Figure 8. Identification of well conserved regions of low interaction potential finalize a working model for the root cause of canonical TCR-MHC docking orientations.

Position-sensitive Shannon entropy (top) and normalized amino acid hydropathy (bottom) for class I (A) and class II (B) HLA molecules. Red lines in the hydropathy plots indicate an average over all HLA molecules, while gray lines give the position-sensitive biophysical properties of individual molecules. Alignments of class I (C) or class II (D) HLA alleles from a subsampling of parental alleles, colored by biophysical property. Color coding for alignment: grey - hydrophilic, blue - positively charged, red - negatively charged, orange - hydrophobic, white - non-interacting. Renders of class I (E, PDB: 6MTM) and class II (F, PDB: 1J8H) HLA molecules with α-helices colored by interaction potential. Green - regions of high interaction potential, cyan - regions of moderate interaction potential, black - regions of negligible interaction potential. Orange ovals give probable contact regions for TCRβ, while purple ovals give probable contact regions for TCRα, defining canonical docking orientations.

Figure 8—figure supplement 1. Across a range of mammalian species, the regions of low interaction potential on class I and class II MHC α-helices are very well conserved.

Species used in this analysis highlighted in (A) as found in the IPD-MHC Database. Color-coded matrix alignments of MHC class I (B), MHC class IIa (C), MHC class IIb (D), TRAV (E), and TRBV (F) highlight the extent of this conservation. Specifically for the MHC alignments, the regions of conserved low interaction potential have the extent of conservation quantified, along with the amino acid identity at these sites. Colors of the named amino acids match the colors in the matrices. By comparison, we can see by eye that outside of the TRBV CASS motif and the TRAV AV motif in the germline-encoded region of CDR3, there is almost no clear conservation in the germline-encoded CDR loops.