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Can ERAP1 and ERAP2 Form Functional Heterodimers? A Structural Dynamics Investigation
Endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and ERAP2) play important roles in the generation of antigenic peptides presented by Major Histocompatibility Class I (MHCI) molecules and indirectly regulate adaptive immune responses. Although the discrete function of these enzymes has been exte...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9065437/ https://www.ncbi.nlm.nih.gov/pubmed/35514997 http://dx.doi.org/10.3389/fimmu.2022.863529 |
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author | Papakyriakou, Athanasios Mpakali, Anastasia Stratikos, Efstratios |
author_facet | Papakyriakou, Athanasios Mpakali, Anastasia Stratikos, Efstratios |
author_sort | Papakyriakou, Athanasios |
collection | PubMed |
description | Endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and ERAP2) play important roles in the generation of antigenic peptides presented by Major Histocompatibility Class I (MHCI) molecules and indirectly regulate adaptive immune responses. Although the discrete function of these enzymes has been extensively characterized, recent reports have suggested that they can also form heterodimers with functional consequences. However, lack of structural characterization of a putative ERAP1/ERAP2 dimer has limited our understanding of its biological role and significance. To address this, we employed computational molecular dynamics calculations to explore the topology of interactions between these two, based on experimentally determined homo-dimerization interfaces observed in crystal structures of ERAP2 or homologous enzymes. Our analysis of 8 possible dimerization models, suggested that the most likely ERAP1/ERAP2 heterodimerization topology involves the exon 10 loop, a non-conserved loop previously implicated in interactions between ERAP1 and the disulfide-bond shuffling chaperone ERp44. This dimerization topology allows access to the active site of both enzymes and is consistent with a previously reported construct in which ERAP1 and ERAP2 were linked by Fos/Jun zipper tags. The proposed model constitutes a tentative structural template to help understand the physiological role and significance of ERAP1/ERAP2 molecular interactions. |
format | Online Article Text |
id | pubmed-9065437 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-90654372022-05-04 Can ERAP1 and ERAP2 Form Functional Heterodimers? A Structural Dynamics Investigation Papakyriakou, Athanasios Mpakali, Anastasia Stratikos, Efstratios Front Immunol Immunology Endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and ERAP2) play important roles in the generation of antigenic peptides presented by Major Histocompatibility Class I (MHCI) molecules and indirectly regulate adaptive immune responses. Although the discrete function of these enzymes has been extensively characterized, recent reports have suggested that they can also form heterodimers with functional consequences. However, lack of structural characterization of a putative ERAP1/ERAP2 dimer has limited our understanding of its biological role and significance. To address this, we employed computational molecular dynamics calculations to explore the topology of interactions between these two, based on experimentally determined homo-dimerization interfaces observed in crystal structures of ERAP2 or homologous enzymes. Our analysis of 8 possible dimerization models, suggested that the most likely ERAP1/ERAP2 heterodimerization topology involves the exon 10 loop, a non-conserved loop previously implicated in interactions between ERAP1 and the disulfide-bond shuffling chaperone ERp44. This dimerization topology allows access to the active site of both enzymes and is consistent with a previously reported construct in which ERAP1 and ERAP2 were linked by Fos/Jun zipper tags. The proposed model constitutes a tentative structural template to help understand the physiological role and significance of ERAP1/ERAP2 molecular interactions. Frontiers Media S.A. 2022-04-20 /pmc/articles/PMC9065437/ /pubmed/35514997 http://dx.doi.org/10.3389/fimmu.2022.863529 Text en Copyright © 2022 Papakyriakou, Mpakali and Stratikos https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Papakyriakou, Athanasios Mpakali, Anastasia Stratikos, Efstratios Can ERAP1 and ERAP2 Form Functional Heterodimers? A Structural Dynamics Investigation |
title | Can ERAP1 and ERAP2 Form Functional Heterodimers? A Structural Dynamics Investigation |
title_full | Can ERAP1 and ERAP2 Form Functional Heterodimers? A Structural Dynamics Investigation |
title_fullStr | Can ERAP1 and ERAP2 Form Functional Heterodimers? A Structural Dynamics Investigation |
title_full_unstemmed | Can ERAP1 and ERAP2 Form Functional Heterodimers? A Structural Dynamics Investigation |
title_short | Can ERAP1 and ERAP2 Form Functional Heterodimers? A Structural Dynamics Investigation |
title_sort | can erap1 and erap2 form functional heterodimers? a structural dynamics investigation |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9065437/ https://www.ncbi.nlm.nih.gov/pubmed/35514997 http://dx.doi.org/10.3389/fimmu.2022.863529 |
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