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* Residue conservation analysis
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DOI no:
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Protein Sci
16:2454-2471
(2007)
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PubMed id:
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Structural and functional analysis of the PDZ domains of human HtrA1 and HtrA3.
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S.T.Runyon,
Y.Zhang,
B.A.Appleton,
S.L.Sazinsky,
P.Wu,
B.Pan,
C.Wiesmann,
N.J.Skelton,
S.S.Sidhu.
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ABSTRACT
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High-temperature requirement A (HtrA) and its homologs contain a serine protease
domain followed by one or two PDZ domains. Bacterial HtrA proteins and the
mitochondrial protein HtrA2/Omi maintain cell function by acting as both
molecular chaperones and proteases to manage misfolded proteins. The biological
roles of the mammalian family members HtrA1 and HtrA3 are less clear. We report
a detailed structural and functional analysis of the PDZ domains of human HtrA1
and HtrA3 using peptide libraries and affinity assays to define specificity,
structural studies to view the molecular details of ligand recognition, and
alanine scanning mutagenesis to investigate the energetic contributions of
individual residues to ligand binding. In common with HtrA2/Omi, we show that
the PDZ domains of HtrA1 and HtrA3 recognize hydrophobic polypeptides, and while
C-terminal sequences are preferred, internal sequences are also recognized.
However, the details of the interactions differ, as different domains rely on
interactions with different residues within the ligand to achieve high affinity
binding. The results suggest that mammalian HtrA PDZ domains interact with a
broad range of hydrophobic binding partners. This promiscuous specificity
resembles that of bacterial HtrA family members and suggests a similar function
for recognizing misfolded polypeptides with exposed hydrophobic sequences. Our
results support a common activation mechanism for the HtrA family, whereby
hydrophobic peptides bind to the PDZ domain and induce conformational changes
that activate the protease. Such a mechanism is well suited to proteases evolved
for the recognition and degradation of misfolded proteins.
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Selected figure(s)
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Figure 3.
Figure 3. Internal peptide ligands for human HtrA PDZ domains. Sequences are shown for peptides selected from an N-terminal
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Figure 6.
Figure 6. Results of shotgun alanine scanning for binding to peptide
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The above figures are
reprinted
by permission from the Protein Society:
Protein Sci
(2007,
16,
2454-2471)
copyright 2007.
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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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K.Luck,
and
G.Travé
(2011).
Phage display can select over-hydrophobic sequences that may impair prediction of natural domain-peptide interactions.
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Bioinformatics,
27,
899-902.
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C.Bachert,
and
A.D.Linstedt
(2010).
Dual anchoring of the GRASP membrane tether promotes trans pairing.
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J Biol Chem,
285,
16294-16301.
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D.Beleford,
R.Rattan,
J.Chien,
and
V.Shridhar
(2010).
High temperature requirement A3 (HtrA3) promotes etoposide- and cisplatin-induced cytotoxicity in lung cancer cell lines.
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J Biol Chem,
285,
12011-12027.
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H.J.Lee,
and
J.J.Zheng
(2010).
PDZ domains and their binding partners: structure, specificity, and modification.
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Cell Commun Signal,
8,
8.
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N.Hornigold,
R.A.Craven,
J.N.Keen,
T.Johnson,
R.E.Banks,
and
A.F.Mooney
(2010).
Upregulation of Hic-5 in glomerulosclerosis and its regulation of mesangial cell apoptosis.
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Kidney Int,
77,
329-338.
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H.J.Lee,
N.X.Wang,
Y.Shao,
and
J.J.Zheng
(2009).
Identification of tripeptides recognized by the PDZ domain of Dishevelled.
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Bioorg Med Chem,
17,
1701-1708.
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J.Chien,
X.He,
and
V.Shridhar
(2009).
Identification of tubulins as substrates of serine protease HtrA1 by mixture-based oriented peptide library screening.
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J Cell Biochem,
107,
253-263.
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P.Hauske,
N.Mamant,
S.Hasenbein,
S.Nickel,
C.Ottmann,
T.Clausen,
M.Ehrmann,
and
M.Kaiser
(2009).
Peptidic small molecule activators of the stress sensor DegS.
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Mol Biosyst,
5,
980-985.
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T.Beuming,
R.Farid,
and
W.Sherman
(2009).
High-energy water sites determine peptide binding affinity and specificity of PDZ domains.
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Protein Sci,
18,
1609-1619.
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R.Tonikian,
Y.Zhang,
S.L.Sazinsky,
B.Currell,
J.H.Yeh,
B.Reva,
H.A.Held,
B.A.Appleton,
M.Evangelista,
Y.Wu,
X.Xin,
A.C.Chan,
S.Seshagiri,
L.A.Lasky,
C.Sander,
C.Boone,
G.D.Bader,
and
S.S.Sidhu
(2008).
A specificity map for the PDZ domain family.
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PLoS Biol,
6,
e239.
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S.M.Gisler,
S.Kittanakom,
D.Fuster,
V.Wong,
M.Bertic,
T.Radanovic,
R.A.Hall,
H.Murer,
J.Biber,
D.Markovich,
O.W.Moe,
and
I.Stagljar
(2008).
Monitoring protein-protein interactions between the mammalian integral membrane transporters and PDZ-interacting partners using a modified split-ubiquitin membrane yeast two-hybrid system.
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Mol Cell Proteomics,
7,
1362-1377.
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T.Krojer,
K.Pangerl,
J.Kurt,
J.Sawa,
C.Stingl,
K.Mechtler,
R.Huber,
M.Ehrmann,
and
T.Clausen
(2008).
Interplay of PDZ and protease domain of DegP ensures efficient elimination of misfolded proteins.
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Proc Natl Acad Sci U S A,
105,
7702-7707.
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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.
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Links
