Mass spectral data for 64 eluted peptides and structural modeling define peptide binding preferences for class I alleles in two chicken MHC-B haplotypes associated with opposite responses to Marek's disease.
In the chicken, resistance to lymphomas that form following infection with oncogenic strains of Marek's herpesvirus is strongly linked to the major histocompatibility complex (MHC)-B complex. MHC-B21 haplotype is associated with lower tumor-related mortality compared to other haplotypes including MHC-B13. The single, dominantly expressed class I gene (BF2) is postulated as responsible for the MHC-B haplotype association. We used mass spectrometry to identify peptides and structural modeling to define the peptide binding preferences of BF2 2101 and BF2 1301 proteins. Endogenous peptides (8-12 residues long) were eluted from affinity-purified BF2 2101 and BF2 1301 proteins obtained from transduced cDNA expressed in RP9 cells, hence expressed in the presence of heterologous TAP. Sequences of individual peptides were identified by mass spectrometry. BF2 2101 peptides appear to be tethered at the binding groove margins with longer peptides arching out but selected by preferred residues at positions P3, P5, and P8: X-X-[AVILFP]-X((1-5))-[AVLFWP]-X((2-3))-[VILFM]. BF2 1301 peptides appear selected for residues at P2, P3, P5, and P8: X-[DE]-[AVILFW]-X((1-2))-[DE]-X-X-[ED]-X((0-4)). Some longer BF2 1301 peptides likely also arch out, but others are apparently accommodated by repositioning of Arg83 so that peptides extend beyond the last preferred residue at P8. Comparisons of these peptides with earlier peptides derived in the presence of homologous TAP transport revealed the same side chain preferences. Scanning of Marek's and other viral proteins with the BF2 2101 motif identified many matches, as did the control human leukocyte antigen A 0201 motif. The BF2 1301 motif is more restricting suggesting that this allele may confer a selective advantage only in infections with a subset of viral pathogens.
Sherman
Mark A
MA
Division of Information Sciences, City of Hope, Beckman Research Institute, Duarte, CA 91010, USA.
Goto
Ronald M
RM
Moore
Roger E
RE
Hunt
Henry D
HD
Lee
Terry D
TD
Miller
Marcia M
MM
D000818:Animals; D002460:Cell Line; D002645:Chickens; D002853:Chromatography, Liquid; D004247:DNA / Q000235:genetics / Q000276:immunology; D004277:DNA, Single-Stranded / Q000235:genetics / Q000276:immunology; D005805:Genes, MHC Class I; D006239:Haplotypes; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D025922:Mardivirus / Q000235:genetics / Q000378:metabolism; D008380:Marek Disease / Q000276:immunology* / Q000821:virology; D008958:Models, Molecular; D010455:Peptides / Q000378:metabolism*; D011485:Protein Binding; D053719:Tandem Mass Spectrometry; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
D004277:DNA, Single-Stranded; D015395:Histocompatibility Antigens Class I; D010455:Peptides; D014764:Viral Proteins; D004247:DNA