ERAP1 (endoplasmic reticulum aminopeptidase 1), ERAP2 and IRAP (insulin-regulated aminopeptidase) are three homologous enzymes that play critical roles in the generation of antigenic peptides. These aminopeptidases excise amino acids from N-terminally extended precursors of antigenic peptides in order to generate the correct length epitopes for binding on to MHC class I molecules. The specificity of these peptidases can affect antigenic peptide selection, but has not yet been investigated in detail. In the present study we utilized a collection of 82 fluorigenic substrates to define a detailed selectivity profile for each of the three enzymes and to probe structural and functional features of the S1 (primary specificity) pocket. Molecular modelling of the three S1 pockets reveals substrate–enzyme interactions that are critical determinants for specificity. The substrate selectivity profiles suggest that IRAP largely combines the S1 specificity of ERAP1 and ERAP2, consistent with its proposed biological function. IRAP, however, does not achieve this dual specificity by simply combining structural features of ERAP1 and ERAP2, but rather by an unique amino acid change at position 541. The results of the present study provide insights on antigenic peptide selection and may prove valuable in designing selective inhibitors or activity markers for this class of enzymes.
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Research Article|
March 29 2011
Probing the S1 specificity pocket of the aminopeptidases that generate antigenic peptides
Efthalia Zervoudi;
Efthalia Zervoudi
1
*Protein Chemistry Laboratory, IRRP, National Centre for Scientific Research Demokritos, Agia Paraskevi, Athens 15310, Greece
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Athanasios Papakyriakou;
Athanasios Papakyriakou
1
†Chemical Biology Laboratory, Institute of Physical Chemistry, National Centre for Scientific Research Demokritos, Agia Paraskevi, Athens 15310, Greece
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Dimitra Georgiadou;
Dimitra Georgiadou
*Protein Chemistry Laboratory, IRRP, National Centre for Scientific Research Demokritos, Agia Paraskevi, Athens 15310, Greece
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Irini Evnouchidou;
Irini Evnouchidou
*Protein Chemistry Laboratory, IRRP, National Centre for Scientific Research Demokritos, Agia Paraskevi, Athens 15310, Greece
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Anna Gajda;
Anna Gajda
‡Division of Medicinal Chemistry and Microbiology, Wroclaw University of Technology, 50-370 Wroclaw, Poland
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Marcin Poreba;
Marcin Poreba
‡Division of Medicinal Chemistry and Microbiology, Wroclaw University of Technology, 50-370 Wroclaw, Poland
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Guy S. Salvesen;
Guy S. Salvesen
§Program in Apoptosis and Cell Death Research, Sanford-Burnham Medical Research Institute,10901 North Torrey Pines Road, La Jolla, CA 92037, U.S.A.
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Marcin Drag;
Marcin Drag
‡Division of Medicinal Chemistry and Microbiology, Wroclaw University of Technology, 50-370 Wroclaw, Poland
§Program in Apoptosis and Cell Death Research, Sanford-Burnham Medical Research Institute,10901 North Torrey Pines Road, La Jolla, CA 92037, U.S.A.
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Akira Hattori;
Akira Hattori
∥Graduate School of Pharmaceutical Sciences, Kyoto University, Department of System Chemotherapy and Molecular Sciences, Sakyo, Kyoto 606-8501, Japan
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Luc Swevers;
Luc Swevers
¶Insect Molecular Genetics and Biotechnology Group, Institute of Biology, National Centre for Scientific Research Demokritos, Agia Paraskevi, Athens 15310, Greece
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Dionisios Vourloumis;
Dionisios Vourloumis
†Chemical Biology Laboratory, Institute of Physical Chemistry, National Centre for Scientific Research Demokritos, Agia Paraskevi, Athens 15310, Greece
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Efstratios Stratikos
Efstratios Stratikos
2
*Protein Chemistry Laboratory, IRRP, National Centre for Scientific Research Demokritos, Agia Paraskevi, Athens 15310, Greece
2To whom correspondence should be addressed (email stratos@rrp.demokritos.gr or stratikos@gmail.com).
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Publisher: Portland Press Ltd
Received:
December 13 2010
Revision Received:
February 07 2011
Accepted:
February 11 2011
Accepted Manuscript online:
February 11 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem J (2011) 435 (2): 411–420.
Article history
Received:
December 13 2010
Revision Received:
February 07 2011
Accepted:
February 11 2011
Accepted Manuscript online:
February 11 2011
Citation
Efthalia Zervoudi, Athanasios Papakyriakou, Dimitra Georgiadou, Irini Evnouchidou, Anna Gajda, Marcin Poreba, Guy S. Salvesen, Marcin Drag, Akira Hattori, Luc Swevers, Dionisios Vourloumis, Efstratios Stratikos; Probing the S1 specificity pocket of the aminopeptidases that generate antigenic peptides. Biochem J 15 April 2011; 435 (2): 411–420. doi: https://doi.org/10.1042/BJ20102049
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