How H13 histocompatibility peptides differing by a single methyl group and lacking conventional MHC binding anchor motifs determine self-nonself discrimination.
The mouse H13 minor histocompatibility (H) Ag, originally detected as a barrier to allograft transplants, is remarkable in that rejection is a consequence of an extremely subtle interchange, P4(Val/Ile), in a nonamer H2-D(b)-bound peptide. Moreover, H13 peptides lack the canonical P5(Asn) central anchor residue normally considered important for forming a peptide/MHC complex. To understand how these noncanonical peptide pMHC complexes form physiologically active TCR ligands, crystal structures of allelic H13 pD(b) complexes and a P5(Asn) anchored pD(b) analog were solved to high resolution. The structures show that the basis of TCRs to distinguish self from nonself H13 peptides is their ability to distinguish a single solvent-exposed methyl group. In addition, the structures demonstrate that there is no need for H13 peptides to derive any stabilization from interactions within the central C pocket to generate fully functional pMHC complexes. These results provide a structural explanation for a classical non-MHC-encoded H Ag, and they call into question the requirement for contact between anchor residues and the major MHC binding pockets in vaccine design.
Ostrov
David A
DA
Department of Biochemistry, Albert Einstein College of Medicine, 1600 Morris Boulevard, Bronx, NY 10461, USA.
Roden
Matthew M
MM
Shi
Wuxian
W
Palmieri
Edith
E
Christianson
Gregory J
GJ
Mendoza
Lisa
L
Villaflor
Gilbert
G
Tilley
Darcie
D
Shastri
Nilabh
N
Grey
Howard
H
Almo
Steven C
SC
Roopenian
Derry
D
Nathenson
Stanley G
SG
D020816:Amino Acid Motifs; D019943:Amino Acid Substitution; D000818:Animals; D001216:Asparagine / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D018604:Epitope Mapping; D000939:Epitopes / Q000276:immunology; D006183:H-2 Antigens / Q000378:metabolism*; D064532:Histocompatibility Antigen H-2D; D006825:Hybridomas; D051379:Mice; D015778:Minor Histocompatibility Antigens / Q000737:chemistry* / Q000276:immunology* / Q000378:metabolism; D008958:Models, Molecular; D011487:Protein Conformation; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000737:chemistry / Q000378:metabolism; D017634:Self Tolerance; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D023001:Transplantation Tolerance; D014867:Water / Q000737:chemistry
D000939:Epitopes; D006183:H-2 Antigens; C108856:H13 protein, mouse; D064532:Histocompatibility Antigen H-2D; D015778:Minor Histocompatibility Antigens; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D014867:Water; D001216:Asparagine