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The carboxyl-terminal di-lysine motif is essential for catalytic activity of UDP-glucuronosyltransferase 1A9 |
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| Institution: | 1. Division of Pharmaceutical Cell Biology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan;2. Laboratory of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan;3. Clinical Pharmacology, College of Medicine and Public Health, Flinders Medical Centre and Flinders University, Adelaide, Australia;4. Laboratory of Molecular Life Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan;1. Graduate School of Life Science, Hokkaido University, Kita-10-jo, Nishi-8-chome, Kita-ku, Sapporo 060-0810, Japan;2. School of Pharmaceutical Sciences and Pharmacy, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan;3. Department of Pharmacy, Hokkaido University Hospital, Kita-14-jo, Nishi-5-chome, Kita-ku, Sapporo 060-8648, Japan;4. Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan;5. Global Station for Biosurfaces and Drug Discovery, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo, Japan;1. Department of Biomedical Chemistry, School of Science and Technology, Kwansei Gakuin University, Gakuen 2-1, Sanda, 669-1337, Japan;2. Program of Biomedical Science, Graduate School of Integrated Sciences for Life, Hiroshima University, Hiroshima, 739-8521, Japan;1. Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Japan;2. Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima-city, Japan;3. Shin Nippon Biomedical Laboratories, Ltd, Kainan, Wakayama, Japan;1. Membrane Transport and Biopharmaceutics, Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan;2. Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan;3. WPI Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, Kanazawa, Japan;1. Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan;2. Division of Cancer Genome and Pharmacotherapy, Department of Clinical Pharmacy, Showa University School of Pharmacy, Tokyo, Japan |
| Abstract: | UDP-Glucuronosyltransferase (UGT) is a type I membrane protein localized to the endoplasmic reticulum (ER). UGT has a di-lysine motif (KKXX/KXKXX) in its cytoplasmic domain, which is defined as an ER retention signal. However, our previous study has revealed that UGT2B7, one of the major UGT isoform in human, localizes to the ER in a manner that is independent of this motif. In this study, we focused on another UGT isoform, UGT1A9, and investigated the role of the di-lysine motif in its ER localization, glucuronidation activity, and homo-oligomer formation. Immunofluorescence microscopy indicated that the cytoplasmic domain of UGT1A9 functioned as an ER retention signal in a chimeric protein with CD4, but UGT1A9 itself could localize to the ER in a di-lysine motif-independent manner. In addition, UGT1A9 formed homo-oligomers in the absence of the motif. However, deletion of the di-lysine motif or substitution of lysines in the motif for alanines, severely impaired glucuronidation activity of UGT1A9. This is the first study that re-defines the cytoplasmic di-lysine motif of UGT as an essential peptide for retaining glucuronidation capacity. |
| Keywords: | UDP-Glucuronosyltransferase Endoplasmic reticulum Di-lysine motif Secretary pathway Cellular localization Glucuronidation 4-Methylumbelliferone Oligomerization CD4"} {"#name":"keyword" "$":{"id":"kwrd0055"} "$$":[{"#name":"text" "_":"T-cell surface glycoprotein CD4 CNX"} {"#name":"keyword" "$":{"id":"kwrd0065"} "$$":[{"#name":"text" "_":"calnexin CT"} {"#name":"keyword" "$":{"id":"kwrd0075"} "$$":[{"#name":"text" "_":"cytoplasmic domain DAPI"} {"#name":"keyword" "$":{"id":"kwrd0085"} "$$":[{"#name":"text" "_":"4′ 6-diamidino-2-phenylindole DM"} {"#name":"keyword" "$":{"id":"kwrd0095"} "$$":[{"#name":"text" "_":"di-lysine motif ER"} {"#name":"keyword" "$":{"id":"kwrd0105"} "$$":[{"#name":"text" "_":"endoplasmic reticulum 4-MU"} {"#name":"keyword" "$":{"id":"kwrd0115"} "$$":[{"#name":"text" "_":"4-methylumbelliferone 4-MUG"} {"#name":"keyword" "$":{"id":"kwrd0125"} "$$":[{"#name":"text" "_":"4-methylumbelliferone-glucuronide TM"} {"#name":"keyword" "$":{"id":"kwrd0135"} "$$":[{"#name":"text" "_":"transmembrane UGT"} {"#name":"keyword" "$":{"id":"kwrd0145"} "$$":[{"#name":"text" "_":"UDP-glucuronosyltransferase WT"} {"#name":"keyword" "$":{"id":"kwrd0155"} "$$":[{"#name":"text" "_":"wild-type |
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