Article

  • The EMBO Journal (2005) 24, 3747 - 3756
  • doi:10.1038/sj.emboj.7600832

Published online: 6 October 2005

Structure and mechanisms of the proteasome-associated deubiquitinating enzyme USP14

Min Hu1,a, Pingwei Li1,a, Ling Song2, Philip D Jeffrey1, Tatiana A Chernova3, Keith D Wilkinson3, Robert E Cohen2 and Yigong Shi1

  1. Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, NJ, USA
  2. Department of Biochemistry, University of Iowa, Iowa City, IA, USA
  3. Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA

Correspondence to:

Yigong Shi, Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Princeton, NJ 08544, USA. Tel.: +1 609 258 6071; Fax: +1 609 258 6730; E-mail: yshi@molbio.princeton.edu

aThese authors contributed equally to this work

Received 11 July 2005; Accepted 12 September 2005


The ubiquitin-specific processing protease (UBP) family of deubiquitinating enzymes plays an essential role in numerous cellular processes. Mammalian USP14 (Ubp6 in yeast) is unique among known UBP enzymes in that it is activated catalytically upon specific association with the 26S proteasome. Here, we report the crystal structures of the 45-kDa catalytic domain of USP14 in isolation and in a complex with ubiquitin aldehyde, which reveal distinct structural features. In the absence of ubiquitin binding, the catalytic cleft leading to the active site of USP14 is blocked by two surface loops. Binding by ubiquitin induces a significant conformational change that translocates the two surface loops thereby allowing access of the ubiquitin C-terminus to the active site. These structural observations, in conjunction with biochemical characterization, identify important regulatory mechanisms for USP14.

  • Keywords:

    • crystal structure,
    • deubiquitination,
    • deubiquitinating enzymes,
    • mechanism,
    • UBP
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