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J Biol Chem, Vol. 273, Issue 24, 14671-14674, June 12, 1998
From the Medical Research Council Group in Membrane Biology,
Department of Medicine and Department of Biochemistry, University of
Toronto, Toronto, Ontario M5S 1A8, Canada
Misprocessed mutants of human P-glycoprotein
accumulate as core-glycosylated intermediates in the endoplasmic
reticulum and are rapidly degraded. Trypsin digestion was used to test
for structural differences between mature and core-glycosylated forms
of P-glycoprotein. We found that the core-glycosylated wild-type and
mutant P-glycoproteins were both 100-fold more sensitive to trypsin
compared with the mature form of the wild-type enzyme. This result
suggested that the core-glycosylated forms of both wild-type and mutant
P-glycoproteins have similar unfolded structures, whereas the mature
enzyme is folded into a more compact structure. The core-glycosylated
mutant P-glycoproteins could be converted to the mature
trypsin-resistant form by synthesis in the presence of drug substrate.
Addition of proteasome inhibitor MG-132 to stabilize the
core-glycosylated intermediate resulted in the accumulation but not
maturation of the mutant protein. Further analysis showed that the
second transmembrane domain TMD2 also became more resistant to trypsin
digestion only after coexpression with TMD1 in the presence of
substrate. Taken together, these results suggest that simply
stabilizing the core-glycosylated intermediate is not sufficient to
promote maturation of the processing mutants and that drug substrates
induce maturation by promoting superfolding of the transmembrane
domains.
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