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

Mpakali, Anastasia; Giastas, Petros; Mathioudakis, N.; Mavridis, Irene M.; Saridakis, Emmanuel; Stratikos, Efstratios

doi:10.1074/jbc.m115.685909

Cited by 81 publications

(124 citation statements)

References 54 publications

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“…Similarly, Lys685 makes a direct hydrogen-bonding with peptide's PC-1 main chain carbonyl (Figure 3b). Interestingly, in the recently reported ERAP2-analog complex structure, the conserved residue equivalent to ERAP1's Arg841 (Arg864 in ERAP2) also makes a hydrogen bond contact with the carboxyl end of the DG025 peptide analog 26 .…”

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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“…ERAP2 is more efficient than ERAP1 with substrates of lower length, such as nonamers (12). Moreover, although increased trimming of basic residues may occur upon ERAP2-induced activation of ERAP1, this would result in even higher cleavage of ERAP1-susceptible residues, actually leading to an increased percentage of the basic ones, as observed with highly active ERAP1 variants (33,36).…”

Section: Arthritis and Rheumatologymentioning

confidence: 99%

“…In recent crystallographic studies (12), some His side chains of the substrate established π-stacking interactions in the peptide-binding site of ERAP2. Thus, peptides with internal His residues might bind and be trimmed better by ERAP2, explaining their lower abundance in the presence of this enzyme.…”

Section: Arthritis and Rheumatologymentioning

confidence: 99%

Functional Interaction of the Ankylosing Spondylitis–Associated Endoplasmic Reticulum Aminopeptidase 2 With the HLA–B*27 Peptidome in Human Cells

Martín-Esteban

Guasp

Barnea

et al. 2016

Arthritis & Rheumatology

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ERAP-2 significantly influences the B*27:05-bound peptidome by destroying some ligands and decreasing the abundance of many more ligands with N-terminal basic residues, while increasing the abundance of nonamers. The former effects are best explained by direct ERAP-2 trimming. The effects on peptide length might be attributed to ERAP-2-induced activation of ERAP-1 trimming. These data support the notion of a peptide-mediated mechanism as the basis for the association of ERAP-2 with ankylosing spondylitis. Analogous effects on other major histocompatibility complex class I peptidomes might explain the involvement of ERAP-2 in HLA-B27-negative spondyloarthritis.

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“…The trimming activity of ERAP2 is complementary to that of ERAP1 for both Nterminal substrate specificity and peptide length. Indeed, ERAP2 cleaves positively charged residues preferentially and its activity is maximal on octameric substrates and lower on longer peptides [63,[72][73][74]. Therefore, the two aminopeptidases would operate in a concerted manner, ensuring an efficient generation and/or destruction of MHC class I epitopes for a proper functioning and regulation of the adaptive immunity.…”

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

Cited by 81 publications

References 54 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

Functional Interaction of the Ankylosing Spondylitis–Associated Endoplasmic Reticulum Aminopeptidase 2 With the HLA–B*27 Peptidome in Human Cells

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

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