Synergy of endoplasmic reticulum aminopeptidase 1 and 2 (ERAP1 and ERAP2) polymorphisms in atopic dermatitis: Effects on disease prevalence

2020 ◽  
Author(s):  
Wanda Niepiekło-Miniewska ◽  
Łukasz Matusiak ◽  
Joanna Narbutt ◽  
Aleksandra Lesiak ◽  
Piotr Kuna ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Atopic Dermatitis ◽  
Disease Prevalence ◽  
Endoplasmic Reticulum Aminopeptidase 1

scholarly journals Mechanism for antigenic peptide selection by endoplasmic reticulum aminopeptidase 1

2019 ◽  
Vol 116 (52) ◽  
pp. 26709-26716 ◽  
Author(s):  
Petros Giastas ◽  
Anastasia Mpakali ◽  
Athanasios Papakyriakou ◽  
Aggelos Lelis ◽  
Paraskevi Kokkala ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Structural Motif ◽  
Internal Cavity ◽  
Sequence Specificity ◽  
Substrate Selection ◽  
Class I Mhc ◽  
Mhc I ◽  
Intracellular Enzyme ◽  
C Terminus ◽  
Endoplasmic Reticulum Aminopeptidase 1

Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an intracellular enzyme that optimizes the peptide cargo of major histocompatibility class I (MHC-I) molecules and regulates adaptive immunity. It has unusual substrate selectivity for length and sequence, resulting in poorly understood effects on the cellular immunopeptidome. To understand substrate selection by ERAP1, we solved 2 crystal structures of the enzyme with bound transition-state pseudopeptide analogs at 1.68 Å and 1.72 Å. Both peptides have their N terminus bound at the active site and extend away along a large internal cavity, interacting with shallow pockets that can influence selectivity. The longer peptide is disordered through the central region of the cavity and has its C terminus bound in an allosteric pocket of domain IV that features a carboxypeptidase-like structural motif. These structures, along with enzymatic and computational analyses, explain how ERAP1 can select peptides based on length while retaining the broad sequence-specificity necessary for its biological function.

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

2015 ◽  
Vol 67 (2) ◽  
pp. 426-435 ◽  
Author(s):  
Athanasios Stamogiannos ◽  
Despoina Koumantou ◽  
Athanasios Papakyriakou ◽  
Efstratios Stratikos
Keyword(s):  
Endoplasmic Reticulum ◽  
Polymorphic Variation ◽  
Endoplasmic Reticulum Aminopeptidase 1

scholarly journals Critical Role of Endoplasmic Reticulum Aminopeptidase 1 in Determining the Length and Sequence of Peptides Bound and Presented by HLA-B27

2014 ◽  
Vol 66 (2) ◽  
pp. 284-294 ◽  
Author(s):  
Liye Chen ◽  
Roman Fischer ◽  
Yanchun Peng ◽  
Emma Reeves ◽  
Kirsty McHugh ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Critical Role ◽  
Hla B27 ◽  
Endoplasmic Reticulum Aminopeptidase 1

scholarly journals Identification of an Unconventional Subpeptidome Bound to the Behçet's Disease-associated HLA-B*51:01 that is Regulated by Endoplasmic Reticulum Aminopeptidase 1 (ERAP1)

2020 ◽  
Vol 19 (5) ◽  
pp. 871-883 ◽  
Author(s):  
Liye Chen ◽  
Hui Shi ◽  
Danai Koftori ◽  
Takuya Sekine ◽  
Annalisa Nicastri ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Surface ◽  
Behçet’S Disease ◽  
Behcet’S Disease ◽  
Behçet's Disease ◽  
Cell Surface Expression ◽  
Dependent Manner ◽  
Behcet's Disease ◽  
Terminal Residue ◽  
Endoplasmic Reticulum Aminopeptidase 1

Human leukocyte antigen (HLA) B*51:01 and endoplasmic reticulum aminopeptidase 1 (ERAP1) are strongly genetically associated with Behçet's disease (BD). Previous studies have defined two subgroups of HLA-B*51 peptidome containing proline (Pro) or alanine (Ala) at position 2 (P2). Little is known about the unconventional non-Pro/Ala2 HLA-B*51-bound peptides. We aimed to study the features of this novel subpeptidome, and investigate its regulation by ERAP1. CRISPR-Cas9 was used to generate an HLA-ABC-triple knockout HeLa cell line (HeLa.ABC-KO), which was subsequently transduced to express HLA-B*51:01 (HeLa.ABC-KO.B51). ERAP1 was silenced using lentiviral shRNA. Peptides bound to HLA-B*51:01 were eluted and analyzed by mass spectrometry. The characteristics of non-Pro/Ala2, Pro2, and Ala2 peptides and their alteration by ERAP1 silencing were investigated. Effects of ERAP1 silencing on cell surface expression of HLA-B*51:01 were studied using flow cytometry. More than 20% of peptides eluted from HLA-B*51:01 lacked Pro or Ala at P2. This unconventional group of HLA-B*51:01-bound peptides was relatively enriched for 8-mers (with relatively fewer 9-mers) compared with the Pro2 and Ala2 subpeptidomes and had similar N-terminal and C-terminal residue usages to Ala2 peptides (with the exception of the less abundant leucine at position Ω). Knockdown of ERAP1 increased the percentage of non-Pro/Ala2 from 20% to ∼40%, increased the percentage of longer (10-mer and 11-mer) peptides eluted from HLA-B*51:01 complexes, and abrogated the predominance of leucine at P1. Interestingly knockdown of ERAP1 altered the length and N-terminal residue usage of non-Ala2&Pro2 and Ala2 but not the Pro2 peptides. Finally, ERAP1 silencing regulated the expression levels of cell surface HLA-B*51 in a cell-type-dependent manner. In conclusion, we have used a novel methodology to identify an unconventional but surprisingly abundant non-Pro/Ala2 HLA-B*51:01 subpeptidome. It is increased by knockdown of ERAP1, a gene affecting the risk of developing BD. This has implications for theories of disease pathogenesis.

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