Cutting Edge: Coding single nucleotide polymorphisms of endoplasmic reticulum aminopeptidase 1 can affect antigenic peptide generation in vitro by influencing basic enzymatic properties of the enzyme.
ER aminopeptidase 1 (ERAP1) customizes antigenic peptide precursors for MHC class I presentation and edits the antigenic peptide repertoire. Coding single nucleotide polymorphisms (SNPs) in ERAP1 were recently linked with predisposition to autoimmune disease, suggesting a link between pathogenesis of autoimmunity and ERAP1-mediated Ag processing. To investigate this possibility, we analyzed the effect that disease-linked SNPs have on Ag processing by ERAP1 in vitro. Michaelis-Menten analysis revealed that the presence of SNPs affects the Michaelis constant and turnover number of the enzyme. Strikingly, specific ERAP1 allele-substrate combinations deviate from standard Michaelis-Menten behavior, demonstrating substrate-inhibition kinetics; to our knowledge, this phenomenon has not been described for this enzyme. Cell-based Ag-presentation analysis was consistent with changes in the substrate inhibition constant K(i), further supporting that ERAP1 allelic composition may affect Ag processing in vivo. We propose that these phenomena should be taken into account when evaluating the possible link between Ag processing and autoimmunity.
Protein Chemistry Laboratory, National Centre for Scientific Research Demokritos, Agia Paraskevi, Athens 15310, Greece.
Irini
I
Evnouchidou
Ram P
RP
Kamal
Sergey S
SS
Seregin
Yoshikuni
Y
Goto
Masafumi
M
Tsujimoto
Akira
A
Hattori
Paraskevi V
PV
Voulgari
Alexandros A
AA
Drosos
Andrea
A
Amalfitano
Ian A
IA
York
Efstratios
E
Stratikos
D020121:5' Untranslated Regions / Q000276:immunology; D000483:Alleles; D019943:Amino Acid Substitution / Q000235:genetics; D000626:Aminopeptidases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D017951:Antigen Presentation / Q000235:genetics; D000941:Antigens / Q000096:biosynthesis*; D001120:Arginine / Q000235:genetics; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000201:enzymology* / Q000235:genetics / Q000276:immunology*; D005973:Glutamine / Q000235:genetics; D015234:HLA-A Antigens / Q000235:genetics / Q000378:metabolism; D015796:HLA-B27 Antigen / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008239:Lysine / Q000235:genetics; D015778:Minor Histocompatibility Antigens; D010452:Peptide Biosynthesis / Q000235:genetics* / Q000276:immunology; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000276:immunology*; D013379:Substrate Specificity / Q000235:genetics
D020121:5' Untranslated Regions; D000941:Antigens; D015234:HLA-A Antigens; D015796:HLA-B27 Antigen; D015778:Minor Histocompatibility Antigens; D010446:Peptide Fragments; D005973:Glutamine; D001120:Arginine; D000626:Aminopeptidases; C464841:ERAP1 protein, human; D008239:Lysine
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