Structural highlights
Function
[SL9A1_HUMAN] Involved in pH regulation to eliminate acids generated by active metabolism or to counter adverse environmental conditions. Major proton extruding system driven by the inward sodium ion chemical gradient. Plays an important role in signal transduction.[1] [2] [3]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The Na+/H+ exchanger isoform 1 is a ubiquitously expressed integral membrane protein. It resides on the plasma membrane of cells and regulates intracellular pH in mammals by extruding an intracellular H+ in exchange for one extracellular Na+. We characterized structural and functional aspects of the transmembrane (TM) segment VI (residues 227-249) by using cysteine scanning mutagenesis and high resolution NMR. Each residue of TM VI was mutated to cysteine in the background of the cysteineless NHE1 protein and the sensitivity to water soluble sulfhydryl reactive compounds MTSET ([2- (Trimethylammonium) Ethyl]Methanethiosulfonate) and MTSES ([2-Sulfonatoethyl]Methanethiosulfonate) was determined for those residues with significant activity remaining. Three residues were essentially inactive when mutated to Cys, Asp238, Pro239 and Glu247. Of the remaining residues, proteins with the mutations N227C, I233C, and L243C were strongly inhibited by MTSET while amino acids Phe230, Gly231, Aal236, Val237, Ala244, Val245 and Glu248 were partially inhibited by MTSET. MTSES did not affect activity of the mutant NHE1 proteins. The structure of a peptide representing TM VI was determined using high resolution NMR spectroscopy in dodecylphosphocholine (DPC) micelles. TM VI contains two helical regions oriented at an approximate right angle to each other (residues 229-236 and 239-250) surrounding a central unwound region. This structure bares a resemblance to TM IV of the E. coli protein NhaA. The results demonstrate that TM VI of NHE1 is a discontinuous pore lining helix with residues Asn227, Ile233 and Leu243 lining the translocation pore.
Structural and functional analysis of transmembrane VI of the NHE1 isoform of the Na+/H+ exchanger.,Tzeng J, Lee BL, Sykes BD, Fliegel L J Biol Chem. 2010 Sep 15. PMID:20843797[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Lin X, Barber DL. A calcineurin homologous protein inhibits GTPase-stimulated Na-H exchange. Proc Natl Acad Sci U S A. 1996 Oct 29;93(22):12631-6. PMID:8901634
- ↑ Pang T, Su X, Wakabayashi S, Shigekawa M. Calcineurin homologous protein as an essential cofactor for Na+/H+ exchangers. J Biol Chem. 2001 May 18;276(20):17367-72. Epub 2001 Feb 28. PMID:11350981 doi:http://dx.doi.org/10.1074/jbc.M100296200
- ↑ Pang T, Hisamitsu T, Mori H, Shigekawa M, Wakabayashi S. Role of calcineurin B homologous protein in pH regulation by the Na+/H+ exchanger 1: tightly bound Ca2+ ions as important structural elements. Biochemistry. 2004 Mar 30;43(12):3628-36. PMID:15035633 doi:http://dx.doi.org/10.1021/bi0360004
- ↑ Tzeng J, Lee BL, Sykes BD, Fliegel L. Structural and functional analysis of transmembrane VI of the NHE1 isoform of the Na+/H+ exchanger. J Biol Chem. 2010 Sep 15. PMID:20843797 doi:10.1074/jbc.M110.161471
