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J. Biol. Chem., Vol. 275, Issue 35, 27069-27074, September 1, 2000
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From the Polarization of cystic fibrosis
transmembrane conductance regulator (CFTR), a cAMP-activated
chloride channel to the apical plasma membrane in epithelial cells is
critical for vectorial chloride transport. Previously, we reported that
the C terminus of CFTR constitutes a PDZ-interacting domain that is
required for CFTR polarization to the apical plasma membrane and
interaction with the PDZ domain-containing protein EBP50 (NHERF).
PDZ-interacting domains are typically composed of the C-terminal three
to five amino acids, which in CFTR are QDTRL. Our goal was to identify the key amino acid(s) in the PDZ-interacting domain of CFTR with regard
to its apical polarization, interaction with EBP50, and ability to
mediate transepithelial chloride secretion. Point substitution of the
C-terminal leucine (Leu at position 0) with alanine abrogated apical polarization of CFTR, interaction between CFTR and EBP50, efficient expression of CFTR in the apical membrane, and chloride secretion. Point substitution of the threonine (Thr at position
The PDZ-interacting Domain of Cystic Fibrosis Transmembrane
Conductance Regulator Is Required for Functional Expression in
the Apical Plasma Membrane*
§,,,,,,,
,,,
Dartmouth Medical School, Department of
Physiology, Hanover, New Hampshire 03755, ¶ The Johns Hopkins
University, School of Medicine, Departments of Physiology and
Neuroscience, Baltimore, Maryland 21205, The Johns Hopkins
University, Center for Medical Genetics, Johns Hopkins Hospital/CMSC
1004, Baltimore, Maryland 21287, and ** The Johns Hopkins University,
School of Medicine, Department of Physiology,
Baltimore, Maryland 21205
2)
with alanine or valine had no effect on the apical polarization of
CFTR, but reduced interaction between CFTR and EBP50, efficient expression of CFTR in the apical membrane as well as chloride secretion. By contrast, individual point substitution of the other C-terminal amino acids (Gln at position 4, Asp at position 3 and
Arg at position 1) with alanine had no effect on measured parameters.
We conclude that the PDZ-interacting domain, in particular the leucine
(position 0) and threonine (position 2) residues, are required for
the efficient, polarized expression of CFTR in the apical plasma
membrane, interaction of CFTR with EBP50, and for the ability of CFTR
to mediate chloride secretion. Mutations that delete the C terminus of
CFTR may cause cystic fibrosis because CFTR is not polarized, complexed
with EBP50, or efficiently expressed in the apical membrane of
epithelial cells.
*
This work was supported by The Cystic Fibrosis Foundation
Grant STANTO98PO and National Institutes of Health Grants HL 47122, DK
48977, and DK 32753 (to W. B. G.), RO1-NS33334 (to M. L.), and DK-45881 and DK-51067 (to B. A. S.).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.
To whom correspondence should be addressed: Dept. of
Physiology, Dartmouth Medical School, Hanover, NH 03755. Tel.:
603-650-1775; Fax: 603-650-1130; E-mail:
bruce.a.stanton@dartmouth.edu.
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