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PDBsum entry 3d25
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Immune system
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PDB id
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3d25
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References listed in PDB file
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Key reference
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Title
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Secondary anchor polymorphism in the ha-1 minor histocompatibility antigen critically affects mhc stability and tcr recognition.
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Authors
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S.Nicholls,
K.P.Piper,
F.Mohammed,
T.R.Dafforn,
S.Tenzer,
M.Salim,
P.Mahendra,
C.Craddock,
P.Van endert,
H.Schild,
M.Cobbold,
V.H.Engelhard,
P.A.Moss,
B.E.Willcox.
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Ref.
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Proc Natl Acad Sci U S A, 2009,
106,
3889-3894.
[DOI no: ]
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PubMed id
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Note: In the PDB file this reference is
annotated as "TO BE PUBLISHED". The citation details given above have
been manually determined.
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Abstract
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T cell recognition of minor histocompatibility antigens (mHags) underlies
allogeneic immune responses that mediate graft-versus-host disease and the
graft-versus-leukemia effect following stem cell transplantation. Many mHags
derive from single amino acid polymorphisms in MHC-restricted epitopes, but our
understanding of the molecular mechanisms governing mHag immunogenicity and
recognition is incomplete. Here we examined antigenic presentation and T-cell
recognition of HA-1, a prototypic autosomal mHag derived from single nucleotide
dimorphism (HA-1(H) versus HA-1(R)) in the HMHA1 gene. The HA-1(H) peptide is
restricted by HLA-A2 and is immunogenic in HA-1(R/R) into HA-1(H) transplants,
while HA-1(R) has been suggested to be a "null allele" in terms of T cell
reactivity. We found that proteasomal cleavage and TAP transport of the 2
peptides is similar and that both variants can bind to MHC. However, the
His>Arg change substantially decreases the stability and affinity of HLA-A2
association, consistent with the reduced immunogenicity of the HA-1(R) variant.
To understand these findings, we determined the structure of an HLA-A2-HA-1(H)
complex to 1.3A resolution. Whereas His-3 is accommodated comfortably in the D
pocket, incorporation of the lengthy Arg-3 is predicted to require local
conformational changes. Moreover, a soluble TCR generated from HA-1(H)-specific
T-cells bound HA-1(H) peptide with moderate affinity but failed to bind HA-1(R),
indicating complete discrimination of HA-1 variants at the level of TCR/MHC
interaction. Our results define the molecular mechanisms governing
immunogenicity of HA-1, and highlight how single amino acid polymorphisms in
mHags can critically affect both MHC association and TCR recognition.
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Figure 3.
Crystallographic structure of HLA-A2-VLH at 1.3Å. (A)
Overall structure of HLA-A2-VLH complex, with heavy chain
(gray), β2m (cyan), and VLH peptide (blue) shown. (B) 2Fo-Fc
electron density for the VLH peptide, with primary anchors and
P3 to P5 highlighted. (C) Structure of the VLH mHag in the
HLA-A2-antigen binding groove, with antigen-binding pockets A to
F indicated, and VLH peptide surface indicated in green. The
structure highlights relatively poor contacts with pockets E and
F. (D) Orientation of H3 in and around the D pocket. H3 packs
snugly against the walls of the D pocket, maintaining van der
Waal's contacts with Tyr-159, Leu-156, and Gln-155, and also to
Asp-4 of the peptide. It is also participates in a
hydrogen-bonding network to Gln-155, and peptide residues Asp-4
and Asp-5, via ordered water molecules. Semitransparent peptide
surface shown in green.
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Figure 4.
Surface plasmon resonance analysis of TCR/HLA-A2-HA-1
interaction. (A) Specific binding of KP7 TCR to HLA-A2-VLH
(solid line), with control (HLA-B7-TPR) and HLA-A2-VLR signals
also shown (dashed and dotted lines, respectively). (B)
Equilibrium affinity analysis of TCR/HLA-A2-VLH interaction.
Scatchard plot is shown inset.
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