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PDBsum entry 2av7
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Immune system
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PDB id
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2av7
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References listed in PDB file
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Key reference
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Title
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Unraveling a hotspot for tcr recognition on hla-A2: evidence against the existence of peptide-Independent tcr binding determinants.
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Authors
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S.J.Gagnon,
O.Y.Borbulevych,
R.L.Davis-Harrison,
T.K.Baxter,
J.R.Clemens,
K.M.Armstrong,
R.V.Turner,
M.Damirjian,
W.E.Biddison,
B.M.Baker.
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Ref.
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J Mol Biol, 2005,
353,
556-573.
[DOI no: ]
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PubMed id
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Abstract
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T cell receptor (TCR) recognition of peptide takes place in the context of the
major histocompatibility complex (MHC) molecule, which accounts for
approximately two-thirds of the peptide/MHC buried surface. Using the class I
MHC HLA-A2 and a large panel of mutants, we have previously shown that surface
mutations that disrupt TCR recognition vary with the identity of the peptide.
The single exception is Lys66 on the HLA-A2 alpha1 helix, which when mutated to
alanine disrupts recognition for 93% of over 250 different T cell clones or
lines, independent of which peptide is bound. Thus, Lys66 could serve as a
peptide-independent TCR binding determinant. Here, we have examined the role of
Lys66 in TCR recognition of HLA-A2 in detail. The structure of a peptide/HLA-A2
molecule with the K66A mutation indicates that although the mutation induces no
major structural changes, it results in the exposure of a negatively charged
glutamate (Glu63) underneath Lys66. Concurrent replacement of Glu63 with
glutamine restores TCR binding and function for T cells specific for five
different peptides presented by HLA-A2. Thus, the positive charge on Lys66 does
not serve to guide all TCRs onto the HLA-A2 molecule in a manner required for
productive signaling. Furthermore, electrostatic calculations indicate that
Lys66 does not contribute to the stability of two TCR-peptide/HLA-A2 complexes.
Our findings are consistent with the notion that each TCR arrives at a unique
solution of how to bind a peptide/MHC, most strongly influenced by the chemical
and structural features of the bound peptide. This would not rule out an
intrinsic affinity of TCRs for MHC molecules achieved through multiple weak
interactions, but for HLA-A2 the collective mutational data place limits on the
role of any single MHC amino acid side-chain in driving TCR binding in a
peptide-independent fashion.
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Figure 3.
Figure 3. The conformation of the Tax peptide in the K66A,
E63Q/K66A, and wild-type Tax/HLA-A2 structures is identical. (a)
and (b) 2F[o] -F[c] peptide densities contoured at 1s for the
(a) K66A and (b) E63Q/K66A structures. (c) Superimposition of
the Tax peptide from the K66A, E63Q/K66A, and wild-type
structures. K66A is yellow, E63Q/K66A is white, and wild-type is
blue.
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Figure 5.
Figure 5. Effects of the K66A and E63Q/K66A mutations on
electrostatic surface potentials. (a) Electrostatic potential on
the surface of wild-type Tax/HLA-A2. The circled region,
enlarged on the right-hand side, is characterized by a positive
surface potential. (b) The K66A mutation reverses the potential
at this position. (c) The E63Q/K66A double mutation results in a
surface potential close to neutrality. The scale, from red to
blue, is -5 to +5kT/e.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2005,
353,
556-573)
copyright 2005.
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