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NEDD8 recruits E2‐ubiquitin to SCF E3 ligase

Takayuki Kawakami, Tomoki Chiba, Toshiaki Suzuki, Kazuhiro Iwai, Koji Yamanaka, Nagahiro Minato, Hiroshi Suzuki, Naoki Shimbara, Yuko Hidaka, Fumio Osaka, Masao Omata, Keiji Tanaka

Author Affiliations

  1. Takayuki Kawakami1,2,
  2. Tomoki Chiba2,
  3. Toshiaki Suzuki2,
  4. Kazuhiro Iwai3,
  5. Koji Yamanaka3,
  6. Nagahiro Minato3,
  7. Hiroshi Suzuki4,
  8. Naoki Shimbara5,
  9. Yuko Hidaka6,
  10. Fumio Osaka7,
  11. Masao Omata1 and
  12. Keiji Tanaka*,2
  1. 1 Department of Gastroenterology, Faculty of Medicine, University of Tokyo, 7‐3‐1 Hongo, Bunkyo‐ku, Tokyo, 113‐8655, Japan
  2. 2 The Tokyo Metropolitan Institute of Medical Science, and CREST, Japan Science and Technology Corporation (JST), 3‐18‐22 Honkomagome, Bunkyo‐ku, Tokyo, 113‐8613, Japan
  3. 3 Department of Molecular and System Biology, Graduate School of Biostudies, Kyoto University, Kyoto, 606‐8501, Japan
  4. 4 Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd, 21 Miyukigaoka, Tsukuba‐shi, Ibaraki, 305‐8585, Japan
  5. 5 Department of Research, UP Science, Inc. 1, Taya‐cho, Sakae‐ku, Yokohama, 244‐8588, Japan
  6. 6 Sumitomo Electric Industry, 1, Taya‐cho, Sakae‐ku, Yokohama, 244‐8588, Japan
  7. 7 Kato Cytoprotein Network Project, ERATO, Japan Science and Technology Corporation (JST), c/o Sagami Chemical Research Center, Nishi‐ohnuma 4–4‐1, Sagamihara, Kanagawa, 229‐0012, Japan
  1. *Corresponding author. E-mail: tanakak{at}rinshoken.or.jp
  1. T.Kawakami and T.Chiba contributed equally to this work

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Abstract

NEDD8/Rub1 is a ubiquitin (Ub)‐like post‐translational modifier that is covalently linked to cullin (Cul)‐family proteins in a manner analogous to ubiquitylation. NEDD8 is known to enhance the ubiquitylating activity of the SCF complex (composed of Skp1, Cul‐1, ROC1 and F‐box protein), but the mechanistic role is largely unknown. Using an in vitro reconstituted system, we report here that NEDD8 modification of Cul‐1 enhances recruitment of Ub‐conjugating enzyme Ubc4 (E2) to the SCF complex (E3). This recruitment requires thioester linkage of Ub to Ubc4. Our findings indicate that the NEDD8‐modifying system accelerates the formation of the E2–E3 complex, which stimulates protein polyubiquitylation.

  • Received October 23, 2000.
  • Revision received March 23, 2001.
  • Accepted June 5, 2001.
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