ERAP1: a potential therapeutic target for a myriad of diseases

Reeves, Emma; Islam, Yasmin; James, Estelle

doi:10.1080/14728222.2020.1751821

Cited by 29 publications

(27 citation statements)

References 83 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since peptides of 10 to 12 residues can be immunogenic, accumulation of distinct intermediates by different allotypes could contribute to differences in immune responses between individuals. ERAP1 is an emerging pharmacological target for cancer immunotherapy and the control of inflammatory autoimmunity, including rheumatic conditions such as AS (36,37). Given the wide distribution of common allotypes in the population, it is crucial to know if inhibitors with clinical potential can effectively inhibit all allotypes.…”

Section: Resultsmentioning

confidence: 99%

Common allotypes of ER aminopeptidase 1 have substrate-dependent and highly variable enzymatic properties

Hutchinson

Temponeras

Kuiper

et al. 2021

Journal of Biological Chemistry

View full text Add to dashboard Cite

Polymorphic variation of immune system proteins can drive variability of individual immune responses. Endoplasmic reticulum aminopeptidase 1 (ERAP1) generates antigenic peptides for presentation by major histocompatibility complex class I molecules. Coding SNPs in ERAP1 have been associated with predisposition to inflammatory rheumatic disease and shown to affect functional properties of the enzyme, but the interplay between combinations of these SNPs as they exist in allotypes has not been thoroughly explored. We used phased genotype data to estimate ERAP1 allotype frequency in 2504 individuals across five major human populations, generated highly pure recombinant enzymes corresponding to the ten most common ERAP1 allotypes, and systematically characterized their in vitro enzymatic properties. We find that ERAP1 allotypes possess a wide range of enzymatic activities, up to 60-fold, whose ranking is substrate dependent. Strikingly, allotype 10, previously associated with Behçet’s disease, is consistently a low-activity outlier, suggesting that a significant percentage of individuals carry a subactive ERAP1 gene. Enzymatic analysis revealed that ERAP1 allotypes can differ in both catalytic efficiency and substrate affinity, differences that can change intermediate accumulation in multistep trimming reactions. Alterations in efficacy of an allosteric inhibitor that targets the regulatory site suggest that allotypic variation influences the communication between the regulatory and the active site. Our work defines the wide landscape of ERAP1 activity in human populations and demonstrates how common allotypes can induce substrate-dependent variability in antigen processing, thus contributing, in synergy with major histocompatibility complex haplotypes, to immune response variability and predisposition to chronic inflammatory conditions.

show abstract

Section: Resultsmentioning

confidence: 99%

Common allotypes of ER aminopeptidase 1 have substrate-dependent and highly variable enzymatic properties

Hutchinson

Temponeras

Kuiper

et al. 2021

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…This comes as a sharp contrast to their ability to trim the 10mer peptide shown in Figure 3B. (40,41). Given the wide distribution of common allotypes in the human population, it is crucial to know if inhibitors with clinical potential are able to inhibit all allotypes with efficacy.…”

Section: Resultsmentioning

confidence: 99%

“…ERAP1 is an emerging pharmacological target for cancer immunotherapy and the control of inflammatory autoimmunity, including rheumatic conditions such as ankylosing spondylitis [39, 40]. Given the wide distribution of common allotypes in the population, it is crucial to know if inhibitors with clinical potential can effectively inhibit all allotypes.…”

Section: Resultsmentioning

confidence: 99%

Common allotypes of ER aminopeptidase 1 have substrate-dependent and highly variable enzymatic properties

Hutchinson

Temponeras

Kuiper

et al. 2020

Preprint

View full text Add to dashboard Cite

ObjectivePolymorphic variation of immune system proteins can drive variability of individual immune responses. ER aminopeptidase 1 (ERAP1) generates antigenic peptides for presentation by MHC class I molecules. Coding single nucleotide polymorphisms (SNPs) in ERAP1 have been associated with predisposition to inflammatory rheumatic disease and shown to affect functional properties of the enzyme, but the interplay between combinations of these SNPs as they exist in allotypes, has not been thoroughly explored.MethodsWe used phased genotype data to estimate ERAP1 allotype frequency in 2,504 individuals across five major human populations, generated highly pure recombinant enzymes corresponding to the 10 most common ERAP1 allotypes and systematically characterized their in vitro enzymatic properties.ResultsWe find that ERAP1 allotypes possess a wide range of enzymatic activities, up to 60-fold, whose ranking is substrate-dependent. Strikingly, allotype 10, previously associated with Behçet’s disease, is consistently a low-activity outlier, suggesting that a significant percentage of individuals carry a sub-active ERAP1 gene. Enzymatic analysis revealed that ERAP1 allotypes can differ in both catalytic efficiency and substrate affinity, differences that can change intermediate accumulation in multi-step trimming reactions. Alterations in efficacy of an allosteric inhibitor that targets the regulatory site suggest that allotypic variation influences the communication between the regulatory and the active site.ConclusionOur work defines the wide landscape of ERAP1 activity in human populations and demonstrates how common allotypes can induce substrate-dependent variability in antigen processing, thus contributing, in synergy with MHC haplotypes, to immune response variability and to predisposition to chronic inflammatory conditions.

show abstract

“…25,000 compounds for further evaluation (top-1%, Figure 2 ). In order to maximize our chances of obtaining IRAP-selective inhibitors, we performed a second round of docking calculations against the corresponding site of ERAP1, the highest homologous enzyme of IRAP within the M1 family of aminopeptidases [ 22 ]. The top-ranked subset of compounds identified for IRAP was then employed in docking to ERAP1, using the high-resolution X-ray structure (PDB ID: 6q4r [ 15 ]).…”

Section: Resultsmentioning

confidence: 99%

Discovery of Selective Inhibitor Leads by Targeting an Allosteric Site in Insulin-Regulated Aminopeptidase

et al. 2021

View full text Add to dashboard Cite

Insulin-Regulated aminopeptidase (IRAP) is a zinc-dependent aminopeptidase with several important biological functions and is an emerging pharmaceutical target for cognitive enhancement and immune system regulation. Aiming to discover lead-like IRAP inhibitors with enhanced selectivity versus homologous enzymes, we targeted an allosteric site at the C-terminal domain pocket of IRAP. We compiled a library of 2.5 million commercially available compounds from the ZINC database, and performed molecular docking at the target pocket of IRAP and the corresponding pocket of the homologous endoplasmic reticulum aminopeptidase 1 (ERAP1). Of the top compounds that showed high selectivity, 305 were further analyzed by molecular dynamics simulations and free energy calculations, leading to the selection of 33 compounds for in vitro evaluation. Two orthogonal functional assays were employed: one using a small fluorogenic substrate and one following the degradation of oxytocin, a natural peptidic substrate of IRAP. In vitro evaluation suggested that several of the compounds tested can inhibit IRAP, but the inhibition profile was dependent on substrate size, consistent with the allosteric nature of the targeted site. Overall, our results describe several novel leads as IRAP inhibitors and suggest that the C-terminal domain pocket of IRAP is a promising target for developing highly selective IRAP inhibitors.

show abstract

ERAP1: a potential therapeutic target for a myriad of diseases

Cited by 29 publications

References 83 publications

Common allotypes of ER aminopeptidase 1 have substrate-dependent and highly variable enzymatic properties

Common allotypes of ER aminopeptidase 1 have substrate-dependent and highly variable enzymatic properties

Common allotypes of ER aminopeptidase 1 have substrate-dependent and highly variable enzymatic properties

Discovery of Selective Inhibitor Leads by Targeting an Allosteric Site in Insulin-Regulated Aminopeptidase

Contact Info

Product

Resources

About