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J Biol Chem. 2011 Dec 30;286(52):45186-96. doi: 10.1074/jbc.M111.310094. Epub 2011 Nov 9.

Protein-linked ubiquitin chain structure restricts activity of deubiquitinating enzymes.

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1
Department of Physiology, University of California at San Francisco, San Francisco, California 94158, USA.

Abstract

The attachment of lysine 48 (Lys(48))-linked polyubiquitin chains to proteins is a universal signal for degradation by the proteasome. Here, we report that long Lys(48)-linked chains are resistant to many deubiquitinating enzymes (DUBs). Representative enzymes from this group, Ubp15 from yeast and its human ortholog USP7, rapidly remove mono- and diubiquitin from substrates but are slow to remove longer Lys(48)-linked chains. This resistance is lost if the structure of Lys(48)-linked chains is disrupted by mutation of ubiquitin or if chains are linked through Lys(63). In contrast to Ubp15 and USP7, Ubp12 readily cleaves the ends of long chains, regardless of chain structure. We propose that the resistance to many DUBs of long, substrate-attached Lys(48)-linked chains helps ensure that proteins are maintained free from ubiquitin until a threshold of ubiquitin ligase activity enables degradation.

PMID:
22072716
PMCID:
PMC3247991
DOI:
10.1074/jbc.M111.310094
[Indexed for MEDLINE]
Free PMC Article
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