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Weber, A. ; Elliott, P.R.* ; Pinto-Fernandez, A.* ; Bonham, S.* ; Kessler, B.M.* ; Komander, D.* ; El Oualid, F.* ; Krappmann, D.

A linear diubiquitin-based probe for efficient and selective detection of the deubiquitinating enzyme OTULIN.

Cell Chem. Bio. 24, 1299-1313.e7 (2017)
Verlagsversion Forschungsdaten DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
The methionine 1 (M1)-specific deubiquitinase (DUB) OTULIN acts as a negative regulator of nuclear factor κB signaling and immune homeostasis. By replacing Gly76 in distal ubiquitin (Ub) by dehydroalanine we designed the diubiquitin (diUb) activity-based probe UbG76Dha-Ub (OTULIN activity-based probe [ABP]) that couples to the catalytic site of OTULIN and thereby captures OTULIN in its active conformation. The OTULIN ABP displays high selectivity for OTULIN and does not label other M1-cleaving DUBs, including CYLD. The only detectable cross-reactivities were the labeling of USP5 (Isopeptidase T) and an ATP-dependent assembly of polyOTULIN ABP chains via Ub-activating E1 enzymes. Both cross-reactivities were abolished by the removal of the C-terminal Gly in the ABP's proximal Ub, yielding the specific OTULIN probe UbG76Dha-UbΔG76 (OTULIN ABPΔG76). Pull-downs demonstrate that substrate-bound OTULIN associates with the linear ubiquitin chain assembly complex (LUBAC). Thus, we present a highly selective ABP for OTULIN that will facilitate studying the cellular function of this essential DUB.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Dub ; Hoip ; M1-linked ; Otulin ; Activity-based Probe ; Ubiquitin Chains ; Ubiquitin-activating E1; Nf-kappa-b; Ubiquitin-based Probes; Spata2 Links Cyld; Cell-death; Met1-linked Ubiquitination; Polyubiquitin Chains; Signaling Complexes; Molecular-basis; Specificity; Binding
Sprache englisch
Veröffentlichungsjahr 2017
HGF-Berichtsjahr 2017
ISSN (print) / ISBN 2451-9448
e-ISSN 2451-9456
Zeitschrift Cell Chemical Biology
Quellenangaben Band: 24, Heft: 10, Seiten: 1299-1313.e7 Artikelnummer: , Supplement: ,
Verlag Cell Press
Verlagsort Cambridge, Massachusetts
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Signaling and Translation (SAT)
POF Topic(s) 30203 - Molecular Targets and Therapies
Forschungsfeld(er) Enabling and Novel Technologies
PSP-Element(e) G-509800-002
DOI 10.1016/j.chembiol.2017.08.006
WOS ID WOS:000413260900014
Scopus ID 85029429305
PubMed ID 28919039
Erfassungsdatum 2017-09-26
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