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275 a.a.
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100 a.a.
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95 a.a.
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* Residue conservation analysis
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PDB id:
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Viral protein/immune system
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Title:
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Crystal structure of the human cytomegalovirus protein us2 bound to the mhc class i molecule hla-a2/tax
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Structure:
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Hla class i histocompatibility antigen, a-2 alpha chain. Chain: a, e, i, m. Fragment: extracellular domain, heavy chain. Engineered: yes. Beta-2-microglobulin. Chain: b, f, j, n. Fragment: recombinant residues 1-99. Engineered: yes. Human t-cell lymphotropic virus type 1 tax peptide.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: hla-a2. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Gene: beta 2-microglobulin. Synthetic: yes. Other_details: htlv tax peptide (llfgypvyv) was produced by fmoc
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Biol. unit:
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Tetramer (from
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Resolution:
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2.20Å
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R-factor:
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0.206
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R-free:
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0.240
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Authors:
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B.E.Gewurz,R.Gaudet,D.Tortorella,E.W.Wang,H.L.Ploegh,D.C.Wiley
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Key ref:
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B.E.Gewurz
et al.
(2001).
Antigen presentation subverted: Structure of the human cytomegalovirus protein US2 bound to the class I molecule HLA-A2.
Proc Natl Acad Sci U S A,
98,
6794-6799.
PubMed id:
DOI:
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Date:
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09-May-01
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Release date:
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06-Jun-01
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PROCHECK
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Headers
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References
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P04439
(1A03_HUMAN) -
HLA class I histocompatibility antigen, A alpha chain from Homo sapiens
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Seq:
Struc:
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365 a.a.
275 a.a.*
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DOI no:
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Proc Natl Acad Sci U S A
98:6794-6799
(2001)
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PubMed id:
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Antigen presentation subverted: Structure of the human cytomegalovirus protein US2 bound to the class I molecule HLA-A2.
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B.E.Gewurz,
R.Gaudet,
D.Tortorella,
E.W.Wang,
H.L.Ploegh,
D.C.Wiley.
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ABSTRACT
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Many persistent viruses have evolved the ability to subvert MHC class I antigen
presentation. Indeed, human cytomegalovirus (HCMV) encodes at least four
proteins that down-regulate cell-surface expression of class I. The HCMV unique
short (US)2 glycoprotein binds newly synthesized class I molecules within the
endoplasmic reticulum (ER) and subsequently targets them for proteasomal
degradation. We report the crystal structure of US2 bound to the HLA-A2/Tax
peptide complex. US2 associates with HLA-A2 at the junction of the
peptide-binding region and the alpha3 domain, a novel binding surface on class I
that allows US2 to bind independently of peptide sequence. Mutation of class I
heavy chains confirms the importance of this binding site in vivo. Available
data on class I-ER chaperone interactions indicate that chaperones would not
impede US2 binding. Unexpectedly, the US2 ER-luminal domain forms an Ig-like
fold. A US2 structure-based sequence alignment reveals that seven HCMV proteins,
at least three of which function in immune evasion, share the same fold as US2.
The structure allows design of further experiments to determine how US2 targets
class I molecules for degradation.
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Selected figure(s)
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Figure 3.
Fig. 3. US2 binds remotely from peptide-loading proteins.
The positions of mutations (blue) that alter interactions
between class I molecules and the peptide-loading machinery are
shown relative to the US2 binding site on HLA-A2 (magenta). The
HLA-A2 N-linked glycan attachment site, asparagine 86, is also
shown in blue. US2 residues that contact HLA-A2 are yellow.
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Figure 4.
Fig. 4. Protein ligands for class I molecules interact
with different surfaces. Superposition of class I/receptor
complexes for which the structure is known reveals that the five
class I ligand types bind at distinct locations. Class I
interaction surfaces are colored according to each ligand: US2
(magenta), Ly49A (green), B7 TCR (blue), KIR2DL1 (red), CD8  (cyan).
Equivalent C atoms for
class I heavy chain were used to generate pairwise
superpositions. HLA-A2 heavy chain (yellow),  [2]-microglobulin
(gray), US2 (magenta), Tax peptide (green).
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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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L.Li,
Y.Muzahim,
and
M.Bouvier
(2012).
Crystal structure of adenovirus E3-19K bound to HLA-A2 reveals mechanism for immunomodulation.
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Nat Struct Mol Biol,
19,
1176-1181.
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PDB code:
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L.J.Carreño,
E.M.Riquelme,
P.A.González,
N.Espagnolle,
C.A.Riedel,
S.Valitutti,
and
A.M.Kalergis
(2010).
T-cell antagonism by short half-life pMHC ligands can be mediated by an efficient trapping of T-cell polarization toward the APC.
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Proc Natl Acad Sci U S A,
107,
210-215.
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S.O.Lee,
K.Cho,
S.Cho,
I.Kim,
C.Oh,
and
K.Ahn
(2010).
Protein disulphide isomerase is required for signal peptide peptidase-mediated protein degradation.
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EMBO J,
29,
363-375.
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G.E.Dugan,
and
E.W.Hewitt
(2009).
Dependence of the localization and function of the human cytomegalovirus protein US6 on the transporter associated with antigen processing.
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J Gen Virol,
90,
2234-2238.
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J.P.Hodkinson,
T.R.Jahn,
S.E.Radford,
and
A.E.Ashcroft
(2009).
HDX-ESI-MS reveals enhanced conformational dynamics of the amyloidogenic protein beta(2)-microglobulin upon release from the MHC-1.
|
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J Am Soc Mass Spectrom,
20,
278-286.
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M.Miller-Kittrell,
and
T.E.Sparer
(2009).
Feeling manipulated: cytomegalovirus immune manipulation.
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Virol J,
6,
4.
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T.H.Hansen,
and
M.Bouvier
(2009).
MHC class I antigen presentation: learning from viral evasion strategies.
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Nat Rev Immunol,
9,
503-513.
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V.M.Noriega,
and
D.Tortorella
(2009).
Human cytomegalovirus-encoded immune modulators partner to downregulate major histocompatibility complex class I molecules.
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J Virol,
83,
1359-1367.
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A.N.Antoniou,
and
S.J.Powis
(2008).
Pathogen evasion strategies for the major histocompatibility complex class I assembly pathway.
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Immunology,
124,
1.
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C.J.Powers,
and
K.Früh
(2008).
Signal peptide-dependent inhibition of MHC class I heavy chain translation by rhesus cytomegalovirus.
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PLoS Pathog,
4,
e1000150.
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G.E.Dugan,
and
E.W.Hewitt
(2008).
Structural and Functional Dissection of the Human Cytomegalovirus Immune Evasion Protein US6.
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J Virol,
82,
3271-3282.
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K.Oresic,
and
D.Tortorella
(2008).
Endoplasmic reticulum chaperones participate in human cytomegalovirus US2-mediated degradation of class I major histocompatibility complex molecules.
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J Gen Virol,
89,
1122-1130.
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V.M.Noriega,
and
D.Tortorella
(2008).
A bipartite trigger for dislocation directs the proteasomal degradation of an endoplasmic reticulum membrane glycoprotein.
|
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J Biol Chem,
283,
4031-4043.
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Z.Yang,
and
P.J.Bjorkman
(2008).
Structure of UL18, a peptide-binding viral MHC mimic, bound to a host inhibitory receptor.
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Proc Natl Acad Sci U S A,
105,
10095-10100.
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PDB code:
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E.J.Wiertz,
R.Devlin,
H.L.Collins,
and
M.E.Ressing
(2007).
Herpesvirus interference with major histocompatibility complex class II-restricted T-cell activation.
|
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J Virol,
81,
4389-4396.
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L.J.Carreño,
S.M.Bueno,
P.Bull,
S.G.Nathenson,
and
A.M.Kalergis
(2007).
The half-life of the T-cell receptor/peptide-major histocompatibility complex interaction can modulate T-cell activation in response to bacterial challenge.
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Immunology,
121,
227-237.
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M.Miller-Kittrell,
J.Sai,
M.Penfold,
A.Richmond,
and
T.E.Sparer
(2007).
Functional characterization of chimpanzee cytomegalovirus chemokine, vCXCL-1(CCMV).
|
| |
Virology,
364,
454-465.
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P.A.González,
L.J.Carreño,
C.A.Figueroa,
and
A.M.Kalergis
(2007).
Modulation of immunological synapse by membrane-bound and soluble ligands.
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Cytokine Growth Factor Rev,
18,
19-31.
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B.Seliger,
U.Ritz,
and
S.Ferrone
(2006).
Molecular mechanisms of HLA class I antigen abnormalities following viral infection and transformation.
|
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Int J Cancer,
118,
129-138.
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E.Joly,
and
V.Rouillon
(2006).
The orthology of HLA-E and H2-Qa1 is hidden by their concerted evolution with other MHC class I molecules.
|
| |
Biol Direct,
1,
2.
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L.J.Carreño,
P.A.González,
and
A.M.Kalergis
(2006).
Modulation of T cell function by TCR/pMHC binding kinetics.
|
| |
Immunobiology,
211,
47-64.
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B.Meusser,
C.Hirsch,
E.Jarosch,
and
T.Sommer
(2005).
ERAD: the long road to destruction.
|
| |
Nat Cell Biol,
7,
766-772.
|
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B.N.Lilley,
and
H.L.Ploegh
(2005).
Viral modulation of antigen presentation: manipulation of cellular targets in the ER and beyond.
|
| |
Immunol Rev,
207,
126-144.
|
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B.Tirosh,
N.N.Iwakoshi,
B.N.Lilley,
A.H.Lee,
L.H.Glimcher,
and
H.L.Ploegh
(2005).
Human cytomegalovirus protein US11 provokes an unfolded protein response that may facilitate the degradation of class I major histocompatibility complex products.
|
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J Virol,
79,
2768-2779.
|
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C.A.Nelson,
A.Pekosz,
C.A.Lee,
M.S.Diamond,
and
D.H.Fremont
(2005).
Structure and intracellular targeting of the SARS-coronavirus Orf7a accessory protein.
|
| |
Structure,
13,
75-85.
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PDB code:
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H.Liu,
W.F.Stafford,
and
M.Bouvier
(2005).
The endoplasmic reticulum lumenal domain of the adenovirus type 2 E3-19K protein binds to peptide-filled and peptide-deficient HLA-A*1101 molecules.
|
| |
J Virol,
79,
13317-13325.
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L.Lybarger,
X.Wang,
M.Harris,
and
T.H.Hansen
(2005).
Viral immune evasion molecules attack the ER peptide-loading complex and exploit ER-associated degradation pathways.
|
| |
Curr Opin Immunol,
17,
71-78.
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N.T.Pande,
C.Powers,
K.Ahn,
and
K.Früh
(2005).
Rhesus cytomegalovirus contains functional homologues of US2, US3, US6, and US11.
|
| |
J Virol,
79,
5786-5798.
|
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P.A.González,
L.J.Carreño,
D.Coombs,
J.E.Mora,
E.Palmieri,
B.Goldstein,
S.G.Nathenson,
and
A.M.Kalergis
(2005).
T cell receptor binding kinetics required for T cell activation depend on the density of cognate ligand on the antigen-presenting cell.
|
| |
Proc Natl Acad Sci U S A,
102,
4824-4829.
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S.Loch,
and
R.Tampé
(2005).
Viral evasion of the MHC class I antigen-processing machinery.
|
| |
Pflugers Arch,
451,
409-417.
|
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X.Wang,
R.Connors,
M.R.Harris,
T.H.Hansen,
and
L.Lybarger
(2005).
Requirements for the selective degradation of endoplasmic reticulum-resident major histocompatibility complex class I proteins by the viral immune evasion molecule mK3.
|
| |
J Virol,
79,
4099-4108.
|
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D.Blom,
C.Hirsch,
P.Stern,
D.Tortorella,
and
H.L.Ploegh
(2004).
A glycosylated type I membrane protein becomes cytosolic when peptide: N-glycanase is compromised.
|
| |
EMBO J,
23,
650-658.
|
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E.Fiebiger,
C.Hirsch,
J.M.Vyas,
E.Gordon,
H.L.Ploegh,
and
D.Tortorella
(2004).
Dissection of the dislocation pathway for type I membrane proteins with a new small molecule inhibitor, eeyarestatin.
|
| |
Mol Biol Cell,
15,
1635-1646.
|
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H.Huddleston,
and
D.J.Schust
(2004).
Immune interactions at the maternal-fetal interface: a focus on antigen presentation.
|
| |
Am J Reprod Immunol,
51,
283-289.
|
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S.Misaghi,
Z.Y.Sun,
P.Stern,
R.Gaudet,
G.Wagner,
and
H.Ploegh
(2004).
Structural and functional analysis of human cytomegalovirus US3 protein.
|
| |
J Virol,
78,
413-423.
|
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B.N.Lilley,
D.Tortorella,
and
H.L.Ploegh
(2003).
Dislocation of a type I membrane protein requires interactions between membrane-spanning segments within the lipid bilayer.
|
| |
Mol Biol Cell,
14,
3690-3698.
|
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C.Hirsch,
D.Blom,
and
H.L.Ploegh
(2003).
A role for N-glycanase in the cytosolic turnover of glycoproteins.
|
| |
EMBO J,
22,
1036-1046.
|
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E.W.Hewitt
(2003).
The MHC class I antigen presentation pathway: strategies for viral immune evasion.
|
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Immunology,
110,
163-169.
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|
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N.R.Hegde,
and
D.C.Johnson
(2003).
Human cytomegalovirus US2 causes similar effects on both major histocompatibility complex class I and II proteins in epithelial and glial cells.
|
| |
J Virol,
77,
9287-9294.
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P.Sliz,
S.C.Harrison,
and
G.Rosenbaum
(2003).
How does radiation damage in protein crystals depend on X-ray dose?
|
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Structure,
11,
13-19.
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B.Tsai,
Y.Ye,
and
T.A.Rapoport
(2002).
Retro-translocation of proteins from the endoplasmic reticulum into the cytosol.
|
| |
Nat Rev Mol Cell Biol,
3,
246-255.
|
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|
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|
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E.Fiebiger,
C.Story,
H.L.Ploegh,
and
D.Tortorella
(2002).
Visualization of the ER-to-cytosol dislocation reaction of a type I membrane protein.
|
| |
EMBO J,
21,
1041-1053.
|
|
|
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|
|
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E.S.Mocarski
(2002).
Immunomodulation by cytomegaloviruses: manipulative strategies beyond evasion.
|
| |
Trends Microbiol,
10,
332-339.
|
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M.H.Furman,
and
H.L.Ploegh
(2002).
Lessons from viral manipulation of protein disposal pathways.
|
| |
J Clin Invest,
110,
875-879.
|
|
|
|
|
|
|
M.H.Furman,
N.Dey,
D.Tortorella,
and
H.L.Ploegh
(2002).
The human cytomegalovirus US10 gene product delays trafficking of major histocompatibility complex class I molecules.
|
| |
J Virol,
76,
11753-11756.
|
|
|
|
|
|
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M.J.Reddehase
(2002).
Antigens and immunoevasins: opponents in cytomegalovirus immune surveillance.
|
| |
Nat Rev Immunol,
2,
831-844.
|
|
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|
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|
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M.S.Chevalier,
G.M.Daniels,
and
D.C.Johnson
(2002).
Binding of human cytomegalovirus US2 to major histocompatibility complex class I and II proteins is not sufficient for their degradation.
|
| |
J Virol,
76,
8265-8275.
|
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|
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R.S.Tirabassi,
and
H.L.Ploegh
(2002).
The human cytomegalovirus US8 glycoprotein binds to major histocompatibility complex class I products.
|
| |
J Virol,
76,
6832-6835.
|
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|
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Y.Y.Yu,
M.R.Harris,
L.Lybarger,
L.A.Kimpler,
N.B.Myers,
H.W.Virgin,
and
T.H.Hansen
(2002).
Physical association of the K3 protein of gamma-2 herpesvirus 68 with major histocompatibility complex class I molecules with impaired peptide and beta(2)-microglobulin assembly.
|
| |
J Virol,
76,
2796-2803.
|
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|
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B.E.Gewurz,
R.Gaudet,
D.Tortorella,
E.W.Wang,
and
H.L.Ploegh
(2001).
Virus subversion of immunity: a structural perspective.
|
| |
Curr Opin Immunol,
13,
442-450.
|
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|
|
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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
