title: Although divergent in residues of the peptide binding site, conserved chimpanzee Patr-AL and polymorphic human HLA-A*02 have overlapping peptide-binding repertoires.
abstract: Patr-AL is an expressed, non-polymorphic MHC class I gene carried by ∼50% of chimpanzee MHC haplotypes. Comparing Patr-AL(+) and Patr-AL(-) haplotypes showed Patr-AL defines a unique 125-kb genomic block flanked by blocks containing classical Patr-A and pseudogene Patr-H. Orthologous to Patr-AL are polymorphic orangutan Popy-A and the 5' part of human pseudogene HLA-Y, carried by ∼10% of HLA haplotypes. Thus, the AL gene alternatively evolved in these closely related species to become classical, nonclassical, and nonfunctional. Although differing by 30 aa substitutions in the peptide-binding α(1) and α(2) domains, Patr-AL and HLA-A*0201 bind overlapping repertoires of peptides; the overlap being comparable with that between the A*0201 and A*0207 subtypes differing by one substitution. Patr-AL thus has the A02 supertypic peptide-binding specificity. Patr-AL and HLA-A*0201 have similar three-dimensional structures, binding peptides in similar conformation. Although comparable in size and shape, the B and F specificity pockets of Patr-AL and HLA-A*0201 differ in both their constituent residues and contacts with peptide anchors. Uniquely shared by Patr-AL, HLA-A*0201, and other members of the A02 supertype are the absence of serine at position 9 in the B pocket and the presence of tyrosine at position 116 in the F pocket. Distinguishing Patr-AL from HLA-A*02 is an unusually electropositive upper face on the α(2) helix. Stimulating PBMCs from Patr-AL(-) chimpanzees with B cells expressing Patr-AL produced potent alloreactive CD8 T cells with specificity for Patr-AL and no cross-reactivity toward other MHC class I molecules, including HLA-A*02. In contrast, PBMCs from Patr-AL(+) chimpanzees are tolerant of Patr-AL.
authors.affiliation: Graduate Program in Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Gleimer
authors.forename: Angela R
authors.initials: AR
authors.lastname: Wahl
authors.forename: Heather D
authors.initials: HD
authors.lastname: Hickman
authors.forename: Laurent
authors.initials: L
authors.lastname: Abi-Rached
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Norman
authors.forename: Lisbeth A
authors.initials: LA
authors.lastname: Guethlein
authors.forename: John A
authors.initials: JA
authors.lastname: Hammond
authors.forename: Monia
authors.initials: M
authors.lastname: Draghi
authors.forename: Erin J
authors.initials: EJ
authors.lastname: Adams
authors.forename: Sean
authors.initials: S
authors.lastname: Juo
authors.forename: Roxana
authors.initials: R
authors.lastname: Jalili
authors.forename: Baback
authors.initials: B
authors.lastname: Gharizadeh
authors.forename: Mostafa
authors.initials: M
authors.lastname: Ronaghi
authors.forename: K Christopher
authors.initials: KC
authors.lastname: Garcia
authors.forename: William H
authors.initials: WH
authors.lastname: Hildebrand
authors.forename: Peter
authors.initials: P
authors.lastname: Parham
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics / Q000276:immunology; D003001:Cloning, Molecular; D017124:Conserved Sequence / Q000235:genetics / Q000276:immunology*; D005807:Genes, Overlapping / Q000276:immunology*; D015234:HLA-A Antigens / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015789:HLA-A2 Antigen; D015395:Histocompatibility Antigens Class I / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D002679:Pan troglodytes; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism
chemical_list: D015234:HLA-A Antigens; C524866:HLA-A*02 antigen; D015789:HLA-A2 Antigen; D015395:Histocompatibility Antigens Class I; D010455:Peptides; D011948:Receptors, Antigen, T-Cell