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Structure and Catalytic Regulatory Function of Ubiquitin Specific Protease 11 N-Terminal and Ubiquitin-like Domains

Harper, Stephen; Gratton, Hayley E.; Cornaciu, Irina; Oberer, Monika; Scott, David J.; Emsley, Jonas; Dreveny, Ingrid

Structure and Catalytic Regulatory Function of Ubiquitin Specific Protease 11 N-Terminal and Ubiquitin-like Domains Thumbnail


Stephen Harper

Hayley E. Gratton

Irina Cornaciu

Monika Oberer

Associate Professor & Reader in Physical Biochemistry

Professor of Macromolecular Crystallography


The ubiquitin specific protease 11 (USP11) is implicated in DNA repair, viral RNA replication, and TGF? signaling. We report the first characterization of the USP11 domain architecture and its role in regulating the enzymatic activity. USP11 consists of an N-terminal "domain present in USPs" (DUSP) and "ubiquitin-like" (UBL) domain, together referred to as DU domains, and the catalytic domain harboring a second UBL domain. Crystal structures of the DU domains show a tandem arrangement with a shortened ?-hairpin at the two-domain interface and altered surface characteristics compared to the homologues USP4 and USP15. A conserved VEVY motif is a signature feature at the two-domain interface that shapes a potential protein interaction site. Small angle X-ray scattering and gel filtration experiments are consistent with the USP11DU domains and full-length USP11 being monomeric. Unexpectedly, we reveal, through kinetic assays of a series of deletion mutants, that the catalytic activity of USP11 is not regulated through intramolecular autoinhibition or activation by the N-terminal DU or UBL domains. Moreover, ubiquitin chain cleavage assays with all eight linkages reveal a preference for Lys(63)-, Lys(6)-, Lys(33)-, and Lys(11)-linked chains over Lys(27)-, Lys(29)-, and Lys(48)-linked and linear chains consistent with USP11's function in DNA repair pathways that is mediated by the protease domain. Our data support a model whereby USP11 domains outside the catalytic core domain serve as protein interaction or trafficking modules rather than a direct regulatory function of the proteolytic activity. This highlights the diversity of USPs in substrate recognition and regulation of ubiquitin deconjugation.

Journal Article Type Article
Acceptance Date Mar 31, 2014
Online Publication Date Apr 29, 2014
Publication Date May 13, 2014
Deposit Date Apr 20, 2017
Publicly Available Date Apr 20, 2017
Journal Biochemistry
Electronic ISSN 1520-4995
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 53
Issue 18
Pages 2966-2978
Public URL
Publisher URL


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