Structural highlights
Function
[CHP2_HUMAN] Functions as an integral cofactor in cell pH regulation by controlling plasma membrane-type Na(+)/H(+) exchange activity. Binds to and activates SLC9A1/NHE1 in a serum-independent manner, thus increasing pH and protecting cells from serum deprivation-induced death. Also plays a role in the regulation of cell proliferation and tumor growth by increasing the phosphatase activity of PPP3CA in a calcium-dependent manner. Activator of the calcineurin/NFAT signaling pathway. Involved in the cytoplasmic translocation of the transcription factor NFATC3 to the nucleus.[1] [2] [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.[3] [4] [5]
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 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.
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. 2006 Jun 7;25(11):2315-25. Epub 2006 May 18. PMID:16710297[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Pang T, Wakabayashi S, Shigekawa M. Expression of calcineurin B homologous protein 2 protects serum deprivation-induced cell death by serum-independent activation of Na+/H+ exchanger. J Biol Chem. 2002 Nov 15;277(46):43771-7. Epub 2002 Sep 10. PMID:12226101 doi:http://dx.doi.org/10.1074/jbc.M208313200
- ↑ Li GD, Zhang X, Li R, Wang YD, Wang YL, Han KJ, Qian XP, Yang CG, Liu P, Wei Q, Chen WF, Zhang J, Zhang Y. CHP2 activates the calcineurin/nuclear factor of activated T cells signaling pathway and enhances the oncogenic potential of HEK293 cells. J Biol Chem. 2008 Nov 21;283(47):32660-8. doi: 10.1074/jbc.M806684200. Epub 2008 , Sep 24. PMID:18815128 doi:http://dx.doi.org/10.1074/jbc.M806684200
- ↑ 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
- ↑ Ammar YB, Takeda S, Hisamitsu T, Mori H, Wakabayashi S. Crystal structure of CHP2 complexed with NHE1-cytosolic region and an implication for pH regulation. EMBO J. 2006 Jun 7;25(11):2315-25. Epub 2006 May 18. PMID:16710297
