OTU deubiquitinases reveal mechanisms of linkage specificity and enable ubiquitin chain restriction analysis

Sixteen ovarian tumor (OTU) family deubiquitinases (DUBs) exist in humans, and most members regulate cell-signaling cascades. Several OTU DUBs were reported to be ubiquitin (Ub) chain linkage specific, but comprehensive analyses are missing, and the underlying mechanisms of linkage specificity are u...

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Vydané v:	Cell Ročník 154; číslo 1; s. 169
Hlavní autori:	Mevissen, Tycho E T, Hospenthal, Manuela K, Geurink, Paul P, Elliott, Paul R, Akutsu, Masato, Arnaudo, Nadia, Ekkebus, Reggy, Kulathu, Yogesh, Wauer, Tobias, El Oualid, Farid, Freund, Stefan M V, Ovaa, Huib, Komander, David
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 03.07.2013
Predmet:	Catalysis Catalytic Domain Crystallography, X-Ray Endopeptidases - chemistry Endopeptidases - genetics Endopeptidases - metabolism Female Humans Models, Molecular Ovarian Neoplasms - enzymology Ovarian Neoplasms - metabolism Protein Structure, Tertiary Thiolester Hydrolases - chemistry Thiolester Hydrolases - metabolism Ubiquitination Ubiquitins - metabolism
ISSN:	1097-4172, 1097-4172
On-line prístup:	Zistit podrobnosti o prístupe
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Abstract	Sixteen ovarian tumor (OTU) family deubiquitinases (DUBs) exist in humans, and most members regulate cell-signaling cascades. Several OTU DUBs were reported to be ubiquitin (Ub) chain linkage specific, but comprehensive analyses are missing, and the underlying mechanisms of linkage specificity are unclear. Using Ub chains of all eight linkage types, we reveal that most human OTU enzymes are linkage specific, preferring one, two, or a defined subset of linkage types, including unstudied atypical Ub chains. Biochemical analysis and five crystal structures of OTU DUBs with or without Ub substrates reveal four mechanisms of linkage specificity. Additional Ub-binding domains, the ubiquitinated sequence in the substrate, and defined S1' and S2 Ub-binding sites on the OTU domain enable OTU DUBs to distinguish linkage types. We introduce Ub chain restriction analysis, in which OTU DUBs are used as restriction enzymes to reveal linkage type and the relative abundance of Ub chains on substrates.
AbstractList	Sixteen ovarian tumor (OTU) family deubiquitinases (DUBs) exist in humans, and most members regulate cell-signaling cascades. Several OTU DUBs were reported to be ubiquitin (Ub) chain linkage specific, but comprehensive analyses are missing, and the underlying mechanisms of linkage specificity are unclear. Using Ub chains of all eight linkage types, we reveal that most human OTU enzymes are linkage specific, preferring one, two, or a defined subset of linkage types, including unstudied atypical Ub chains. Biochemical analysis and five crystal structures of OTU DUBs with or without Ub substrates reveal four mechanisms of linkage specificity. Additional Ub-binding domains, the ubiquitinated sequence in the substrate, and defined S1' and S2 Ub-binding sites on the OTU domain enable OTU DUBs to distinguish linkage types. We introduce Ub chain restriction analysis, in which OTU DUBs are used as restriction enzymes to reveal linkage type and the relative abundance of Ub chains on substrates.Sixteen ovarian tumor (OTU) family deubiquitinases (DUBs) exist in humans, and most members regulate cell-signaling cascades. Several OTU DUBs were reported to be ubiquitin (Ub) chain linkage specific, but comprehensive analyses are missing, and the underlying mechanisms of linkage specificity are unclear. Using Ub chains of all eight linkage types, we reveal that most human OTU enzymes are linkage specific, preferring one, two, or a defined subset of linkage types, including unstudied atypical Ub chains. Biochemical analysis and five crystal structures of OTU DUBs with or without Ub substrates reveal four mechanisms of linkage specificity. Additional Ub-binding domains, the ubiquitinated sequence in the substrate, and defined S1' and S2 Ub-binding sites on the OTU domain enable OTU DUBs to distinguish linkage types. We introduce Ub chain restriction analysis, in which OTU DUBs are used as restriction enzymes to reveal linkage type and the relative abundance of Ub chains on substrates. Sixteen ovarian tumor (OTU) family deubiquitinases (DUBs) exist in humans, and most members regulate cell-signaling cascades. Several OTU DUBs were reported to be ubiquitin (Ub) chain linkage specific, but comprehensive analyses are missing, and the underlying mechanisms of linkage specificity are unclear. Using Ub chains of all eight linkage types, we reveal that most human OTU enzymes are linkage specific, preferring one, two, or a defined subset of linkage types, including unstudied atypical Ub chains. Biochemical analysis and five crystal structures of OTU DUBs with or without Ub substrates reveal four mechanisms of linkage specificity. Additional Ub-binding domains, the ubiquitinated sequence in the substrate, and defined S1' and S2 Ub-binding sites on the OTU domain enable OTU DUBs to distinguish linkage types. We introduce Ub chain restriction analysis, in which OTU DUBs are used as restriction enzymes to reveal linkage type and the relative abundance of Ub chains on substrates.
Author	Arnaudo, Nadia Ekkebus, Reggy El Oualid, Farid Mevissen, Tycho E T Komander, David Freund, Stefan M V Akutsu, Masato Geurink, Paul P Wauer, Tobias Elliott, Paul R Hospenthal, Manuela K Kulathu, Yogesh Ovaa, Huib
Author_xml	– sequence: 1 givenname: Tycho E T surname: Mevissen fullname: Mevissen, Tycho E T organization: Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK – sequence: 2 givenname: Manuela K surname: Hospenthal fullname: Hospenthal, Manuela K – sequence: 3 givenname: Paul P surname: Geurink fullname: Geurink, Paul P – sequence: 4 givenname: Paul R surname: Elliott fullname: Elliott, Paul R – sequence: 5 givenname: Masato surname: Akutsu fullname: Akutsu, Masato – sequence: 6 givenname: Nadia surname: Arnaudo fullname: Arnaudo, Nadia – sequence: 7 givenname: Reggy surname: Ekkebus fullname: Ekkebus, Reggy – sequence: 8 givenname: Yogesh surname: Kulathu fullname: Kulathu, Yogesh – sequence: 9 givenname: Tobias surname: Wauer fullname: Wauer, Tobias – sequence: 10 givenname: Farid surname: El Oualid fullname: El Oualid, Farid – sequence: 11 givenname: Stefan M V surname: Freund fullname: Freund, Stefan M V – sequence: 12 givenname: Huib surname: Ovaa fullname: Ovaa, Huib – sequence: 13 givenname: David surname: Komander fullname: Komander, David
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/23827681$$D View this record in MEDLINE/PubMed
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Snippet	Sixteen ovarian tumor (OTU) family deubiquitinases (DUBs) exist in humans, and most members regulate cell-signaling cascades. Several OTU DUBs were reported to...
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SubjectTerms	Catalysis Catalytic Domain Crystallography, X-Ray Endopeptidases - chemistry Endopeptidases - genetics Endopeptidases - metabolism Female Humans Models, Molecular Ovarian Neoplasms - enzymology Ovarian Neoplasms - metabolism Protein Structure, Tertiary Thiolester Hydrolases - chemistry Thiolester Hydrolases - metabolism Ubiquitination Ubiquitins - metabolism
Title	OTU deubiquitinases reveal mechanisms of linkage specificity and enable ubiquitin chain restriction analysis
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