Department of Pathology
Amino Acids, Peptides, and Proteins | Biochemistry | Enzymes and Coenzymes | Hemic and Immune Systems | Immunity | Immunopathology | Pathology
Endoplasmic reticulum aminopeptidase 1 (ERAP1) trims antigenic peptide precursors to generate mature antigenic peptides for presentation by major histocompatibility complex class I (MHCI) molecules and regulates adaptive immune responses. ERAP1 has been proposed to trim peptide precursors both in solution and in pre-formed MHCI-peptide complexes, but which mode is more relevant to its biological function remains controversial. Here, we compared ERAP1-mediated trimming of antigenic peptide precursors in solution or when bound to three MHCI alleles, HLA-B*58, HLA-B*08 and HLA-A*02. For all MHCI-peptide combinations, peptide binding onto MHCI protected against ERAP1-mediated trimming. In only a single MHCI-peptide combination, trimming of an HLA-B*08-bound 12mer progressed at a considerable rate, albeit still slower than in solution. Results from thermodynamic, kinetic and computational analyses suggested that this 12mer is highly labile and that apparent on-MHC trimming rates are always slower than that of MHCI-peptide dissociation. Both ERAP2 and leucine aminopeptidase, an enzyme unrelated to antigen processing, could trim this labile peptide from pre-formed MHCI complexes as efficiently as ERAP1. A pseudopeptide analogue with high affinity for both HLA-B*08 and the ERAP1 active site could not promote the formation of a ternary ERAP1-MHCI-peptide complex. Similarly, no interactions between ERAP1 and purified peptide loading complex (PLC) were detected in the absence or presence of a pseudopeptide trap. We conclude that MHCI binding protects peptides from ERAP1 degradation and that trimming in solution, along with the dynamic nature of peptide binding to MHCI, are sufficient to explain ERAP1 processing of antigenic peptide precursors.
ER aminopeptidase 1(ERAP1), ER aminopeptidase 2(ERAP2), aminopeptidase, peptide, antigen processing, antigen presentation, trimming mechanism, adaptive immunity, cytotoxic T lymphocyte, histocompatibility complex, immunogenicity regulation
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© 2020 The Author(s). Publisher's paper in press version posted as allowed by publisher's author rights policy at https://www.asbmb.org/journals-news/editorial-policies.
DOI of Published Version
This research was originally published in: Mavridis G, Arya R, Domnick A, Zoidakis J, Makridakis M, Vlahou A, Mpakali A, Lelis A, Georgiadis D, Tampé R, Papakyriakou A, Stern LJ, Stratikos E. A systematic re-examination of processing of MHCI-bound antigenic peptide precursors by ER aminopeptidase 1. J Biol Chem. 2020 Mar 17:jbc.RA120.012976. doi: 10.1074/jbc.RA120.012976. Epub ahead of print. PMID: 32184355. Link to article on publisher's site
The Journal of biological chemistry
Mavridis G, Arya R, Domnick A, Zoidakis J, Makridakis M, Vlahou A, Mpakali A, Lelis A, Georgiadis D, Tampe R, Papakyriakou A, Stern LJ, Stratikos E. (2020). A systematic re-examination of processing of MHCI-bound antigenic peptide precursors by ER aminopeptidase 1. Open Access Publications by UMMS Authors. https://doi.org/10.1074/jbc.RA120.012976. Retrieved from https://escholarship.umassmed.edu/oapubs/4186