Scientific Publications by FDA Staff
Proc Natl Acad Sci U S A 2012 Sep 11;109(37):14960-5
Structural insights into the editing of germ-line-encoded interactions between T-cell receptor and MHC class II by Valpha CDR3.
Deng L, Langley RJ, Wang Q, Topalian SL, Mariuzza RA
The conserved diagonal docking mode observed in structures of T-cell receptors (TCRs) bound to peptide-MHC ligands is believed to reflect coevolution of TCR and MHC genes. This coevolution is supported by the conservation of certain interactions between the germ-line-encoded complementarity-determining region (CDR)1 and CDR2 loops of TCR and MHC. However, the rules governing these interactions are not straightforward, even when the same variable (V) region recognizes the same MHC molecule. Here, we demonstrate that the somatically generated CDR3 loops can markedly alter evolutionarily selected contacts between TCR and MHC ("CDR3 editing"). To understand CDR3 editing at the atomic level, we determined the structure of a human melanoma-specific TCR (G4) bound to the MHC class II molecule HLA-DR1 and an epitope from mutant triose phosphate isomerase (mutTPI). A comparison of the G4-mutTPI-DR1 complex with a complex involving a TCR (E8) that uses the same Valpha region to recognize the same mutTPI-DR1 ligand as G4 revealed that CDR1alpha adopts markedly different conformations in the two TCRs, resulting in an almost entirely different set of contacts with MHC. Based on the structures of unbound G4 and E8, the distinct conformations of CDR1alpha in these TCRs are not induced by binding to mutTPI-DR1 but result from differences in the length and sequence of CDR3alpha that are transmitted to CDR1alpha. The editing of germ-line-encoded TCR-MHC interactions by CDR3 demonstrates that these interactions possess sufficient intrinsic flexibility to accommodate large structural variations in CDR3 and, consequently, in the TCR-binding site.
|Category: Journal Article|
|PubMed ID: #22930819||DOI: 10.1073/pnas.1207186109|
|Includes FDA Authors from Scientific Area(s): Biologics|
|Entry Created: 2012-11-19|