UDP-glucuronosyltransferase, the role of the amino terminus in dimerization

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    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 coexpressed in cell culture, catalytic activity was restored, indicating that UGT2B1 forms functional directs. 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.

    Original languageEnglish
    Pages (from-to)26913-26917
    Number of pages5
    JournalJournal of Biological Chemistry
    Issue number43
    Publication statusPublished - 1 Nov 1997


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