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(Received for publication, September 4, 1996, and in revised form, October 29, 1996)
From the Medical Research Council Group in Membrane Biology,
Departments of Medicine and Biochemistry, University of Toronto,
Toronto, Ontario M5S 1A8, Canada
There is growing evidence that abnormal protein
folding or trafficking (protein kinesis) leads to diseases. We have
used P-glycoprotein as a model protein to develop strategies to
overcome defects in protein kinesis. Misprocessed mutants of the human
P-glycoprotein are retained in the endoplasmic reticulum as
core-glycosylated biosynthetic intermediates and rapidly degraded.
Synthesis of the mutant proteins in the presence of drug substrates or
modulators such as capsaicin, cyclosporin, vinblastine, or verapamil,
however, resulted in the appearance of a fully glycosylated and
functional protein at the cell surface. These effects were
dose-dependent and occurred within a few hours after the
addition of substrate. The ability to facilitate processing of the
misfolded mutants appeared to be independent of the cell lines used and
location of the mutation. P-glycoproteins with mutations in
transmembrane segments, extracellular or cytoplasmic loops, the
nucleotide-binding domains, or the linker region were processed to the
fully mature form in the presence of these substrates. These drug
substrates or modulators acted as specific chemical chaperones for
P-glycoprotein because they were ineffective on the
Volume 272, Number 2,
Issue of January 10, 1997
pp. 709-712
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
COMMUNICATION:
F508 mutant of
cystic fibrosis transmembrane conductance regulator. Therefore, one
possible strategy to prevent protein misfolding is to carry out
synthesis in the presence of specific substrates or modulators of the
protein.
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T. W. Loo and D. M. Clarke Drug-stimulated ATPase Activity of Human P-glycoprotein Requires Movement between Transmembrane Segments 6 and 12 J. Biol. Chem., August 22, 1997; 272(34): 20986 - 20989. [Abstract] [Full Text] [PDF]
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T. W. Loo and D. M. Clarke Determining the Dimensions of the Drug-binding Domain of Human P-glycoprotein Using Thiol Cross-linking Compounds as Molecular Rulers J. Biol. Chem., September 28, 2001; 276(40): 36877 - 36880. [Abstract] [Full Text] [PDF]
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T. W. Loo and D. M. Clarke Identification of Residues within the Drug-binding Domain of the Human Multidrug Resistance P-glycoprotein by Cysteine-scanning Mutagenesis and Reaction with Dibromobimane J. Biol. Chem., December 8, 2000; 275(50): 39272 - 39278. [Abstract] [Full Text] [PDF]
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