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

Yusuke Sato, Azusa Yoshikawa, Atsushi Yamagata, Hisatoshi Mimura, Masami Yamashita, Kayoko Ookata, Osamu Nureki, Kazuhiro Iwai, Masayuki Komada and Shuya Fukai ()
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Yusuke Sato: Structural Biology Laboratory, Synchrotron Radiation Research Organization and Institute of Molecular and Cellular Biosciences, The University of Tokyo
Azusa Yoshikawa: Structural Biology Laboratory, Synchrotron Radiation Research Organization and Institute of Molecular and Cellular Biosciences, The University of Tokyo
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
Kayoko Ookata: and
Osamu Nureki: and
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

Nature, 2008, vol. 455, issue 7211, 358-362

Abstract: 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.

Date: 2008
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DOI: 10.1038/nature07254

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