The inter-locus recombinant HLA-B*4601 has high selectivity in peptide binding and functions characteristic of HLA-C.
The vast majority of new human HLA class I alleles are formed by conversions between existing alleles of the same locus. A notable exception to this rule is HLA-B*4601 formed by replacement of residues 66-76 of the alpha 1 helix of B*1501 by the homologous segment of Cw*0102. This inter-locus recombination, which brings together characteristic elements of HLA-B and HLA-C structure, is shown here to influence function dramatically. Naturally processed peptides bound by B*4601 are distinct from those of its parental allotypes B*1501 and Cw*0102 and dominated by three high abundance peptides. Such increased peptide selectivity by B*4601 is unique among HLA-A,B,C allotypes. For other aspects of function, presence of the small segment of HLA-C-derived sequence in an otherwise HLA-B framework converts B*4601 to an HLA-C-like molecule. Alloreactive cytotoxic T lymphocytes (CTL), natural killer (NK) cells, and cellular glycosidases all recognize B*4601 as though it were an HLA-C allotype. These unusual properties are those of an allotype which has frequencies as high as 20% in south east Asian populations and is associated with predisposition to autoimmune diseases and nasopharyngeal carcinoma.
Barber
L D
LD
Department of Structural Biology and Microbiology, Stanford University, California 94305, USA.
Percival
L
L
Valiante
N M
NM
Chen
L
L
Lee
C
C
Gumperz
J E
JE
Phillips
J H
JH
Lanier
L L
LL
Bigge
J C
JC
Parekh
R B
RB
Parham
P
P
D000595:Amino Acid Sequence; D002478:Cells, Cultured; D005805:Genes, MHC Class I; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology*; D015236:HLA-C Antigens / Q000276:immunology*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000276:immunology*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011995:Recombination, Genetic; D013329:Structure-Activity Relationship; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014162:Transfection
D015235:HLA-B Antigens; D015236:HLA-C Antigens; D010455:Peptides