title: How H13 histocompatibility peptides differing by a single methyl group and lacking conventional MHC binding anchor motifs determine self-nonself discrimination.
abstract: 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.
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, 1600 Morris Boulevard, Bronx, NY 10461, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Ostrov
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Roden
authors.forename: Wuxian
authors.initials: W
authors.lastname: Shi
authors.forename: Edith
authors.initials: E
authors.lastname: Palmieri
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Christianson
authors.forename: Lisa
authors.initials: L
authors.lastname: Mendoza
authors.forename: Gilbert
authors.initials: G
authors.lastname: Villaflor
authors.forename: Darcie
authors.initials: D
authors.lastname: Tilley
authors.forename: Nilabh
authors.initials: N
authors.lastname: Shastri
authors.forename: Howard
authors.initials: H
authors.lastname: Grey
authors.forename: Steven C
authors.initials: SC
authors.lastname: Almo
authors.forename: Derry
authors.initials: D
authors.lastname: Roopenian
authors.forename: Stanley G
authors.initials: SG
authors.lastname: Nathenson
mesh_terms: 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
chemical_list: 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