Structure of human Na+/H+ exchanger NHE1 regulatory region in complex with calmodulin and Ca2+

J Biol Chem. 2011 Nov 25;286(47):40954-61. doi: 10.1074/jbc.M111.286906. Epub 2011 Sep 19.


The ubiquitous mammalian Na(+)/H(+) exchanger NHE1 has critical functions in regulating intracellular pH, salt concentration, and cellular volume. The regulatory C-terminal domain of NHE1 is linked to the ion-translocating N-terminal membrane domain and acts as a scaffold for signaling complexes. A major interaction partner is calmodulin (CaM), which binds to two neighboring regions of NHE1 in a strongly Ca(2+)-dependent manner. Upon CaM binding, NHE1 is activated by a shift in sensitivity toward alkaline intracellular pH. Here we report the 2.23 Å crystal structure of the NHE1 CaM binding region (NHE1(CaMBR)) in complex with CaM and Ca(2+). The C- and N-lobes of CaM bind the first and second helix of NHE1(CaMBR), respectively. Both the NHE1 helices and the Ca(2+)-bound CaM are elongated, as confirmed by small angle x-ray scattering analysis. Our x-ray structure sheds new light on the molecular mechanisms of the phosphorylation-dependent regulation of NHE1 and enables us to propose a model of how Ca(2+) regulates NHE1 activity.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Calcium / metabolism*
  • Calmodulin / chemistry
  • Calmodulin / metabolism*
  • Cation Transport Proteins / chemistry*
  • Cation Transport Proteins / metabolism*
  • Cell Line
  • Crystallography, X-Ray
  • Humans
  • Mice
  • Molecular Sequence Data
  • Phosphorylation
  • Protein Binding
  • Protein Processing, Post-Translational
  • Protein Structure, Tertiary
  • Rats
  • Scattering, Small Angle
  • Sodium-Hydrogen Exchanger 1
  • Sodium-Hydrogen Exchangers / chemistry*
  • Sodium-Hydrogen Exchangers / metabolism*


  • Calmodulin
  • Cation Transport Proteins
  • SLC9A1 protein, human
  • Sodium-Hydrogen Exchanger 1
  • Sodium-Hydrogen Exchangers
  • Calcium

Associated data

  • PDB/2YGG