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Crystal structure of CHP2 complexed with NHE1-cytosolic region and an implication for pH regulation.

Ammar YB, Takeda S, Hisamitsu T, Mori H, Wakabayashi S
EMBO J 25 2315-25 (2006)
Cited: 46 times
EuropePMC logo PMID: 16710297

Abstract

The plasma membrane Na+/H+ exchangers (NHE) require calcineurin B homologous protein (CHP) as an obligatory binding partner for ion transport. Here, we report the first crystal structure of CHP (CHP2 isoform) in complex with its binding domain in NHE1. We show that the cytoplasmic alpha-helix of NHE1 is inserted into the hydrophobic cleft formed by N- and C-lobes of CHP2 and that the size and shape of this crevice together with hydrogen bond formation at multiple positions assure a high degree of specificity for interaction with NHE members. Structure-based mutagenesis revealed the importance of hydrophobic interactions between CHP/NHE1 for the function of NHE1. Furthermore, the crystal structure shows the existence of a protruding CHP-unique region, and deletion of this region in CHP2 inhibited the NHE1 activity by inducing the acidic shift of intracellular pH dependence, while preserving interaction with NHE1. These findings suggest that CHP serves as an obligatory subunit that is required both for supporting the basic activity and regulating the pH-sensing of NHE1 via interactions between distinct parts of these proteins.

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  2. Crystal structure of CHP2 complexed with NHE1-cytosolic region and an implication for pH regulation. Ammar YB, Takeda S, Hisamitsu T, Mori H, Wakabayashi S. EMBO J 25 2315-2325 (2006)
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  8. The epithelial brush border Na+/H+ exchanger NHE3 associates with the actin cytoskeleton by binding to ezrin directly and via PDZ domain-containing Na+/H+ exchanger regulatory factor (NHERF) proteins. Cha B, Donowitz M. Clin Exp Pharmacol Physiol 35 863-871 (2008)
  9. Structural and functional insights into the cardiac Na⁺/H⁺ exchanger. Lee BL, Sykes BD, Fliegel L. J Mol Cell Cardiol 61 60-67 (2013)
  10. Inside out: targeting NHE1 as an intracellular and extracellular regulator of cancer progression. Provost JJ, Wallert MA. Chem Biol Drug Des 81 85-101 (2013)
  11. Emerging roles of the single EF-hand Ca2+ sensor tescalcin in the regulation of gene expression, cell growth and differentiation. Kolobynina KG, Solovyova VV, Levay K, Rizvanov AA, Slepak VZ. J Cell Sci 129 3533-3540 (2016)
  12. Trafficking Ion Transporters to the Apical Membrane of Polarized Intestinal Enterocytes. Engevik AC, Goldenring JR. Cold Spring Harb Perspect Biol 10 a027979 (2018)
  13. How Does Our Knowledge on the Na+/H+ Exchanger NHE1 Obtained by Biochemical and Molecular Analyses Keep up With Its Recent Structure Determination? Poet M, Doyen D, Van Obberghen E, Jarretou G, Bouret Y, Counillon L. Front Physiol 13 907587 (2022)
  14. Host Susceptibility to Nontuberculous Mycobacterial Pulmonary Disease. Namkoong H, Holland SM. Clin Chest Med 44 723-730 (2023)

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