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(Received for publication, May 7, 1997, and in revised form, August 19, 1997)
From the Department of Clinical Pharmacology, Flinders University
School of Medicine, Bedford Park, South Australia 5042, Australia
UDP-glucuronosyltransferases (UGTs) comprise an
important enzyme system in mammals that is involved in detoxification
of a variety of small hydrophobic compounds of both endogenous and exogenous origin. Some evidence suggests that these enzymes may function as oligomers; however, little is known about the domain of
interaction or the mechanism of oligomerization. In this work, evidence
for a functional dimerization between UGTs is provided by studies on
mutated forms of UGT2B1. When two inactive forms of UGT2B1 were
co-expressed in cell culture, catalytic activity was restored,
indicating that UGT2B1 forms functional dimers. To delineate the
dimerization domain, inactive fusion proteins containing the amino- or
carboxyl-terminal domains of UGT2B1 were generated and expressed with
active UGT2B1. Expression of a fusion protein containing only the
amino-terminal half of UGT2B1 with active UGT2B1 caused a reduction in
UGT2B1 catalytic activity. This reduction in activity was not observed
when UGT2B1 was co-expressed with a fusion protein containing only the
carboxyl-terminal half of UGT2B1, strongly suggesting that the
amino-terminal domain is involved in dimerization. Truncation of the
immediate amino terminus of UGT2B1 abolished UGT2B1 activity and dimer
formation. Activity was also abolished by an L4R substitution in this
region of the mature protein, which is highly conserved in the UGT
family. These results indicate that UGTs can interact through their
amino-terminal domains to form catalytically active dimers. Possible
mechanisms resulting in the formation and stabilization of the UGT2B1
dimer are discussed.
Volume 272, Number 43,
Issue of October 24, 1997
pp. 26913-26917
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
UDP-Glucuronosyltransferase, the Role of the Amino Terminus
in Dimerization
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