ERAP1 enzyme-mediated trimming and structural analyses of MHC I–bound precursor peptides yield novel insights into antigen processing and presentation
Abstract
Endoplasmic reticulum aminopeptidase 1 (ERAP1) and ERAP2 critically shape the major histocompatibility complex I (MHC I) immunopeptidome. The ERAPs remove N-terminal residues from antigenic precursor peptides and generate optimal-length peptides (i.e. 8–10-mers) to fit into the MHC class I groove. It is therefore intriguing that MHC class I molecules can present N-terminally extended peptides on the cell surface that can elicit CD8+ T-cell responses. This observation likely reflects gaps in our understanding of how antigens are processed by the ERAP enzymes. To better understand ERAPs' function in antigen processing, here we generated a nested set of N-terminally extended 10–20-mer peptides (RA)nAAKKKYCL covalently bound to the human leukocyte antigen (HLA)-B*0801. We used X-ray crystallography, thermostability assessments, and an ERAP1-trimming assay to characterize these complexes. The X-ray structures determined at 1.40–1.65 Å resolutions revealed that the residue extensions (RA)n unexpectedly protrude out of the A pocket of HLA-B*0801, whereas the AAKKKYCL core of all peptides adopts similar, bound conformations. HLA-B*0801 residue 62 was critical to open the A pocket. We also show that HLA-B*0801 and antigenic precursor peptides form stable complexes. Finally, ERAP1-mediated trimming of the MHC I–bound peptides required a minimal length of 14 amino acids. We propose a mechanistic modelmore »
- Authors:
-
- Univ. of Illinois, Chicago, IL (United States)
- Publication Date:
- Research Org.:
- Argonne National Lab. (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- National Inst. of Health
- OSTI Identifier:
- 1591907
- Grant/Contract Number:
- R01 AI114467; R01 AI108546
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Journal of Biological Chemistry
- Additional Journal Information:
- Journal Volume: 294; Journal Issue: 49; Journal ID: ISSN 0021-9258
- Publisher:
- American Society for Biochemistry and Molecular Biology
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; immunology; antigen presentation; antigen processing; structural biology; endoplasmic reticulum (ER); CD8+ T cells; endoplasmic reticulum aminopeptidase (ERAP); immunopeptidome; major histocompatibility complex I (MHC I); adaptive immunity; HLA-B*0801
Citation Formats
Li, Lenong, Batliwala, Mansoor, and Bouvier, Marlene. ERAP1 enzyme-mediated trimming and structural analyses of MHC I–bound precursor peptides yield novel insights into antigen processing and presentation. United States: N. p., 2019.
Web. doi:10.1074/jbc.RA119.010102.
Li, Lenong, Batliwala, Mansoor, & Bouvier, Marlene. ERAP1 enzyme-mediated trimming and structural analyses of MHC I–bound precursor peptides yield novel insights into antigen processing and presentation. United States. https://doi.org/10.1074/jbc.RA119.010102
Li, Lenong, Batliwala, Mansoor, and Bouvier, Marlene. Thu .
"ERAP1 enzyme-mediated trimming and structural analyses of MHC I–bound precursor peptides yield novel insights into antigen processing and presentation". United States. https://doi.org/10.1074/jbc.RA119.010102. https://www.osti.gov/servlets/purl/1591907.
@article{osti_1591907,
title = {ERAP1 enzyme-mediated trimming and structural analyses of MHC I–bound precursor peptides yield novel insights into antigen processing and presentation},
author = {Li, Lenong and Batliwala, Mansoor and Bouvier, Marlene},
abstractNote = {Endoplasmic reticulum aminopeptidase 1 (ERAP1) and ERAP2 critically shape the major histocompatibility complex I (MHC I) immunopeptidome. The ERAPs remove N-terminal residues from antigenic precursor peptides and generate optimal-length peptides (i.e. 8–10-mers) to fit into the MHC class I groove. It is therefore intriguing that MHC class I molecules can present N-terminally extended peptides on the cell surface that can elicit CD8+ T-cell responses. This observation likely reflects gaps in our understanding of how antigens are processed by the ERAP enzymes. To better understand ERAPs' function in antigen processing, here we generated a nested set of N-terminally extended 10–20-mer peptides (RA)nAAKKKYCL covalently bound to the human leukocyte antigen (HLA)-B*0801. We used X-ray crystallography, thermostability assessments, and an ERAP1-trimming assay to characterize these complexes. The X-ray structures determined at 1.40–1.65 Å resolutions revealed that the residue extensions (RA)n unexpectedly protrude out of the A pocket of HLA-B*0801, whereas the AAKKKYCL core of all peptides adopts similar, bound conformations. HLA-B*0801 residue 62 was critical to open the A pocket. We also show that HLA-B*0801 and antigenic precursor peptides form stable complexes. Finally, ERAP1-mediated trimming of the MHC I–bound peptides required a minimal length of 14 amino acids. We propose a mechanistic model explaining how ERAP1-mediated trimming of MHC I–bound peptides in cells can generate peptides of canonical as well as noncanonical lengths that still serve as stable MHC I ligands. Our results provide a framework to better understand how the ERAP enzymes influence the MHC I immunopeptidome.},
doi = {10.1074/jbc.RA119.010102},
journal = {Journal of Biological Chemistry},
number = 49,
volume = 294,
place = {United States},
year = {2019},
month = {10}
}
Web of Science
Works referenced in this record:
ERAP1-ERAP2 dimers trim MHC I-bound precursor peptides; implications for understanding peptide editing
journal, August 2016
- Chen, Hanna; Li, Lenong; Weimershaus, Mirjana
- Scientific Reports, Vol. 6, Issue 1
Overview of the CCP 4 suite and current developments
journal, March 2011
- Winn, Martyn D.; Ballard, Charles C.; Cowtan, Kevin D.
- Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4
Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition
journal, December 1991
- Phillips, Rodney E.; Rowland-Jones, Sarah; Nixon, Douglas F.
- Nature, Vol. 354, Issue 6353
The C-terminal extension landscape of naturally presented HLA-I ligands
journal, April 2018
- Guillaume, Philippe; Picaud, Sarah; Baumgaertner, Petra
- Proceedings of the National Academy of Sciences, Vol. 115, Issue 20
Analysis of interactions in a tapasin/class I complex provides a mechanism for peptide selection
journal, March 2007
- Chen, Mingnan; Bouvier, Marlene
- The EMBO Journal, Vol. 26, Issue 6
Tapasin enhances MHC class I peptide presentation according to peptide half-life
journal, July 2004
- Howarth, M.; Williams, A.; Tolstrup, A. B.
- Proceedings of the National Academy of Sciences, Vol. 101, Issue 32
Different length peptides bind to HLA-Aw68 similarly at their ends but bulge out in the middle
journal, November 1992
- Guo, Hwai-Chen; Jardetzky, Theodore S.; Garrettt, Thomas P. J.
- Nature, Vol. 360, Issue 6402
High Resolution Structures of Highly Bulged Viral Epitopes Bound to Major Histocompatibility Complex Class I: IMPLICATIONS FOR T-CELL RECEPTOR ENGAGEMENT AND T-CELL IMMUNODOMINANCE
journal, April 2005
- Tynan, Fleur E.; Borg, Natalie A.; Miles, John J.
- Journal of Biological Chemistry, Vol. 280, Issue 25
Balancing Selection Maintains a Form of ERAP2 that Undergoes Nonsense-Mediated Decay and Affects Antigen Presentation
journal, October 2010
- Andrés, Aida M.; Dennis, Megan Y.; Kretzschmar, Warren W.
- PLoS Genetics, Vol. 6, Issue 10
Crystal structure of HLA-B*5801 with a TW10 HIV Gag epitope reveals a novel mode of peptide presentation
journal, May 2017
- Li, Xiaolong; Lamothe, Pedro A.; Walker, Bruce D.
- Cellular & Molecular Immunology, Vol. 14, Issue 7
MHC-I peptides get out of the groove and enable a novel mechanism of HIV-1 escape
journal, February 2017
- Pymm, Phillip; Illing, Patricia T.; Ramarathinam, Sri H.
- Nature Structural & Molecular Biology, Vol. 24, Issue 4
HLA Peptide Length Preferences Control CD8 + T Cell Responses
journal, June 2013
- Rist, Melissa J.; Theodossis, Alex; Croft, Nathan P.
- The Journal of Immunology, Vol. 191, Issue 2
Analysis of Major Histocompatibility Complex-Bound HIV Peptides Identified from Various Cell Types Reveals Common Nested Peptides and Novel T Cell Responses
journal, July 2016
- Rucevic, Marijana; Kourjian, Georgio; Boucau, Julie
- Journal of Virology, Vol. 90, Issue 19
MHC‐restricted Ag85B‐specific CD8 + T cells are enhanced by recombinant BCG prime and DNA boost immunization in mice
journal, June 2019
- Komine‐Aizawa, Shihoko; Jiang, Jiansheng; Mizuno, Satoru
- European Journal of Immunology, Vol. 49, Issue 9
Mechanisms of Function of Tapasin, a Critical Major Histocompatibility Complex Class I Assembly Factor
journal, March 2010
- Rizvi, Syed Monem; Raghavan, Malini
- Traffic, Vol. 11, Issue 3
Naturally Processed Non-canonical HLA-A*02:01 Presented Peptides
journal, December 2014
- Hassan, Chopie; Chabrol, Eric; Jahn, Lorenz
- Journal of Biological Chemistry, Vol. 290, Issue 5
Three-dimensional structure of a peptide extending from one end of a class I MHC binding site
journal, October 1994
- Collins, Edward J.; Garboczi, David N.; Wiley, Don C.
- Nature, Vol. 371, Issue 6498
Unconventional Peptide Presentation by Major Histocompatibility Complex (MHC) Class I Allele HLA-A*02:01: BREAKING CONFINEMENT
journal, February 2017
- Remesh, Soumya G.; Andreatta, Massimo; Ying, Ge
- Journal of Biological Chemistry, Vol. 292, Issue 13
Crystal structures of HLA-A*0201 complexed with antigenic peptides with either the amino- or carboxyl-terminal group substituted by a methyl group
journal, October 1998
- Bouvier, Marlène; Guo, Hwai-Chen; Smith, Kathrine J.
- Proteins: Structure, Function, and Genetics, Vol. 33, Issue 1
Structure of the human MHC-I peptide-loading complex
journal, November 2017
- Blees, Andreas; Januliene, Dovile; Hofmann, Tommy
- Nature, Vol. 551, Issue 7681
XDS
journal, January 2010
- Kabsch, Wolfgang
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2
The impact of human leukocyte antigen (HLA) micropolymorphism on ligand specificity within the HLA-B*41 allotypic family
journal, October 2010
- Bade-Doding, C.; Theodossis, A.; Gras, S.
- Haematologica, Vol. 96, Issue 1
A Structural Basis for LCMV Immune Evasion
journal, December 2002
- Achour, Adnane; Michaëlsson, Jakob; Harris, Robert A.
- Immunity, Vol. 17, Issue 6
Conformational Flexibility of the MHC Class I α1-α2 Domain in Peptide Bound and Free States: A Molecular Dynamics Simulation Study
journal, October 2004
- Zacharias, Martin; Springer, Sebastian
- Biophysical Journal, Vol. 87, Issue 4
The first step of peptide selection in antigen presentation by MHC class I molecules
journal, January 2015
- Garstka, Malgorzata A.; Fish, Alexander; Celie, Patrick H. N.
- Proceedings of the National Academy of Sciences, Vol. 112, Issue 5
Present Yourself! By MHC Class I and MHC Class II Molecules
journal, November 2016
- Rock, Kenneth L.; Reits, Eric; Neefjes, Jacques
- Trends in Immunology, Vol. 37, Issue 11
ERAAP Synergizes with MHC Class I Molecules to Make the Final Cut in the Antigenic Peptide Precursors in the Endoplasmic Reticulum
journal, November 2006
- Kanaseki, Takayuki; Blanchard, Nicolas; Hammer, Gianna Elena
- Immunity, Vol. 25, Issue 5
Large Scale Mass Spectrometric Profiling of Peptides Eluted from HLA Molecules Reveals N-Terminal-Extended Peptide Motifs
journal, September 2008
- Escobar, Hernando; Crockett, David K.; Reyes-Vargas, Eduardo
- The Journal of Immunology, Vol. 181, Issue 7
Antigen processing influences HIV-specific cytotoxic T lymphocyte immunodominance
journal, May 2009
- Tenzer, Stefan; Wee, Edmund; Burgevin, Anne
- Nature Immunology, Vol. 10, Issue 6
Conformational Restraints and Flexibility of 14-Meric Peptides in Complex with HLA-B*3501
journal, October 2004
- Probst-Kepper, Michael; Hecht, Hans-Jürgen; Herrmann, Hanne
- The Journal of Immunology, Vol. 173, Issue 9
Two Polymorphisms Facilitate Differences in Plasticity between Two Chicken Major Histocompatibility Complex Class I Proteins
journal, February 2014
- Bailey, Alistair; van Hateren, Andy; Elliott, Tim
- PLoS ONE, Vol. 9, Issue 2
Concerted peptide trimming by human ERAP1 and ERAP2 aminopeptidase complexes in the endoplasmic reticulum
journal, May 2005
- Saveanu, Loredana; Carroll, Oliver; Lindo, Vivian
- Nature Immunology, Vol. 6, Issue 7
The Length Distribution of Class I–Restricted T Cell Epitopes Is Determined by Both Peptide Supply and MHC Allele–Specific Binding Preference
journal, January 2016
- Trolle, Thomas; McMurtrey, Curtis P.; Sidney, John
- The Journal of Immunology, Vol. 196, Issue 4
HLA-A2-peptide complexes: refolding and crystallization of molecules expressed in Escherichia coli and complexed with single antigenic peptides.
journal, April 1992
- Garboczi, D. N.; Hung, D. T.; Wiley, D. C.
- Proceedings of the National Academy of Sciences, Vol. 89, Issue 8
Structure of the TAPBPR–MHC I complex defines the mechanism of peptide loading and editing
journal, October 2017
- Thomas, Christoph; Tampé, Robert
- Science, Vol. 358, Issue 6366
Crystal structure of a TAPBPR–MHC I complex reveals the mechanism of peptide editing in antigen presentation
journal, October 2017
- Jiang, Jiansheng; Natarajan, Kannan; Boyd, Lisa F.
- Science, Vol. 358, Issue 6366
Structural basis for antigenic peptide precursor processing by the endoplasmic reticulum aminopeptidase ERAP1
journal, April 2011
- Nguyen, Tina T.; Chang, Shih-Chung; Evnouchidou, Irini
- Nature Structural & Molecular Biology, Vol. 18, Issue 5
Coot model-building tools for molecular graphics
journal, November 2004
- Emsley, Paul; Cowtan, Kevin
- Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132
An Endogenous HIV Envelope-derived Peptide without the Terminal NH 3 + Group Anchor Is Physiologically Presented by Major Histocompatibility Complex Class I Molecules
journal, October 2003
- Samino, Yolanda; López, Daniel; Guil, Sara
- Journal of Biological Chemistry, Vol. 279, Issue 2
Selective loading of high-affinity peptides onto major histocompatibility complex class I molecules by the tapasin-ERp57 heterodimer
journal, July 2007
- Wearsch, Pamela A.; Cresswell, Peter
- Nature Immunology, Vol. 8, Issue 8
PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010
- Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
- Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221
Cellular peptide composition governed by major histocompatibility complex class I molecules
journal, November 1990
- Falk, Kirsten; Rötzschke, Olaf; Rammensee, Hans-Georg
- Nature, Vol. 348, Issue 6298
The aminopeptidase ERAAP shapes the peptide repertoire displayed by major histocompatibility complex class I molecules
journal, November 2005
- Hammer, Gianna Elena; Gonzalez, Federico; Champsaur, Marine
- Nature Immunology, Vol. 7, Issue 1
The Three-Dimensional Structure of Peptide-MHC Complexes
journal, April 1995
- Madden, Dean R.
- Annual Review of Immunology, Vol. 13, Issue 1
Antagonist HIV-1 Gag Peptides Induce Structural Changes in HLA B8
journal, December 1996
- Reid, Scott W.; McAdam, Steve; Smith, Kathrine J.
- The Journal of Experimental Medicine, Vol. 184, Issue 6
Importance of peptide amino and carboxyl termini to the stability of MHC class I molecules
journal, July 1994
- Bouvier, M.; Wiley, D.
- Science, Vol. 265, Issue 5170
ERAAP and Tapasin Independently Edit the Amino and Carboxyl Termini of MHC Class I Peptides
journal, July 2013
- Kanaseki, Takayuki; Lind, Kristin Camfield; Escobar, Hernando
- The Journal of Immunology, Vol. 191, Issue 4
The partial dissociation of MHC class I–bound peptides exposes their N terminus to trimming by endoplasmic reticulum aminopeptidase 1
journal, March 2018
- Papakyriakou, Athanasios; Reeves, Emma; Beton, Mary
- Journal of Biological Chemistry, Vol. 293, Issue 20
Naturally Occurring ERAP1 Haplotypes Encode Functionally Distinct Alleles with Fine Substrate Specificity
journal, June 2013
- Reeves, Emma; Edwards, Christopher J.; Elliott, Tim
- The Journal of Immunology, Vol. 191, Issue 1
Proofreading of Peptide—MHC Complexes through Dynamic Multivalent Interactions
journal, February 2017
- Thomas, Christoph; Tampé, Robert
- Frontiers in Immunology, Vol. 8
NMRPipe: A multidimensional spectral processing system based on UNIX pipes
journal, November 1995
- Delaglio, Frank; Grzesiek, Stephan; Vuister, GeertenW.
- Journal of Biomolecular NMR, Vol. 6, Issue 3
Toxoplasma gondii peptide ligands open the gate of the HLA class I binding groove
journal, January 2016
- McMurtrey, Curtis; Trolle, Thomas; Sansom, Tiffany
- eLife, Vol. 5
The Energetic Basis Underpinning T-cell Receptor Recognition of a Super-bulged Peptide Bound to a Major Histocompatibility Complex Class I Molecule
journal, February 2012
- Liu, Yu Chih; Chen, Zhenjun; Burrows, Scott R.
- Journal of Biological Chemistry, Vol. 287, Issue 15
ERAP1–ERAP2 Dimerization Increases Peptide-Trimming Efficiency
journal, June 2014
- Evnouchidou, Irini; Weimershaus, Mirjana; Saveanu, Loredana
- The Journal of Immunology, Vol. 193, Issue 2
Peptide trimming by endoplasmic reticulum aminopeptidases: Role of MHC class I binding and ERAP dimerization
journal, May 2019
- Evnouchidou, Irini; van Endert, Peter
- Human Immunology, Vol. 80, Issue 5
Have we cut ourselves too short in mapping CTL epitopes?
journal, January 2006
- Burrows, Scott R.; Rossjohn, Jamie; McCluskey, James
- Trends in Immunology, Vol. 27, Issue 1
Direct Interrogation of Viral Peptides Presented by the Class I HLA of HIV-Infected T Cells
journal, August 2014
- Yaciuk, J. C.; Skaley, M.; Bardet, W.
- Journal of Virology, Vol. 88, Issue 22
Human Leukocyte Antigen F Presents Peptides and Regulates Immunity through Interactions with NK Cell Receptors
journal, June 2017
- Dulberger, Charles L.; McMurtrey, Curtis P.; Hölzemer, Angelique
- Immunity, Vol. 46, Issue 6
How ERAP1 and ERAP2 Shape the Peptidomes of Disease-Associated MHC-I Proteins
journal, October 2018
- López de Castro, José A.
- Frontiers in Immunology, Vol. 9
Phaser crystallographic software
journal, July 2007
- McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D.
- Journal of Applied Crystallography, Vol. 40, Issue 4
The Carboxy Terminus of the Ligand Peptide Determines the Stability of the MHC Class I Molecule H-2Kb: A Combined Molecular Dynamics and Experimental Study
journal, August 2015
- Abualrous, Esam Tolba; Saini, Sunil Kumar; Ramnarayan, Venkat Raman
- PLOS ONE, Vol. 10, Issue 8
[20] Processing of X-ray diffraction data collected in oscillation mode
book, January 1997
- Otwinowski, Zbyszek; Minor, Wladek
- Macromolecular Crystallography Part A, 307-326
Cavin1 intrinsically disordered domains are essential for fuzzy electrostatic interactions and caveola formation
journal, February 2021
- Tillu, Vikas A.; Rae, James; Gao, Ya
- Nature Communications, Vol. 12, Issue 1
Multi-functionality of a tryptophan residue conserved in substrate-binding groove of GH19 chitinases
journal, January 2021
- Nagata, Takuya; Shinya, Shoko; Ohnuma, Takayuki
- Scientific Reports, Vol. 11, Issue 1
Overview of the CCP4 suite and current developments.
text, January 2011
- Winn, Martyn D.; Ballard, Charles C.; Cowtan, Kevin D.
- Apollo - University of Cambridge Repository
PHENIX: a comprehensive Python-based system for macromolecular structure solution.
text, January 2010
- Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor
- Apollo - University of Cambridge Repository
Structural Basis For Antigenic Peptide Precursor Processing by the Endoplasmic Reticulum Aminopeptidase ERAP1
journal, April 2011
- Nguyen, Tina T.; Chang, Shih‐Chung; Evnouchidou, Irini
- The FASEB Journal, Vol. 25, Issue S1
Works referencing / citing this record:
Cutting antigenic peptides down to size
journal, December 2019
- Natarajan, Kannan; Margulies, David H.
- Journal of Biological Chemistry, Vol. 294, Issue 49