Structural basis for specific cleavage of Lys 63-linked polyubiquitin chains.
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.
Mesh Terms:
Animals, Catalysis, Conserved Sequence, Crystallography, X-Ray, Endopeptidases, Endosomal Sorting Complexes Required for Transport, Humans, Kinetics, Lysine, Mice, Models, Molecular, Polyubiquitin, Protein Structure, Tertiary, Saccharomyces cerevisiae Proteins, Structure-Activity Relationship, Substrate Specificity, Ubiquitin Thiolesterase
Animals, Catalysis, Conserved Sequence, Crystallography, X-Ray, Endopeptidases, Endosomal Sorting Complexes Required for Transport, Humans, Kinetics, Lysine, Mice, Models, Molecular, Polyubiquitin, Protein Structure, Tertiary, Saccharomyces cerevisiae Proteins, Structure-Activity Relationship, Substrate Specificity, Ubiquitin Thiolesterase
Nature
Date: Sep. 18, 2008
PubMed ID: 18758443
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