AUTHOR=Murray Joseph S. 

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

JOURNAL=Frontiers in Immunology

VOLUME=6

YEAR=2015

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2015.00268

DOI=10.3389/fimmu.2015.00268

ISSN=1664-3224

ABSTRACT=<p>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 <italic>germline</italic> V-gene segments and the MHC must entail <italic>somatic</italic> 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 <italic>R65-joint</italic> 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 <italic>pitch</italic> of docked TCRs varies as their <italic>twist/tilt/sway</italic> maintains the <italic>R65-joint</italic> and peptide contacts. Thus, the <italic>R65-joint</italic> appears to have poised the HLA-A lineage toward alloreactivity.</p>