The ERAP1 active site cannot productively access the N-terminus of antigenic peptide precursors stably bound onto MHC class I

Abstract Processing of N-terminally elongated antigenic peptide precursors by Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) is a key step in antigen presentation and the adaptive immune response. Although ERAP1 can efficiently process long peptides in solution, it has been proposed that it can also...

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Autores principales:	George Mavridis, Anastasia Mpakali, Jerome Zoidakis, Manousos Makridakis, Antonia Vlahou, Eleni Kaloumenou, Angeliki Ziotopoulou, Dimitris Georgiadis, Athanasios Papakyriakou, Efstratios Stratikos
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/9bcf23927a2540dbb515f338c76f8451
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spelling	oai:doaj.org-article:9bcf23927a2540dbb515f338c76f84512021-12-02T18:50:57ZThe ERAP1 active site cannot productively access the N-terminus of antigenic peptide precursors stably bound onto MHC class I10.1038/s41598-021-95786-x2045-2322https://doaj.org/article/9bcf23927a2540dbb515f338c76f84512021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-95786-xhttps://doaj.org/toc/2045-2322Abstract Processing of N-terminally elongated antigenic peptide precursors by Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) is a key step in antigen presentation and the adaptive immune response. Although ERAP1 can efficiently process long peptides in solution, it has been proposed that it can also process peptides bound onto Major Histocompatibility Complex I molecules (MHCI). In a previous study, we suggested that the occasionally observed “ontο MHCI” trimming by ERAP1 is likely due to fast peptide dissociation followed by solution trimming, rather than direct action of ERAP1 onto the MHCI complex. However, other groups have proposed that ERAP1 can trim peptides covalently bound onto MHCI, which would preclude peptide dissociation. To explore this interaction, we constructed disulfide-linked MHCI-peptide complexes using HLA-B*08 and a 12mer kinetically labile peptide, or a 16mer carrying a phosphinic transition-state analogue N-terminus with high-affinity for ERAP1. Kinetic and biochemical analyses suggested that while both peptides could access the ERAP1 active site when free in solution, they were unable to do so when tethered in the MHCI binding groove. Our results suggest that MHCI binding protects, rather than promotes, antigenic peptide precursor trimming by ERAP1 and thus solution trimming is the more likely model of antigenic peptide processing.George MavridisAnastasia MpakaliJerome ZoidakisManousos MakridakisAntonia VlahouEleni KaloumenouAngeliki ZiotopoulouDimitris GeorgiadisAthanasios PapakyriakouEfstratios StratikosNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q George Mavridis Anastasia Mpakali Jerome Zoidakis Manousos Makridakis Antonia Vlahou Eleni Kaloumenou Angeliki Ziotopoulou Dimitris Georgiadis Athanasios Papakyriakou Efstratios Stratikos The ERAP1 active site cannot productively access the N-terminus of antigenic peptide precursors stably bound onto MHC class I
description	Abstract Processing of N-terminally elongated antigenic peptide precursors by Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) is a key step in antigen presentation and the adaptive immune response. Although ERAP1 can efficiently process long peptides in solution, it has been proposed that it can also process peptides bound onto Major Histocompatibility Complex I molecules (MHCI). In a previous study, we suggested that the occasionally observed “ontο MHCI” trimming by ERAP1 is likely due to fast peptide dissociation followed by solution trimming, rather than direct action of ERAP1 onto the MHCI complex. However, other groups have proposed that ERAP1 can trim peptides covalently bound onto MHCI, which would preclude peptide dissociation. To explore this interaction, we constructed disulfide-linked MHCI-peptide complexes using HLA-B*08 and a 12mer kinetically labile peptide, or a 16mer carrying a phosphinic transition-state analogue N-terminus with high-affinity for ERAP1. Kinetic and biochemical analyses suggested that while both peptides could access the ERAP1 active site when free in solution, they were unable to do so when tethered in the MHCI binding groove. Our results suggest that MHCI binding protects, rather than promotes, antigenic peptide precursor trimming by ERAP1 and thus solution trimming is the more likely model of antigenic peptide processing.
format	article
author	George Mavridis Anastasia Mpakali Jerome Zoidakis Manousos Makridakis Antonia Vlahou Eleni Kaloumenou Angeliki Ziotopoulou Dimitris Georgiadis Athanasios Papakyriakou Efstratios Stratikos
author_facet	George Mavridis Anastasia Mpakali Jerome Zoidakis Manousos Makridakis Antonia Vlahou Eleni Kaloumenou Angeliki Ziotopoulou Dimitris Georgiadis Athanasios Papakyriakou Efstratios Stratikos
author_sort	George Mavridis
title	The ERAP1 active site cannot productively access the N-terminus of antigenic peptide precursors stably bound onto MHC class I
title_short	The ERAP1 active site cannot productively access the N-terminus of antigenic peptide precursors stably bound onto MHC class I
title_full	The ERAP1 active site cannot productively access the N-terminus of antigenic peptide precursors stably bound onto MHC class I
title_fullStr	The ERAP1 active site cannot productively access the N-terminus of antigenic peptide precursors stably bound onto MHC class I
title_full_unstemmed	The ERAP1 active site cannot productively access the N-terminus of antigenic peptide precursors stably bound onto MHC class I
title_sort	erap1 active site cannot productively access the n-terminus of antigenic peptide precursors stably bound onto mhc class i
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/9bcf23927a2540dbb515f338c76f8451
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The ERAP1 active site cannot productively access the N-terminus of antigenic peptide precursors stably bound onto MHC class I

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