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PDBsum entry 2vfj
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* Residue conservation analysis
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Enzyme class 1:
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E.C.2.3.2.-
- ?????
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Enzyme class 2:
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E.C.3.4.19.12
- ubiquitinyl hydrolase 1.
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Reaction:
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Thiol-dependent hydrolysis of ester, thiolester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal).
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Note, where more than one E.C. class is given (as above), each may
correspond to a different protein domain or, in the case of polyprotein
precursors, to a different mature protein.
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Biochem J
409:77-85
(2008)
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PubMed id:
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Structure of the A20 OTU domain and mechanistic insights into deubiquitination.
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D.Komander,
D.Barford.
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ABSTRACT
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The NF-kappaB (nuclear factor kappaB) regulator A20 antagonises IKK [IkappaB
(inhibitor of kappaB) kinase] activation by modulating Lys63-linked
polyubiquitination of cytokine-receptor-associated factors including TRAF2/6
(tumour-necrosis-factor-receptor-associated factor 2/6) and RIP1
(receptor-interacting protein 1). In the present paper we describe the crystal
structure of the N-terminal OTU (ovarian tumour) deubiquitinase domain of A20,
which differs from other deubiquitinases but shares the minimal catalytic core
with otubain-2. Analysis of conserved surface regions allows prediction of
ubiquitin-binding sites for the proximal and distal ubiquitin molecules.
Structural and biochemical analysis suggests a novel architecture of the
catalytic triad, which might be present in a subset of OTU domains including
Cezanne and TRABID (TRAF-binding domain). Biochemical analysis shows a
preference of the isolated A20 OTU domain for Lys48-linked tetraubiquitin in
vitro suggesting that additional specificity factors might be required for the
physiological function of A20 in cells.
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Literature references that cite this PDB file's key reference
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PubMed id
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Reference
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A.Ma,
and
B.A.Malynn
(2012).
A20: linking a complex regulator of ubiquitylation to immunity and human disease.
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Nat Rev Immunol,
12,
774-785.
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J.D.Licchesi,
J.Mieszczanek,
T.E.Mevissen,
T.J.Rutherford,
M.Akutsu,
S.Virdee,
F.El Oualid,
J.W.Chin,
H.Ovaa,
M.Bienz,
and
D.Komander
(2012).
An ankyrin-repeat ubiquitin-binding domain determines TRABID's specificity for atypical ubiquitin chains.
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Nat Struct Mol Biol,
19,
62-71.
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PDB code:
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O.W.Huang,
X.Ma,
J.Yin,
J.Flinders,
T.Maurer,
N.Kayagaki,
Q.Phung,
I.Bosanac,
D.Arnott,
V.M.Dixit,
S.G.Hymowitz,
M.A.Starovasnik,
and
A.G.Cochran
(2012).
Phosphorylation-dependent activity of the deubiquitinase DUBA.
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Nat Struct Mol Biol,
19,
171-175.
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PDB codes:
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C.Zheng,
Q.Yin,
and
H.Wu
(2011).
Structural studies of NF-κB signaling.
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Cell Res,
21,
183-195.
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E.W.Harhaj,
and
V.M.Dixit
(2011).
Deubiquitinases in the regulation of NF-κB signaling.
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Cell Res,
21,
22-39.
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T.W.James,
N.Frias-Staheli,
J.P.Bacik,
J.M.Levingston Macleod,
M.Khajehpour,
A.García-Sastre,
and
B.L.Mark
(2011).
Structural basis for the removal of ubiquitin and interferon-stimulated gene 15 by a viral ovarian tumor domain-containing protease.
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Proc Natl Acad Sci U S A,
108,
2222-2227.
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PDB codes:
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A.Bremm,
S.M.Freund,
and
D.Komander
(2010).
Lys11-linked ubiquitin chains adopt compact conformations and are preferentially hydrolyzed by the deubiquitinase Cezanne.
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Nat Struct Mol Biol,
17,
939-947.
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PDB code:
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I.Bosanac,
I.E.Wertz,
B.Pan,
C.Yu,
S.Kusam,
C.Lam,
L.Phu,
Q.Phung,
B.Maurer,
D.Arnott,
D.S.Kirkpatrick,
V.M.Dixit,
and
S.G.Hymowitz
(2010).
Ubiquitin binding to A20 ZnF4 is required for modulation of NF-κB signaling.
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Mol Cell,
40,
548-557.
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PDB codes:
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S.G.Hymowitz,
and
I.E.Wertz
(2010).
A20: from ubiquitin editing to tumour suppression.
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Nat Rev Cancer,
10,
332-341.
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A.Clarke,
and
T.J.Vyse
(2009).
Genetics of rheumatic disease.
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Arthritis Res Ther,
11,
248.
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B.Coornaert,
I.Carpentier,
and
R.Beyaert
(2009).
A20: central gatekeeper in inflammation and immunity.
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J Biol Chem,
284,
8217-8221.
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B.Skaug,
X.Jiang,
and
Z.J.Chen
(2009).
The role of ubiquitin in NF-kappaB regulatory pathways.
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Annu Rev Biochem,
78,
769-796.
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D.Komander,
F.Reyes-Turcu,
J.D.Licchesi,
P.Odenwaelder,
K.D.Wilkinson,
and
D.Barford
(2009).
Molecular discrimination of structurally equivalent Lys 63-linked and linear polyubiquitin chains.
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EMBO Rep,
10,
466-473.
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PDB codes:
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D.Komander,
M.J.Clague,
and
S.Urbé
(2009).
Breaking the chains: structure and function of the deubiquitinases.
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Nat Rev Mol Cell Biol,
10,
550-563.
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F.E.Reyes-Turcu,
and
K.D.Wilkinson
(2009).
Polyubiquitin binding and disassembly by deubiquitinating enzymes.
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Chem Rev,
109,
1495-1508.
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F.E.Reyes-Turcu,
K.H.Ventii,
and
K.D.Wilkinson
(2009).
Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes.
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Annu Rev Biochem,
78,
363-397.
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J.Han,
M.S.Rutherford,
and
K.S.Faaberg
(2009).
The porcine reproductive and respiratory syndrome virus nsp2 cysteine protease domain possesses both trans- and cis-cleavage activities.
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J Virol,
83,
9449-9463.
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T.Wang,
L.Yin,
E.M.Cooper,
M.Y.Lai,
S.Dickey,
C.M.Pickart,
D.Fushman,
K.D.Wilkinson,
R.E.Cohen,
and
C.Wolberger
(2009).
Evidence for bidentate substrate binding as the basis for the K48 linkage specificity of otubain 1.
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J Mol Biol,
386,
1011-1023.
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V.G.Bhoj,
and
Z.J.Chen
(2009).
Ubiquitylation in innate and adaptive immunity.
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Nature,
458,
430-437.
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Y.H.Chiu,
M.Zhao,
and
Z.J.Chen
(2009).
Ubiquitin in NF-kappaB signaling.
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Chem Rev,
109,
1549-1560.
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H.Tran,
F.Hamada,
T.Schwarz-Romond,
and
M.Bienz
(2008).
Trabid, a new positive regulator of Wnt-induced transcription with preference for binding and cleaving K63-linked ubiquitin chains.
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Genes Dev,
22,
528-542.
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L.Li,
D.W.Hailey,
N.Soetandyo,
W.Li,
J.Lippincott-Schwartz,
H.B.Shu,
and
Y.Ye
(2008).
Localization of A20 to a lysosome-associated compartment and its role in NFkappaB signaling.
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Biochim Biophys Acta,
1783,
1140-1149.
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M.Y.Balakirev,
and
K.D.Wilkinson
(2008).
OTU takes the chains OUT.
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Nat Chem Biol,
4,
227-228.
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O.Hitotsumatsu,
R.C.Ahmad,
R.Tavares,
M.Wang,
D.Philpott,
E.E.Turer,
B.L.Lee,
N.Shiffin,
R.Advincula,
B.A.Malynn,
C.Werts,
and
A.Ma
(2008).
The ubiquitin-editing enzyme A20 restricts nucleotide-binding oligomerization domain containing 2-triggered signals.
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Immunity,
28,
381-390.
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S.C.Sun
(2008).
Deubiquitylation and regulation of the immune response.
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Nat Rev Immunol,
8,
501-511.
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The most recent references are shown first.
Citation data come partly from CiteXplore and partly
from an automated harvesting procedure. Note that this is likely to be
only a partial list as not all journals are covered by
either method. However, we are continually building up the citation data
so more and more references will be included with time.
Where a reference describes a PDB structure, the PDB
code is
shown on the right.
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Links
