RGD Reference Report - A dominant negative mutant of the KCC1 K-Cl cotransporter: both N- and C-terminal cytoplasmic domains are required for K-Cl cotransport activity.

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A dominant negative mutant of the KCC1 K-Cl cotransporter: both N- and C-terminal cytoplasmic domains are required for K-Cl cotransport activity.
Authors:	Casula, S Shmukler, B E Wilhelm, S Stuart-Tilley, A K Su, W Chernova, M N Brugnara, C Alper, S L
Citation:	Casula S, etal., J Biol Chem. 2001 Nov 9;276(45):41870-8. doi: 10.1074/jbc.M107155200. Epub 2001 Sep 10.
RGD ID:	153298944
Pubmed:	PMID:11551954 (View Abstract at PubMed)
DOI:	DOI:10.1074/jbc.M107155200 (Journal Full-text)
K-Cl cotransport regulates cell volume and chloride equilibrium potential. Inhibition of erythroid K-Cl cotransport has emerged as an important adjunct strategy for the treatment of sickle cell anemia. However, structure-function relationships among the polypeptide products of the four K-Cl cotransporter (KCC) genes are little understood. We have investigated the importance of the N- and C-terminal cytoplasmic domains of mouse KCC1 to its K-Cl cotransport function expressed in Xenopus oocytes. Truncation of as few as eight C-terminal amino acids (aa) abolished function despite continued polypeptide accumulation and surface expression. These C-terminal loss-of-function mutants lacked a dominant negative phenotype. Truncation of the N-terminal 46 aa diminished function. Removal of 89 or 117 aa (Delta(N)117) abolished function despite continued polypeptide accumulation and surface expression and exhibited dominant negative phenotypes that required the presence of the C-terminal cytoplasmic domain. The dominant negative loss-of-function mutant Delta(N)117 was co-immunoprecipitated with wild type KCC1 polypeptide, and its co-expression did not reduce wild type KCC1 at the oocyte surface. Delta(N)117 also exhibited dominant negative inhibition of human KCC1 and KCC3 and, with lower potency, mouse KCC4 and rat KCC2.

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
Slc12a5	Rat	potassium ion transmembrane transport	involved_in	IDA		PMID:11551954	UniProt

Molecular Function

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Object Symbol	Species	Term	Qualifier	Evidence	With	Notes	Source	Original Reference(s)
Slc12a5	Rat	potassium:chloride symporter activity	enables	IDA		PMID:11551954	UniProt

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Genes (Rattus norvegicus)

Slc12a5 (solute carrier family 12 member 5)

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A dominant negative mutant of the KCC1 K-Cl cotransporter: both N- and C-terminal cytoplasmic domains are required for K-Cl cotransport activity.