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PDBsum entry 3fqw
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Immune system
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PDB id
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3fqw
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References listed in PDB file
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Key reference
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Title
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Phosphorylated self-Peptides alter human leukocyte antigen class i-Restricted antigen presentation and generate tumor-Specific epitopes.
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Authors
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J.Petersen,
S.J.Wurzbacher,
N.A.Williamson,
S.H.Ramarathinam,
H.H.Reid,
A.K.Nair,
A.Y.Zhao,
R.Nastovska,
G.Rudge,
J.Rossjohn,
A.W.Purcell.
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Ref.
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Proc Natl Acad Sci U S A, 2009,
106,
2776-2781.
[DOI no: ]
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PubMed id
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Abstract
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Human leukocyte antigen (HLA) class I molecules present a variety of
posttranslationally modified epitopes at the cell surface, although the
consequences of such presentation remain largely unclear. Phosphorylation plays
a critical cellular role, and deregulation in phosphate metabolism is associated
with disease, including autoimmunity and tumor immunity. We have solved the
high-resolution structures of 3 HLA A2-restricted phosphopeptides associated
with tumor immunity and compared them with the structures of their
nonphosphorylated counterparts. Phosphorylation of the epitope was observed to
affect the structure and mobility of the bound epitope. In addition, the
phosphoamino acid stabilized the HLA peptide complex in an epitope-specific
manner and was observed to exhibit discrete flexibility within the
antigen-binding cleft. Collectively, our data suggest that phosphorylation
generates neoepitopes that represent demanding targets for T-cell receptor
ligation. These findings provide insights into the mode of phosphopeptide
presentation by HLA as well as providing a platform for the rational design of a
generation of posttranslationally modified tumor vaccines.
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Figure 1.
Peptide conformations within the antigen-binding cleft.
CDC25b (A), IRS2 (B), β-catenin (C), CDC25b-phospho (D),
IRS2-phospho (E), and β-catenin–phospho (F). Blue mesh
indicates unbiased 2Fo-Fc maps contoured at 1σ. Yellow
indicates nonphosphorylated peptides. Green indicates
phosphorylated peptides. The bound peptide is shown from a
side-on view with the α2-helix removed for clarity.
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Figure 2.
Interactions of the phosphorylation site in nonphosphopeptide
and phosphopeptide HLA A2 complexes. Accommodation of the
phosphate moiety by HLA A2 is accompanied by changed
interactions in the complex, adding to the differential
presentation of altered self. Stick representation of peptides
and of heavy-chain side chains that interact with the
phosphorylation site. Yellow indicates nonphospho-pHLA A2
complexes. Green indicates phospho-pHLA A2 complexes. (A–C)
Phosphorylation of P5-Ser in CDC25b leads to an altered peptide
conformation attributable to steric constraints. (D–F)
Phosphorylation of P4-Ser in IRS2 gives rise to numerous
interactions and subtly alters the conformation of Arg 65 and
Lys 66. (G–I) Phosphorylation of P4-Ser in β-catenin
stabilizes the mobile peptide residues P3 to P6.
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