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J Biol Chem, Vol. 274, Issue 32, 22813-22820, August 6, 1999
From the Department of Biochemistry and Molecular Biology,
University of Florida College of Medicine,
Gainesville, Florida 32610
The mature insulin receptor is a cell surface
heterotetrameric glycoprotein composed of two
Effect of Alternative Glycosylation on Insulin Receptor
Processing
- and two
-subunits. In 3T3-L1 adipocytes as in other cell types, the receptor
is synthesized as a single polypeptide consisting of uncleaved - and
-subunits, migrating as a 190-kDa glycoprotein. To examine the
importance of N-linked glycosylation on insulin receptor
processing, we have used glucose deprivation as a tool to alter protein
glycosylation. Western blot analysis shows that glucose deprivation led
to a time-dependent accumulation of an alternative
proreceptor of 170 kDa in a subcellular fraction consistent with
endoplasmic reticulum localization. Co-precipitation assays provide
evidence that the alternative proreceptor bound GRP78, an endoplasmic
reticulum molecular chaperone. N-Glycosidase F treatment
shows that the alternative proreceptor contained N-linked
oligosaccharides. Yet, endoglycosidase H insensitivity indicates an
aberrant oligosaccharide structure. Using pulse-chase methodology, we
show that the synthetic rate was similar between the normal and
alternative proreceptor. However, the normal proreceptor was processed
into - and -subunits (t1/2 = 1.3 ± 0.6 h), while the alternative proreceptor was degraded
(t1/2 = 5.1 ± 0.6 h). Upon refeeding
cells that were initially deprived of glucose, the alternative
proreceptor was processed to a higher molecular weight form and gained
sensitivity to endoglycosidase H. This "intermediate" form of the
proreceptor was also degraded, although a small fraction escaped
degradation, resulting in cleavage to the - and -subunits. These
data provide evidence for the first time that glucose deprivation leads
to the accumulation of an alternative proreceptor, which can be
post-translationally glycosylated with the readdition of glucose
inducing both accelerated degradation and maturation.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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