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J Biol Chem, Vol. 275, Issue 5, 3655-3660, February 4, 2000
From the Cystic Fibrosis Research Center, Department of Cell
Biology and Physiology, University of Pittsburgh School of Medicine,
Pittsburgh, Pennsylvania 15261
The cystic fibrosis transmembrane conductance
regulator (CFTR) undergoes rapid and efficient endocytosis. Since
functionally active CFTR is found in purified clathrin-coated vesicles
isolated from both cultured epithelial cells and intact epithelial
tissues, we investigated the molecular mechanisms whereby CFTR could
enter such endocytic clathrin-coated vesicles. In vivo
cross-linking and in vitro pull-down assays show that
full-length CFTR binds to the endocytic adaptor complex AP-2. Fusion
proteins containing the carboxyl terminus of CFTR (amino acids
1404-1480) were also able to bind AP-2 but did not bind the
Golgi-specific adaptor complex AP-1. Substitution of an alanine residue
for tyrosine at position 1424 significantly reduced the ability of AP-2
to bind the carboxyl terminus of CFTR; however, mutation to a
phenylalanine residue (an amino acid found at position 1424 in dogfish
CFTR) did not perturb AP-2 binding. Secondary structure predictions suggest that Tyr1424 is present in a The amino acid sequence of CFTR can be accessed through NCBI
Protein Database under NCBI accession numbers P13569 (human), AAC14012
(monkey), Q0055 (sheep), AAC48608 (rabbit), AAC60023 (frog), M60493
(mouse), AF000271 (killifish), P35071 (cow), and P26362
(dogfish).
The Carboxyl Terminus of the Cystic Fibrosis Transmembrane
Conductance Regulator Binds to AP-2 Clathrin Adaptors*
-turn conformation,
a conformation disrupted by alanine but not phenylalanine. Together,
these data suggest that the carboxyl terminus of CFTR contains a
tyrosine-based internalization signal that interacts with the endocytic
adaptor complex AP-2 to facilitate efficient entry of CFTR into
clathrin-coated vesicles.
*
This work was funded by grants from the Cystic Fibrosis
Foundation and the National Institutes of Health (DK47850).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 Cell Biology
and Physiology, University of Pittsburgh School of Medicine, 3500 Terrace St., Pittsburgh, PA 15261. Tel.: 412-648-2845; Fax: 412-648-2844; E-mail: nabrad@pitt.edu.
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