Topology of T cell receptor-peptide class I MHC interaction defined by charge reversal complementation and functional analysis

被引:39
作者
Chang, HC
Smolyar, A
Spoerl, R
Witte, T
Yao, Y
Goyarts, EC
Nathenson, SG
Reinherz, EL
机构
[1] HARVARD UNIV,SCH MED,DEPT MED,BOSTON,MA 02115
[2] YESHIVA UNIV ALBERT EINSTEIN COLL MED,DEPT MICROBIOL & IMMUNOL,BRONX,NY 10461
关键词
T cell receptor; receptor-ligand interactions; MHC; mutagenesis; VSV8/H-2K(b);
D O I
10.1006/jmbi.1997.1169
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The molecular interactions between the CD8 co-receptor dependent N15 and N26 T tell receptors (TCRs) and their common ligand, the vesicular stomatitis virus octapeptide (VSV8) bound to H-2K(b), were studied to define the docking orientation(s) of MHC class I restricted TCRs during immune recognition. Guided by the molecular surfaces of the crystallographically defined peptide/MHC and modeled TCRs, a series of mutations in exposed residues likely contacting the TCR ligand were analyzed for their ability to alter peptide-triggered IL-2 production in T cell transfectants. Critical residues which diminished antigen recognition by 1000 to 10,000-fold in molar terms were identified in both N15 V alpha (alpha E94A or alpha E94R, Y98A and K99) and V beta (beta R96A, beta W97A and beta D99A) CDR3 loops. Mutational analysis indicated that the Rp1 residue of VSV8 is critical for antigen recognition of N15 TCR, but R62 of H-2K(b) is less critical. More importantly, the alpha E94R mutant could be fully complemented by a reciprocal charge reversal at K-b R62 (R62E). This result suggests a direct interaction between N15 TCR V alpha E94R and K-b R62E residues. As Rp1 of VSV8 is adjacent to R62 in the VSV8/K-b complex and essential for T cell activation, this orientation implies that the N15 V alpha CDR3 loop interacts with the N-terminal residues of VSV8 with the V alpha domain docking to the K-b alpha 2 helix while the N15 V beta CDR3 loop interacts with the more C-terminal peptide residues and the VP domain overlies the K-b alpha 1 helix. An equivalent orientation is suggested for N26, a second VSV8/K-b specific TCR. Given that genetic analysis of two different class II MHC-restricted TCRs and two crystallographic studies of class I restricted TCRs offers a similar overall orientation of V domains relative to alpha-helices, these data raise the possibility of a common docking mode between TCRs and their ligands regardless of MHC restriction. (C) 1997 Academic Press Limited.
引用
收藏
页码:278 / 293
页数:16
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