title: Structural basis for specific cleavage of Lys 63-linked polyubiquitin chains.
abstract: Deubiquitinating enzymes (DUBs) remove ubiquitin from conjugated substrates to regulate various cellular processes. The Zn(2+)-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 A and 1.6 A resolutions, respectively. The AMSH-LP DUB domain consists of a Zn(2+)-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.
authors.affiliation: Structural Biology Laboratory, Life Science Division, Synchrotron Radiation Research Organization and Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sato
authors.forename: Azusa
authors.initials: A
authors.lastname: Yoshikawa
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yamagata
authors.forename: Hisatoshi
authors.initials: H
authors.lastname: Mimura
authors.forename: Masami
authors.initials: M
authors.lastname: Yamashita
authors.forename: Kayoko
authors.initials: K
authors.lastname: Ookata
authors.forename: Osamu
authors.initials: O
authors.lastname: Nureki
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Iwai
authors.forename: Masayuki
authors.initials: M
authors.lastname: Komada
authors.forename: Shuya
authors.initials: S
authors.lastname: Fukai