Effects of polymorphic variation on the mechanism of Endoplasmic Reticulum Aminopeptidase 1

Stamogiannos, Athanasios; Koumantou, Despoina; Papakyriakou, Athanasios; Stratikos, Efstratios

doi:10.1016/j.molimm.2015.07.010

Cited by 59 publications

(90 citation statements)

References 59 publications

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“…The most common protein variants, reported as ERAP1 allotypes, are encoded by haplotypes created by missense variant combinations of SNPs harboured in an ancestral haplotype found in humans as well as in primates [78]. The most investigated ERAP1 allotypes (from 10 to 13) [78,79] are distinguished by enzymatic functions with both qualitative (substrate preferences) and quantitative (high, intermediate and low activity variants) effects [5,64,[80][81][82]. Interestingly, some non-synonymous SNPs influence the gene expression level of ERAP1 [83].…”

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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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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“…We first evaluated the length selection of ERAP2 using a series of peptides of length between 5 and 12 amino acids that carry the motif LG n L where n ϭ 3-12. This series has been used before to demonstrate the length selection of ERAP1 in a sequence-unbiased manner (28,30). ERAP2 displayed the fastest kinetics for 7-mer peptides and a reduced trimming rate for peptides larger than 10 amino acids (Fig.…”

Section: Erap2 Does Not Clearly Recognize the C Terminus Of The Peptimentioning

confidence: 99%

“…Both enzymes form large internal cavities that are located adjacent to their catalytic site and can accommodate large peptides. Interestingly, in the only known conformation of ERAP2 and in one of the two known conformations of ERAP1, this cavity has no access to the external solvent, suggesting obligatory conformational changes so that substrate exchange can take place (9,29,30). Indeed, ERAP1 has also been crystallized in a more open conformation in which the internal cavity has direct access to the solvent (28).…”

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confidence: 99%

Structural Basis for Antigenic Peptide Recognition and Processing by Endoplasmic Reticulum (ER) Aminopeptidase 2

Mpakali

Giastas

Mathioudakis

et al. 2015

Journal of Biological Chemistry

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Background: ER aminopeptidases generate antigenic peptides, but how they recognize their substrates is unclear. Results: We solved crystal structures of ERAP2 in complex with a substrate analogue and a peptide product. Conclusion: The peptides were found trapped inside a large cavity adjacent to the catalytic site. Significance: Interactions of the substrate with the internal cavity can result in both substrate permissiveness and limited sequence bias.

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“…These studies reported the association of various naturally occurring single nucleotide polymorphisms (SNPs) in ERAP1 with ankylosing spondylitis (AS) and other diseases 1,9-12 . Some identified SNPs, such as K528R and Q730E mutations, are situated near the substrate binding and regulatory sites and could thus affect peptide processing and trimming specificity 13 . Similarly studies suggested mutations of ERAP2 gene leads to an increased risk of preeclampsia with altered ERAP2 expressions 14 .…”

Section: Introductionmentioning

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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Effects of polymorphic variation on the mechanism of Endoplasmic Reticulum Aminopeptidase 1

Cited by 59 publications

References 59 publications

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

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

Structural Basis for Antigenic Peptide Recognition and Processing by Endoplasmic Reticulum (ER) Aminopeptidase 2

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

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