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Crystal structure of CHP2 complexed with NHE1‐cytosolic region and an implication for pH regulation
Author(s) -
Ammar Youssef Ben,
Takeda Soichi,
Hisamitsu Takashi,
Mori Hidezo,
Wakabayashi Shigeo
Publication year - 2006
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601145
Subject(s) - biology , intracellular ph , cytosol , biochemistry , mutagenesis , biophysics , cytoplasm , gene isoform , intracellular , microbiology and biotechnology , mutation , enzyme , gene
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 α‐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.