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Structural basis for specific cleavage of Lys 63-linked polyubiquitin chains

Author

Listed:
  • Yusuke Sato

    (Structural Biology Laboratory, Synchrotron Radiation Research Organization and Institute of Molecular and Cellular Biosciences, The University of Tokyo
    and)

  • Azusa Yoshikawa

    (Structural Biology Laboratory, Synchrotron Radiation Research Organization and Institute of Molecular and Cellular Biosciences, The University of Tokyo
    and)

  • Atsushi Yamagata

    (Structural Biology Laboratory, Synchrotron Radiation Research Organization and Institute of Molecular and Cellular Biosciences, The University of Tokyo)

  • Hisatoshi Mimura

    (Structural Biology Laboratory, Synchrotron Radiation Research Organization and Institute of Molecular and Cellular Biosciences, The University of Tokyo)

  • Masami Yamashita

    (Structural Biology Laboratory, Synchrotron Radiation Research Organization and Institute of Molecular and Cellular Biosciences, The University of Tokyo
    Graduate School of Frontier Sciences, The University of Tokyo)

  • Kayoko Ookata

    (and)

  • Osamu Nureki

    (and
    Present address: Department of Basic Medical Sciences, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.)

  • Kazuhiro Iwai

    (Graduate School of Medicine, Osaka University)

  • Masayuki Komada

    (Biological Sciences, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama 226-8501, Japan)

  • Shuya Fukai

    (Structural Biology Laboratory, Synchrotron Radiation Research Organization and Institute of Molecular and Cellular Biosciences, The University of Tokyo
    Graduate School of Frontier Sciences, The University of Tokyo)

Abstract

Deubiquitinating enzymes (DUBs) remove ubiquitin from conjugated substrates to regulate various cellular processes. The Zn2+-dependent DUBs AMSH and AMSH-LP regulate receptor trafficking by specifically cleaving Lys 63-linked polyubiquitin chains from internalized receptors. Here we report the crystal structures of the human AMSH-LP DUB domain alone and in complex with a Lys 63-linked di-ubiquitin at 1.2 Å and 1.6 Å resolutions, respectively. The AMSH-LP DUB domain consists of a Zn2+-coordinating catalytic core and two characteristic insertions, Ins-1 and Ins-2. The distal ubiquitin interacts with Ins-1 and the core, whereas the proximal ubiquitin interacts with Ins-2 and the core. The core and Ins-1 form a catalytic groove that accommodates the Lys 63 side chain of the proximal ubiquitin and the isopeptide-linked carboxy-terminal tail of the distal ubiquitin. This is the first reported structure of a DUB in complex with an isopeptide-linked ubiquitin chain, which reveals the mechanism for Lys 63-linkage-specific deubiquitination by AMSH family members.

Suggested Citation

  • Yusuke Sato & Azusa Yoshikawa & Atsushi Yamagata & Hisatoshi Mimura & Masami Yamashita & Kayoko Ookata & Osamu Nureki & Kazuhiro Iwai & Masayuki Komada & Shuya Fukai, 2008. "Structural basis for specific cleavage of Lys 63-linked polyubiquitin chains," Nature, Nature, vol. 455(7211), pages 358-362, September.
    • Handle: RePEc:nat:nature:v:455:y:2008:i:7211:d:10.1038_nature07254
    DOI: 10.1038/nature07254
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    Cited by:

    1. Mai Morita & Miyu Takao & Honoka Tokuhisa & Ryotaro Chiba & Shota Tomomatsu & Yoshino Akizuki & Takuya Tomita & Akinori Endo & Yasushi Saeki & Yusuke Sato & Fumiaki Ohtake, 2025. "Combinatorial ubiquitin code degrades deubiquitylation-protected substrates," Nature Communications, Nature, vol. 16(1), pages 1-17, December.

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