A novel three-TMH Na +/H + antiporter and the functional role of its oligomerization

J Mol Biol. 2021 Jan 22;433(2):166730. doi: 10.1016/j.jmb.2020.166730. Epub 2020 Dec 3.


Na+/H+antiportersare a category of ubiquitous transmembrane proteins with various important physiological roles in almost all living organisms ranging from bacteria to humans. However, the knowledge of novel Na+/H+antiporters remains to be broadened, and the functional roles ofoligomerization in theseantiportershave not yet been thoroughly understood. Here, we reported functional analysis of an unknown transmembrane protein composed of 103 amino acid residues. This protein was found to function as a Na+(Li+, K+)/H+ antiporter. To the best of our knowledge, this antiporter is the minimal one of known Na+/H+antiporters and thus designated as NhaM to represent the minimal Na+/H+antiporter. NhaM and its homologs have not yet been classified into any protein family. Based on phylogenetic analysis and protein alignment, we propose NhaM and its homologs to constitute a novel transporter family designated as NhaM family. More importantly, we found that NhaM is assembled with parallel protomers into a homo-oligomer and oligomerization is vital for the function of this antiporter. This implies that NhaM may adopt and require an oligomer structure for its normal function to create a similar X-shaped structure to that of the NhaA fold. Taken together, current findings not only present the proposal of a novel transporter family but also positively contribute to the functional roles of oligomerization in Na+/H+antiporters.

Keywords: NhaA fold; NhaM family; Oligomerization; Three-TMH Na(+)/H(+) antiporter; Transmembrane protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Cloning, Molecular
  • Gene Expression
  • Membrane Proteins / chemistry
  • Membrane Proteins / metabolism
  • Multigene Family
  • Open Reading Frames
  • Phylogeny
  • Protein Conformation
  • Protein Multimerization*
  • Sequence Analysis, DNA
  • Sequence Homology, Amino Acid
  • Sodium-Hydrogen Exchangers / chemistry*
  • Sodium-Hydrogen Exchangers / genetics
  • Sodium-Hydrogen Exchangers / metabolism*
  • Spectrum Analysis
  • Structure-Activity Relationship


  • Bacterial Proteins
  • Membrane Proteins
  • Sodium-Hydrogen Exchangers