RGD Reference Report - Calcineurin B homologous protein 3 promotes the biosynthetic maturation, cell surface stability, and optimal transport of the Na+/H+ exchanger NHE1 isoform.

General

Calcineurin B homologous protein 3 promotes the biosynthetic maturation, cell surface stability, and optimal transport of the Na+/H+ exchanger NHE1 isoform.
Authors:	Zaun, HC Shrier, A Orlowski, J
Citation:	Zaun HC, etal., J Biol Chem. 2008 May 2;283(18):12456-67. doi: 10.1074/jbc.M800267200. Epub 2008 Mar 5.
RGD ID:	8554433
Pubmed:	PMID:18321853 (View Abstract at PubMed)
PMCID:	PMC2431010 (View Article at PubMed Central)
DOI:	DOI:10.1074/jbc.M800267200 (Journal Full-text)
Calcineurin B homologous protein (CHP) 1 and 2 are Ca(2+)-binding proteins that modulate several cellular processes, including cytoplasmic pH by positively regulating plasma membrane-type Na(+)/H(+) exchangers (NHEs). Recently another CHP-related protein, termed tescalcin or CHP3, was also shown to interact with the ubiquitous NHE1 isoform, but seemingly suppressed its activity. However, the precise physical and functional nature of this association was not examined in detail. In this study, biochemical and cellular studies were undertaken to further delineate this relationship. Glutathione S-transferase-NHE1 fusion protein pulldown assays revealed that full-length CHP3 binds directly to the proximal juxtamembrane C-terminal region (amino acids 505-571) of rat NHE1 in the same region that binds CHP1 and CHP2. The interaction was further validated by coimmunoprecipitation and coimmunolocalization experiments using full-length CHP3 and wild-type NHE1 in transfected Chinese hamster ovary AP-1 cells. Simultaneous mutation of four hydrophobic residues within this region ((530)FLDHLL(535)) to either Ala, Gln, or Arg (FL-A, FL-Q, or FL-R) abrogated this interaction both in vitro and in intact cells. The NHE1 mutants were sorted properly to the cell surface but showed markedly reduced (FL-A) or minimal (FL-R and FL-Q) activity. Interestingly, and contrary to an earlier finding, ectopic coexpression of CHP3 up-regulated the cell surface activity of wild-type NHE1. This stimulation was not observed with the CHP3 binding-defective mutants. Mechanistically, overexpression of CHP3 did not alter the H(+) sensitivity of wild-type NHE1 but rather promoted its biosynthetic maturation and half-life at the cell surface, thereby increasing the steady-state abundance of functional NHE1 protein.

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Biological Process

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Term	Qualifier	Evidence	With	Reference	Notes	Source	Original Reference(s)
response to acidic pH	involved_in	IDA		8554433	PMID:18321853	UniProt

Cellular Component

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Term	Qualifier	Evidence	With	Reference	Notes	Source	Original Reference(s)
plasma membrane	located_in	IDA		8554433	PMID:18321853	UniProt

Molecular Function

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Term	Qualifier	Evidence	With	Reference	Notes	Source	Original Reference(s)
protein binding	enables	IPI	UniProtKB:Q96BS2	8554433	PMID:18321853	UniProt
sodium:proton antiporter activity	enables	IDA		8554433	PMID:18321853	UniProt

Objects Annotated

Genes (Rattus norvegicus)

Slc9a1 (solute carrier family 9 member A1)

Additional Information

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Calcineurin B homologous protein 3 promotes the biosynthetic maturation, cell surface stability, and optimal transport of the Na+/H+ exchanger NHE1 isoform.