TcR recognition of the MHC-peptide dimer: structural properties of a ternary complex.
We have developed a method that utilizes site-specific mutation data, sequence analysis, immunological data and free-energy minimization, to determine structural features of the ternary complex formed by the T-cell receptor (TcR) and the class I major histocompatibility complex (MHC) molecule bound by peptide. The analysis focuses on the mouse Kd MHC system, for which a large set of clones with sequenced T-cell receptors is available for specific peptides. The general philosophy is to reduce the uncertainties and computation time in a free-energy minimization procedure by identifying and imposing experimental constraints. In addition to assessing compatibility with various kinds of immunological data, we are particularly interested in differentiating the structural features peculiar to this particular system from generic features, and in ascertaining the robustness of the structure; i.e. determining, in so far as possible, the variations in the structure that leave its compatibility with experiment unaltered from those that do not. This last is equivalent to recognizing that certain features of the model are presented with a reasonable degree of confidence, while others remain highly tentative. The central conclusion in the former category is a placement of the TcR on the Kd peptide complex, which has its beta 2, beta 3 and alpha 3 loops (i.e. the second and third complementarity-determining region of the TcR beta chain, and the third complementarity-determining region of the alpha chain) covering the peptide; the alpha 1 and alpha 2 loops covering the MHC alpha 1 helix; the alpha 2 loop interacting with residues on the MHC beta sheet; and the beta 1 and (part of) the beta 2 loops covering the alpha 2 MHC helix. More specifically, our findings include the following. (1) A highly conserved histidine residue in the first complementarity-determining region of the TcR beta chain (beta:CDR1) points outward and interacts with highly conserved side-chains on the MHC alpha 2 helix. (2) The amino-terminal portion of the beta 2 loop interacts with the carboxyl portion of the peptide. A particularly important interaction is K4 of the loop interacting with E8 of the peptide. (3) Charged side-chains of the 11-residue TcR alpha 2 loop interact with conserved charged side-chains at positions 44, 58, 61 and 68 on the MHC. (4) The TcR beta 3 loop interacts with the amino-terminal part of the peptide, up through position 4. (5) the TcR alpha 3 loop interacts with the central portion of the peptide and stacks against the beta 2 loop. (6) Because of the interaction between the beta 2 loop and the peptide, and stacking of beta 2 on alpha 3, alpha 3 gene and V beta gene selection can be correlated. (7) Using the topology of the recently solved TcR alpha chain we predict that the alpha 2 loop interacts with the loop on the MHC beta sheet floor, which encompasses residues 42 to 44.
Vasmatzis
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Department of Mathematics, Iowa State University, Ames 50011, USA.
Cornette
J
J
Sezerman
U
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DeLisi
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C
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D006183:H-2 Antigens / Q000737:chemistry* / Q000378:metabolism; D064532:Histocompatibility Antigen H-2D; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry* / Q000378:metabolism
D006183:H-2 Antigens; D064532:Histocompatibility Antigen H-2D; D010455:Peptides; D016693:Receptors, Antigen, T-Cell, alpha-beta