–1216. ISSN 0027-8424. PMC 45842. PMID 8381959.
  8. 1 2 Padan, Etana (2008-09-01). "The enlightening encounter between structure and function in the NhaA Na+-H+ antiporter". Trends in Biochemical Sciences 33 (9): 435–443. doi:10.1016/j.tibs.2008.06.007. ISSN 0968-0004. PMID 18707888.
  9. ↑ Radchenko, Martha V.; Waditee, Rungaroon; Oshimi, Sawako; Fukuhara, Masahiro; Takabe, Teruhiro; Nakamura, Tatsunosuke (2006-01-01). "Cloning, functional expression and primary characterization of Vibrio parahaemolyticus K+/H+ antiporter genes in Escherichia coli". Molecular Microbiology 59 (2): 651–663. doi:10.1111/j.1365-2958.2005.04966.x. ISSN 0950-382X. PMID 16390457.
  10. ↑ Diab, Mohammad; Rimon, Abraham; Tzubery, Tzvi; Padan, Etana (2011-10-28). "Helix VIII of NhaA Na(+)/H(+) antiporter participates in the periplasmic cation passage and pH regulation of the antiporter". Journal of Molecular Biology 413 (3): 604–614. doi:10.1016/j.jmb.2011.08.046. ISSN 1089-8638. PMID 21907722.
  11. ↑ "2.A.33 The NhaA Na+:H+Antiporter (NhaA) Family". Transporter Classification Database. Retrieved 2016-03-14.

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