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

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

Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) generates antigenic peptides for loading onto Major Histocompatibility Class I molecules (MHCI) and can regulate adaptive immune responses. During the last few years, many genetic studies have revealed strong associations between coding Single Nucleotide Polymorphisms (SNPs) in ERAP1 and common human diseases ranging from viral infections to cancer and autoimmunity. Functional studies have established that these SNPs affect enzyme activity resulting to changes in antigenic peptide processing, presentation by MHCI and cellular cytotoxic responses. These disease-associated polymorphisms are, however, located away from the enzyme's active site and are interspersed to different structural domains. As a result, the mechanism by which these SNPs can affect function remains largely elusive. ERAP1 utilizes a complex catalytic mechanism that involves a large conformational change between inactive and active forms and has the unique property to trim larger peptides more efficiently than smaller ones. We analyzed two of the most consistently discovered disease-associated polymorphisms, namely K528R and Q730E, for their effect on the ability of the enzyme to select substrates based on length and to undergo conformational changes. By utilizing enzymatic and computational analysis we propose that disease-associated SNPs can affect ERAP1 function by influencing: (i) substrate length selection and (ii) the conformational distribution of the protein ensemble. Our results provide novel insight on the mechanisms by which polymorphic variation distal from the active site of ERAP1 can translate to changes in function and contribute to immune system variability in humans.

Accelerated molecular dynamics, Aminopeptidase, Antigen epitopes, Antigen processing, Peptides, Principle component analysis, Single nucleotide polymorphisms (SNPs)
0161-5890
426-435
Stamogiannos, Athanasios
bc884e02-7a77-4746-911d-b21d80bf08f6
Koumantou, Despoina
f3be878d-38f1-4842-971b-ed368afba55f
Papakyriakou, Athanasios
939bc8c9-1693-4530-9099-c55772b22f1d
Stratikos, Efstratios
85f4a2e4-422a-4dab-a067-f50ea7238c00
Stamogiannos, Athanasios
bc884e02-7a77-4746-911d-b21d80bf08f6
Koumantou, Despoina
f3be878d-38f1-4842-971b-ed368afba55f
Papakyriakou, Athanasios
939bc8c9-1693-4530-9099-c55772b22f1d
Stratikos, Efstratios
85f4a2e4-422a-4dab-a067-f50ea7238c00

Stamogiannos, Athanasios, Koumantou, Despoina, Papakyriakou, Athanasios and Stratikos, Efstratios (2015) Effects of polymorphic variation on the mechanism of Endoplasmic Reticulum Aminopeptidase 1. Molecular Immunology, 67 (2), 426-435. (doi:10.1016/j.molimm.2015.07.010).

Record type: Article

Abstract

Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) generates antigenic peptides for loading onto Major Histocompatibility Class I molecules (MHCI) and can regulate adaptive immune responses. During the last few years, many genetic studies have revealed strong associations between coding Single Nucleotide Polymorphisms (SNPs) in ERAP1 and common human diseases ranging from viral infections to cancer and autoimmunity. Functional studies have established that these SNPs affect enzyme activity resulting to changes in antigenic peptide processing, presentation by MHCI and cellular cytotoxic responses. These disease-associated polymorphisms are, however, located away from the enzyme's active site and are interspersed to different structural domains. As a result, the mechanism by which these SNPs can affect function remains largely elusive. ERAP1 utilizes a complex catalytic mechanism that involves a large conformational change between inactive and active forms and has the unique property to trim larger peptides more efficiently than smaller ones. We analyzed two of the most consistently discovered disease-associated polymorphisms, namely K528R and Q730E, for their effect on the ability of the enzyme to select substrates based on length and to undergo conformational changes. By utilizing enzymatic and computational analysis we propose that disease-associated SNPs can affect ERAP1 function by influencing: (i) substrate length selection and (ii) the conformational distribution of the protein ensemble. Our results provide novel insight on the mechanisms by which polymorphic variation distal from the active site of ERAP1 can translate to changes in function and contribute to immune system variability in humans.

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More information

Published date: 1 October 2015
Keywords: Accelerated molecular dynamics, Aminopeptidase, Antigen epitopes, Antigen processing, Peptides, Principle component analysis, Single nucleotide polymorphisms (SNPs)

Identifiers

Local EPrints ID: 413408
URI: http://eprints.soton.ac.uk/id/eprint/413408
ISSN: 0161-5890
PURE UUID: 1efafd30-d1d1-46b7-822a-048b7050f8e9
ORCID for Athanasios Papakyriakou: ORCID iD orcid.org/0000-0003-3931-6232

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Date deposited: 23 Aug 2017 16:32
Last modified: 06 Jun 2024 01:58

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Contributors

Author: Athanasios Stamogiannos
Author: Despoina Koumantou
Author: Athanasios Papakyriakou ORCID iD
Author: Efstratios Stratikos

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