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An old Twist in HLA-A: CDR3? Hook up at an R65-joint.


ABSTRACT: T-cell ontogeny optimizes the ?/? 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 (CDR3?/?); however, it is still not clear how. Herein, a conspicuous structural link between the V-J? 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 CDR3? loop maintains its CDR2? loop at a distance of ~4?Å from polymorphic amino acid (a.a.) positions of the ?-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.

SUBMITTER: Murray JS 

PROVIDER: S-EPMC4445401 | BioStudies | 2015-01-01

REPOSITORIES: biostudies

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