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J. Biol. Chem., Vol. 276, Issue 45, 41870-41878, November 9, 2001
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From the 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
(
A Dominant Negative Mutant of the KCC1 K-Cl Cotransporter
BOTH N- AND C-TERMINAL CYTOPLASMIC DOMAINS ARE REQUIRED FOR K-Cl
COTRANSPORT ACTIVITY*
§,¶,,,,¶,
, and¶**§§
Molecular Medicine and ** Renal
Units, Beth Israel Deaconess Medical Center, Boston, Massachusetts
02215, the § Department of Laboratory Medicine, The
Children's Hospital, Boston, Massachusetts 02115, and the Departments
of ¶ Medicine, Cell Biology, and
Pathology, Harvard Medical School,
Boston, Massachusetts 02115
N117) 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
N117 was co-immunoprecipitated with wild type KCC1
polypeptide, and its co-expression did not reduce wild type KCC1 at the
oocyte surface. N117 also exhibited dominant negative
inhibition of human KCC1 and KCC3 and, with lower potency, mouse
KCC4 and rat KCC2.
*
This work was supported by Boston Sickle Cell Center
Grant HL15157 (to C. B. and S. L. A.), Fellowship F32-HL09853
(to B. E. S.), Grant RO1-DK50422 (to C. B.), and Harvard Digestive
Diseases Center Grant DK35854 (to S. L. A.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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