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* Residue conservation analysis
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Enzyme class:
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Chain A:
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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DOI no:
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J Biol Chem
283:11038-11049
(2008)
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PubMed id:
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Structural basis for ubiquitin recognition by the Otu1 ovarian tumor domain protein.
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T.E.Messick,
N.S.Russell,
A.J.Iwata,
K.L.Sarachan,
R.Shiekhattar,
J.R.Shanks,
F.E.Reyes-Turcu,
K.D.Wilkinson,
R.Marmorstein.
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ABSTRACT
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Ubiquitination of proteins modifies protein function by either altering their
activities, promoting their degradation, or altering their subcellular
localization. Deubiquitinating enzymes are proteases that reverse this
ubiquitination. Previous studies demonstrate that proteins that contain an
ovarian tumor (OTU) domain possess deubiquitinating activity. This domain of
approximately 130 amino acids is weakly similar to the papain family of
proteases and is highly conserved from yeast to mammals. Here we report
structural and functional studies on the OTU domain-containing protein from
yeast, Otu1. We show that Otu1 binds polyubiquitin chain analogs more tightly
than monoubiquitin and preferentially hydrolyzes longer polyubiquitin chains
with Lys(48) linkages, having little or no activity on Lys(63)- and
Lys(29)-linked chains. We also show that Otu1 interacts with Cdc48, a regulator
of the ER-associated degradation pathway. We also report the x-ray crystal
structure of the OTU domain of Otu1 covalently complexed with ubiquitin and
carry out structure-guided mutagenesis revealing a novel mode of ubiquitin
recognition and a variation on the papain protease catalytic site configuration
that appears to be conserved within the OTU family of ubiquitin hydrolases.
Together, these studies provide new insights into ubiquitin binding and
hydrolysis by yeast Otu1 and other OTU domain-containing proteins.
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Selected figure(s)
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Figure 4.
FIGURE 4. The Otu1-ubiquitin interface. A, three regions of
interaction between Otu1 and ubiquitin. The figure is rendered
in a surface representation and shown in "open book" format
highlighting contact regions 1 (blue), 2 (green), and 3 (red).
B, close-up of Otu1-ubiquitin interactions in region 1. Side
chains that mediate hydrogen bonds (dotted line) and van der
Waals interactions are shown. C, close-up of Otu1-ubiquitin
interactions in region 2. Water molecules are indicated as white
spheres. D, close-up of Otu1-ubiquitin interactions in region 3.
E, superimposed active sites of deubiquitinating enzymes. The
catalytic triad cysteine, histidine, and aspartate as well as
ubiquitin (magenta) are shown as a stick models. Otu1 is shown
as cyan, UCH-L3 (Protein Data Bank code 1xd3) is shown in
violet, and HAUSP/USP7 (Protein Data Bank code 1nbf) is shown in
green.
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Figure 6.
FIGURE 6. Comparison of the Otu1-ubiquitin complex with
otubain 2. A, superposition of the Otu1-ubiquitin complex (cyan
and magenta, respectively) with nascent otubain 2 (yellow). B,
close-up view of the β4-loop region of Otu1 (cyan) with bound
ubiquitin (magenta) with the corresponding region of nascent
otubain 2 (yellow).
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2008,
283,
11038-11049)
copyright 2008.
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Figures were
selected
by an automated process.
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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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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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R.Wiener,
X.Zhang,
T.Wang,
and
C.Wolberger
(2012).
The mechanism of OTUB1-mediated inhibition of ubiquitination.
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Nature,
483,
618-622.
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PDB codes:
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J.H.Shin,
H.S.Ko,
H.Kang,
Y.Lee,
Y.I.Lee,
O.Pletinkova,
J.C.Troconso,
V.L.Dawson,
and
T.M.Dawson
(2011).
PARIS (ZNF746) repression of PGC-1α contributes to neurodegeneration in Parkinson's disease.
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Cell,
144,
689-702.
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M.Akutsu,
Y.Ye,
S.Virdee,
J.W.Chin,
and
D.Komander
(2011).
Molecular basis for ubiquitin and ISG15 cross-reactivity in viral ovarian tumor domains.
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Proc Natl Acad Sci U S A,
108,
2228-2233.
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PDB codes:
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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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W.Bao,
V.V.Kapitonov,
and
J.Jurka
(2010).
Ginger DNA transposons in eukaryotes and their evolutionary relationships with long terminal repeat retrotransposons.
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Mob DNA,
1,
3.
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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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E.M.Cooper,
C.Cutcliffe,
T.Z.Kristiansen,
A.Pandey,
C.M.Pickart,
and
R.E.Cohen
(2009).
K63-specific deubiquitination by two JAMM/MPN+ complexes: BRISC-associated Brcc36 and proteasomal Poh1.
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EMBO J,
28,
621-631.
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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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M.E.French,
B.R.Kretzmann,
and
L.Hicke
(2009).
Regulation of the RSP5 ubiquitin ligase by an intrinsic ubiquitin-binding site.
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J Biol Chem,
284,
12071-12079.
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R.Ernst,
B.Mueller,
H.L.Ploegh,
and
C.Schlieker
(2009).
The otubain YOD1 is a deubiquitinating enzyme that associates with p97 to facilitate protein dislocation from the ER.
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Mol Cell,
36,
28-38.
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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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Y.Sato,
A.Yoshikawa,
A.Yamagata,
H.Mimura,
M.Yamashita,
K.Ookata,
O.Nureki,
K.Iwai,
M.Komada,
and
S.Fukai
(2008).
Structural basis for specific cleavage of Lys 63-linked polyubiquitin chains.
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Nature,
455,
358-362.
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PDB codes:
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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
