ERAP1-ERAP2 dimers trim MHC I-bound precursor peptides; implications for understanding peptide editing

Hanna, Calvin; Li, Lenong; Weimershaus, Mirjana; Evnouchidou, Irini; Endert, Peter Van; Bouvier, Marlène

doi:10.1038/srep28902

Cited by 82 publications

(76 citation statements)

References 43 publications

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“…Thus to study a productive complex structure of ERAP1 or ERAP2, the challenge in the field is to prepare a complex with substrate peptides containing natural N- and C-termini, with appropriate anchor residues at both ends, and with more than 8-9 residues in length. A recent study described a slower editing activity of MHC-I bound peptides by ERAP1-ERAP2 heterodimers 30 . Nonetheless, that MHC-I assisted activity is different from the molecular ruler mechanism studied in this report since it has been well demonstrated that purified ERAP1 and/or ERAP2 enzyme is able to efficiently process antigenic precursors in the absence of MHC molecules 2,3,16,20 .…”

Section: Resultsmentioning

confidence: 99%

Crystal structure of a polypeptide’s C-terminus in complex with the regulatory domain of ER aminopeptidase 1

Sui

Gandhi

Guo

2016

Molecular Immunology

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Endoplasmic reticulum aminopeptidase 1 (ERAP1) is involved in the final processing of peptide precursors to generate the N-termini of MHC class I-restricted epitopes. ERAP1 thus influences immunodominance and cytotoxic immune responses by controlling the peptide repertoire available for cell surface presentation by MHC molecules. To enable this critical role in antigen processing, ERAP1 trims peptides by a unique molecular ruler mechanism that turns on/off hydrolysis activity in a peptide-length and -sequence dependent manner. Thus unlike other aminopeptidases, ERAP1 could recognize both the N- and C-termini of peptides in order to read the substrate's length. To exemplify and validate this molecular ruler mechanism, we have carried out crystallographic studies on molecular recognition of antigenic peptide's C-terminus by ERAP1. In this report, we have determined a 2.8Å-resolution crystal structure of an intermolecular complex between the ERAP1 regulatory domain and a natural epitope's C-terminus displayed in a fusion protein. It reveals the structural details of peptide's C-termini recognition by ERAP1. ERAP1 uses specificity pockets on the regulatory domain to bind the peptide's carboxyl end and side chain of the C-terminal anchoring residue. At the same time, flexibility in length and sequence at the middle of peptides is accommodated by a kink with minimal interactions with ERAP1.

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Section: Resultsmentioning

confidence: 99%

Crystal structure of a polypeptide’s C-terminus in complex with the regulatory domain of ER aminopeptidase 1

Sui

Gandhi

Guo

2016

Molecular Immunology

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“…This reflects the lack of LD between the protein-coding Figure 9). The lack of detailed MHC-I data hampered further investigation of this phenomena, because ERAP2 may not equally contribute to the peptidome of each MHC-I molecule [26,34]. However, this would demand a large population study with sufficient power to investigate the ERAP1-ERAP2 haplotypes for distinct MHC-I haplotypes.…”

Section: Discussionmentioning

confidence: 99%

“…Whether ERAP1 and ERAP2 contribute to disease by direct interaction in the endoplasmic reticulum is not known [36,42,46]. In the absence of ERAP2 protein, cells with distinct ERAP1 haplotypes show substantial differences in HLA-A29 peptidome composition, which demonstrates that ERAP1 is able to directly influence HLA-A29 [45]. Also, ERAP2 has different peptide preferences compared to ERAP1 [36,41] and MHC-I peptidome studies support separate contributions of Hap10 and ERAP2 in manipulating the peptide composition presented on the cell surface [46].…”

Section: Discussionmentioning

confidence: 99%

Functionally distinct ERAP1 and ERAP2 are a hallmark of HLA-A29-(Birdshot) Uveitis

Kuiper

Setten

Devall

et al. 2018

Preprint

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Birdshot Uveitis (Birdshot) is a rare eye condition that affects HLA-A29-positive individuals and could be considered a prototypic member of the recently proposed "MHC-I-opathy" family. Genetic studies have pinpointed the ERAP1 and ERAP2 genes as shared associations across MHC-I-opathies, which suggests ERAP dysfunction may be a root cause for MHC-I-opathies. We mapped the ERAP1 and ERAP2 haplotypes in 84 Dutch cases and 890 controls. We identified association at variant rs10044354, which mediated a marked increase in ERAP2 expression.We also identified and cloned an independently associated ERAP1 haplotype (tagged by rs2287987) present in more than half of the cases; this ERAP1 haplotype is also the primary risk and protective haplotype for other MHC- 6)) replicated and showed consistent direction of effect in an independent Spanish cohort of 46 cases and 2,103 controls. In both cohorts, the combined rs2287987-rs10044354 haplotype associated with Birdshot more strongly than either SNP alone (meta-analysis: p=3.9 × 10(-9)). Finally, we observed that ERAP2 protein expression is dependent on the ERAP1 background across three European populations (n=3,353). In conclusion, a functionally distinct combination of ERAP1 and ERAP2 are a hallmark of Birdshot and provide rationale for strategies designed to correct ERAP function for treatment of Birdshot and MHC-I-opathies more broadly.

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“…However, less than 30% of each enzyme is engaged in the heterodimers [75]. Recently, it has also been shown that the ERAP1/ ERAP2 dimer could work as a peptide editor by trimming 'on MHC I' substrates until the correct length enabling the MHC groove to reach a closed conformation [77].…”

Section: Hla-b27 a Molecule With Two Faces: Protection From Viral Inmentioning

confidence: 99%

The interplay between HLA-B27 and ERAP1/ERAP2 aminopeptidases: from anti-viral protection to spondyloarthritis

Vitulano

Tedeschi

Paladini

et al. 2017

Clinical and Experimental Immunology

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1These authors contributed equally to this study. SummaryThe human leukocyte antigen class I gene HLA-B27 is the strongest risk factor for ankylosing spondylitis (AS), a chronic inflammatory arthritic disorder. More recently, the Endoplasmic Reticulum Aminopeptidase (ERAP) 1 and 2 genes have been identified by genome wide association studies (GWAS) as additional susceptibility factors. In the ER, these aminopeptidases trim the peptides to a length suitable to fit into the groove of the major histocompatibility complex (MHC) class I molecules. It is noteworthy that an epistatic interaction between HLA-B27 and ERAP1, but not between HLA-B27 and ERAP2, has been highlighted. However, these observations suggest a paramount centrality for the HLA-B27 peptide repertoire that determines the natural B27 immunological function, i.e. the T cell antigen presentation and, as a by-product, elicits HLA-B27 aberrant behaviours: (i) the misfolding leading to ER stress responses and autophagy and (ii) the surface expression of homodimers acting as ligands for innate immune receptors. In this context, it has been observed that the HLA-B27 carriers, besides being prone to autoimmunity, display a far better surveillance to some viral infections. This review focuses on the ambivalent role of HLA-B27 in autoimmunity and viral protection correlating its functions to the quantitative and qualitative effects of ERAP1 and ERAP2 polymorphisms on their enzymatic activity.

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ERAP1-ERAP2 dimers trim MHC I-bound precursor peptides; implications for understanding peptide editing

Cited by 82 publications

References 43 publications

Crystal structure of a polypeptide’s C-terminus in complex with the regulatory domain of ER aminopeptidase 1

Crystal structure of a polypeptide’s C-terminus in complex with the regulatory domain of ER aminopeptidase 1

Functionally distinct ERAP1 and ERAP2 are a hallmark of HLA-A29-(Birdshot) Uveitis

The interplay between HLA-B27 and ERAP1/ERAP2 aminopeptidases: from anti-viral protection to spondyloarthritis

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