Proteopedia

2kbv

Structural and functional analysis of TM XI of the NHE1 isoform of thE NA+/H+ exchangerStructural and functional analysis of TM XI of the NHE1 isoform of thE NA+/H+ exchanger

Structural highlights

2kbv is a 1 chain structure with sequence from Homo sapiens. Full experimental information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Solution NMR, 40 models
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

Publication Abstract from PubMed

The Na(+)/H(+) exchanger isoform 1 is a ubiquitously expressed integral membrane protein that regulates intracellular pH in mammals by extruding an intracellular H(+) in exchange for one extracellular Na(+). We characterized structural and functional aspects of the critical transmembrane (TM) segment XI (residues 449-470) by using cysteine scanning mutagenesis and high resolution NMR. Each residue of TM XI was mutated to cysteine in the background of the cysteine-less 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 at least moderate activity remaining. Of the residues tested, only proteins with mutations L457C, I461C, and L465C were inhibited by MTSET. The activity of the L465C mutant was almost completely eliminated, whereas that of the L457C and I461C mutants was partially affected. The structure of a peptide representing TM XI (residues Lys(447)-Lys(472)) was determined using high resolution NMR spectroscopy in dodecylphosphocholine micelles. The structure consisted of helical regions between Asp(447)-Tyr(454) and Phe(460)-Lys(471) at the N and C termini of the peptide, respectively, connected by a region with poorly defined, irregular structure consisting of residues Gly(455)-Gly(459). TM XI of NHE1 had a structural similarity to TM XI of the Escherichia coli Na(+)/H(+) exchanger NhaA. The results suggest that TM XI is a discontinuous helix, with residue Leu(465) contributing to the pore.

Structural and functional analysis of transmembrane XI of the NHE1 isoform of the Na+/H+ exchanger.,Lee BL, Li X, Liu Y, Sykes BD, Fliegel L J Biol Chem. 2009 Apr 24;284(17):11546-56. Epub 2009 Jan 28. PMID:19176522[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ Lee BL, Li X, Liu Y, Sykes BD, Fliegel L. Structural and functional analysis of transmembrane XI of the NHE1 isoform of the Na+/H+ exchanger. J Biol Chem. 2009 Apr 24;284(17):11546-56. Epub 2009 Jan 28. PMID:19176522 doi:10.1074/jbc.M809201200
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