Extended repertoire of permissible peptide ligands for HLA-B*2702.
Recognition of self peptides bound to the class I major histocompatibility complex molecule HLA-B27 is thought to trigger proliferation of autoreactive T cells and result in autoimmune arthritic diseases. Previous work from other laboratories established that a predominant feature of endogenous peptides eluted from purified B27 is an arginine at position 2. We studied the binding of peptides containing both natural and unnatural amino acids by the subtype HLA-B*2702, with the goal of gaining insight into peptide binding by this B27 subtype that is associated with susceptibility to arthritic disease. A soluble from of B*2702 was depleted of endogenous peptides. We tested the binding of peptides substituted with cysteine, homocysteine, or an alpha-amino-epsilon-mercapto hexanoic acid side chain (Amh) instead of the naturally occurring arginine at position 2, to determine whether the peptide sulfhydryl residue could be covalently linked to cysteine 67 in the B*2702 binding cleft. Although none of the altered peptide sequences bound covalently to B*2702, the affinities of the homocysteine- and Amh-substituted peptides were close to that of the native peptide sequence. Substitutions at position 2 with other side chains, such as glutamine and methionine, also resulted in peptides that bound with only slightly reduced affinity. These results demonstrate that peptide side chains other than arginine at position 2 can be accomodated within the B*2702 peptide binding site with only minor reductions in affinity. This extended repertoire of permissible B27-binding peptides should be taken into account for a consideration of disease-associated peptide sequences.
Raghavan
M
M
Division of Biology, California Institute of Technology, Pasadena 91125, USA.
Lebrón
J A
JA
Johnson
J L
JL
Bjorkman
P J
PJ
D000818:Animals; D017951:Antigen Presentation; D001120:Arginine / Q000737:chemistry; D001168:Arthritis / Q000276:immunology; D001324:Autoantigens / Q000737:chemistry / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D015796:HLA-B27 Antigen / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D019151:Peptide Library; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism
D001324:Autoantigens; D015796:HLA-B27 Antigen; D008024:Ligands; D019151:Peptide Library; D010455:Peptides; D011993:Recombinant Fusion Proteins; D001120:Arginine