AUTHOR=Murray Joseph S. 

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

JOURNAL=Frontiers in Immunology

VOLUME=Volume 6 - 2015

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=T-cell ontogeny optimizes the alpha/beta 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 (CDR3alpha/beta); however, it is still not clear how.  Here-in, a conspicuous structural link between the V-J alpha 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 CDR3alpha loop maintains its CDR2alpha loop at a distance of ~4 Å from polymorphic amino acid (a.a.) positions of the apha-2 helix in all but one of the analyzed crystal structures.  Indeed, the pitch of docked TCRs vary as their twist/tilt/sway maintains the R65-joint and peptide contacts.  Thus, the R65-joint appears to have poised the HLA-A lineage towards alloreactivity.