An old Twist in HLA-A: CDR3α Hook up at an R65-joint.

Joseph S Murray

doi:10.3389/fimmu.2015.00268

Abstract

T-cell ontogeny optimizes the α/β T-cell receptor (TCR) repertoire for recognition of major histocompatibility complex (MHC) class-I/II genetic polymorphism, and co-evolution of TCR germline V-gene segments and the MHC must entail somatic diversity generated in the third complimentary determining regions (CDR3α/β); however, it is still not clear how. Herein, a conspicuous structural link between the V-Jα used by several different TCR [all in complex with the same MHC molecule (HLA-A2)], and a conserved MHC motif (a.a., R65-X-X-K-A-X-S-Q72) is described. We model this R65-joint in detail, and show that the same TCR’s CDR3α loop maintains its CDR2α loop at a distance of ~4 Å from polymorphic amino acid (a.a.) positions of the α-2 helix in all but one of the analyzed crystal structures. Indeed, the pitch of docked TCRs varies as their twist/tilt/sway maintains the R65-joint and peptide contacts. Thus, the R65-joint appears to have poised the HLA-A lineage toward alloreactivity.

Highlights

The same DNA-recombinase system (RAG-1/-2) used in B cells for the generation of variants of the canonical immunoglobulin (Ig) cell-surface receptor is used in T cells to generate a vast diverse repertoire of T-cell receptor (TCR) variants; these variants of the TCR are clonally distributed on T cells, as are sIg on B cells [1]
As can be seen from the closest contacts made by the TCR, one can classify these TCR as alpha-dominant, alpha/beta, An old twist in HLA-A
TCRA were reverse translated subjected to joint analysis. [(B), bottom] CDR3α joints; contacts were measured with VMD software

Summary

Introduction

The same DNA-recombinase system (RAG-1/-2) used in B cells for the generation of variants of the canonical immunoglobulin (Ig) cell-surface receptor is used in T cells to generate a vast diverse repertoire of T-cell receptor (TCR) variants; these variants of the TCR are clonally distributed on T cells, as are sIg on B cells [1]. R65-Joint As shown in Figure 2 (compiled in Figure 1B), individual CDR3α rearrangements lead to structurally distinct types of contact with the R65 motif, principally, projection-type (dovetail), concavetype (mortise), or flat-type (dado), all best appreciated with spacefilled models. The dovetail joint of the A6 TCR (in 1AO7, 3PWP, and 3H9S complexes) fits W101 into the complimentary slot made by the side-chains of the R65 motif, i.e., within the α-helical secondary structure of the α-1 helix (Figures 2A,B).

Results

Conclusion