Functional interaction of the ankylosing spondylitis-associated endoplasmic reticulum aminopeptidase 1 polymorphism and HLA-B27 in vivo.
The association of ERAP1 with ankylosing spondylitis (AS)1 among HLA-B27-positive individuals suggests that ERAP1 polymorphism may affect pathogenesis by altering peptide-dependent features of the HLA-B27 molecule. Comparisons of HLA-B*27:04-bound peptidomes from cells expressing different natural variants of ERAP1 revealed significant differences in the size, length, and amount of many ligands, as well as in HLA-B27 stability. Peptide analyses suggested that the mechanism of ERAP1/HLA-B27 interaction is a variant-dependent alteration in the balance between epitope generation and destruction determined by the susceptibility of N-terminal flanking and P1 residues to trimming. ERAP1 polymorphism associated with AS susceptibility ensured efficient peptide trimming and high HLA-B27 stability. Protective polymorphism resulted in diminished ERAP1 activity, less efficient trimming, suboptimal HLA-B27 peptidomes, and decreased molecular stability. This study demonstrates that natural ERAP1 polymorphism affects HLA-B27 antigen presentation and stability in vivo and proposes a mechanism for the interaction between these molecules in AS.
Centro de Biología Molecular Severo Ochoa, CSIC-UAM, 28049 Madrid, Spain.
Noel
N
García-Medel
Alejandro
A
Sanz-Bravo
Dung
D
Van Nguyen
Begoña
B
Galocha
Patricia
P
Gómez-Molina
Adrián
A
Martín-Esteban
Carlos
C
Alvarez-Navarro
José A López
JA
de Castro
D000595:Amino Acid Sequence; D000626:Aminopeptidases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D001331:Automation; D002460:Cell Line; D020022:Genetic Predisposition to Disease; D015796:HLA-B27 Antigen / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D015778:Minor Histocompatibility Antigens; D008970:Molecular Weight; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011485:Protein Binding; D055550:Protein Stability; D013167:Spondylitis, Ankylosing / Q000201:enzymology* / Q000235:genetics*; D013696:Temperature
D015796:HLA-B27 Antigen; D008024:Ligands; D015778:Minor Histocompatibility Antigens; D010455:Peptides; D000626:Aminopeptidases; C464841:ERAP1 protein, human; C503944:ERAP2 protein, human