ERAP1 enzyme-mediated trimming and structural analyses of MHC I–bound precursor peptides yield novel insights into antigen processing and presentation

Li, Lenong; Batliwala, Mansoor; Bouvier, Marlene

doi:10.1074/jbc.RA119.010102

Title: ERAP1 enzyme-mediated trimming and structural analyses of MHC I–bound precursor peptides yield novel insights into antigen processing and presentation

Journal Article · Thu Oct 10 00:00:00 EDT 2019 · Journal of Biological Chemistry

DOI:https://doi.org/10.1074/jbc.RA119.010102· OSTI ID:1591907

^[1]; Batliwala, Mansoor ^[1];

^[1]

Univ. of Illinois, Chicago, IL (United States)

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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Inst. of Health

Grant/Contract Number:: R01 AI114467; R01 AI108546

OSTI ID:: 1591907

Journal Information:: Journal of Biological Chemistry, Vol. 294, Issue 49; ISSN 0021-9258

Publisher:: American Society for Biochemistry and Molecular BiologyCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 19 works

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References (66)

ERAP1-ERAP2 dimers trim MHC I-bound precursor peptides; implications for understanding peptide editing Chen, Hanna; Li, Lenong; Weimershaus, Mirjana Scientific Reports, Vol. 6, Issue 1 https://doi.org/10.1038/srep28902	journal	August 2016
Overview of the CCP 4 suite and current developments Winn, Martyn D.; Ballard, Charles C.; Cowtan, Kevin D. Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S0907444910045749	journal	March 2011
Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition Phillips, Rodney E.; Rowland-Jones, Sarah; Nixon, Douglas F. Nature, Vol. 354, Issue 6353 https://doi.org/10.1038/354453a0	journal	December 1991
The C-terminal extension landscape of naturally presented HLA-I ligands Guillaume, Philippe; Picaud, Sarah; Baumgaertner, Petra Proceedings of the National Academy of Sciences, Vol. 115, Issue 20 https://doi.org/10.1073/pnas.1717277115	journal	April 2018
Analysis of interactions in a tapasin/class I complex provides a mechanism for peptide selection Chen, Mingnan; Bouvier, Marlene The EMBO Journal, Vol. 26, Issue 6 https://doi.org/10.1038/sj.emboj.7601624	journal	March 2007
Tapasin enhances MHC class I peptide presentation according to peptide half-life Howarth, M.; Williams, A.; Tolstrup, A. B. Proceedings of the National Academy of Sciences, Vol. 101, Issue 32 https://doi.org/10.1073/pnas.0306294101	journal	July 2004
Different length peptides bind to HLA-Aw68 similarly at their ends but bulge out in the middle Guo, Hwai-Chen; Jardetzky, Theodore S.; Garrettt, Thomas P. J. Nature, Vol. 360, Issue 6402 https://doi.org/10.1038/360364a0	journal	November 1992
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 Tynan, Fleur E.; Borg, Natalie A.; Miles, John J. Journal of Biological Chemistry, Vol. 280, Issue 25 https://doi.org/10.1074/jbc.M503060200	journal	April 2005
Balancing Selection Maintains a Form of ERAP2 that Undergoes Nonsense-Mediated Decay and Affects Antigen Presentation Andrés, Aida M.; Dennis, Megan Y.; Kretzschmar, Warren W. PLoS Genetics, Vol. 6, Issue 10 https://doi.org/10.1371/journal.pgen.1001157	journal	October 2010
Crystal structure of HLA-B*5801 with a TW10 HIV Gag epitope reveals a novel mode of peptide presentation Li, Xiaolong; Lamothe, Pedro A.; Walker, Bruce D. Cellular & Molecular Immunology, Vol. 14, Issue 7 https://doi.org/10.1038/cmi.2017.24	journal	May 2017
MHC-I peptides get out of the groove and enable a novel mechanism of HIV-1 escape Pymm, Phillip; Illing, Patricia T.; Ramarathinam, Sri H. Nature Structural & Molecular Biology, Vol. 24, Issue 4 https://doi.org/10.1038/nsmb.3381	journal	February 2017
HLA Peptide Length Preferences Control CD8 + T Cell Responses Rist, Melissa J.; Theodossis, Alex; Croft, Nathan P. The Journal of Immunology, Vol. 191, Issue 2 https://doi.org/10.4049/jimmunol.1300292	journal	June 2013
Analysis of Major Histocompatibility Complex-Bound HIV Peptides Identified from Various Cell Types Reveals Common Nested Peptides and Novel T Cell Responses Rucevic, Marijana; Kourjian, Georgio; Boucau, Julie Journal of Virology, Vol. 90, Issue 19 https://doi.org/10.1128/JVI.00599-16	journal	July 2016
MHC‐restricted Ag85B‐specific CD8 + T cells are enhanced by recombinant BCG prime and DNA boost immunization in mice Komine‐Aizawa, Shihoko; Jiang, Jiansheng; Mizuno, Satoru European Journal of Immunology, Vol. 49, Issue 9 https://doi.org/10.1002/eji.201847988	journal	June 2019
Mechanisms of Function of Tapasin, a Critical Major Histocompatibility Complex Class I Assembly Factor Rizvi, Syed Monem; Raghavan, Malini Traffic, Vol. 11, Issue 3 https://doi.org/10.1111/j.1600-0854.2009.01025.x	journal	March 2010
Naturally Processed Non-canonical HLA-A*02:01 Presented Peptides Hassan, Chopie; Chabrol, Eric; Jahn, Lorenz Journal of Biological Chemistry, Vol. 290, Issue 5 https://doi.org/10.1074/jbc.M114.607028	journal	December 2014
Three-dimensional structure of a peptide extending from one end of a class I MHC binding site Collins, Edward J.; Garboczi, David N.; Wiley, Don C. Nature, Vol. 371, Issue 6498 https://doi.org/10.1038/371626a0	journal	October 1994
Unconventional Peptide Presentation by Major Histocompatibility Complex (MHC) Class I Allele HLA-A*02:01: BREAKING CONFINEMENT Remesh, Soumya G.; Andreatta, Massimo; Ying, Ge Journal of Biological Chemistry, Vol. 292, Issue 13 https://doi.org/10.1074/jbc.M117.776542	journal	February 2017
Crystal structures of HLA-A*0201 complexed with antigenic peptides with either the amino- or carboxyl-terminal group substituted by a methyl group Bouvier, Marlène; Guo, Hwai-Chen; Smith, Kathrine J. Proteins: Structure, Function, and Genetics, Vol. 33, Issue 1 https://doi.org/10.1002/(SICI)1097-0134(19981001)33:1<97::AID-PROT9>3.0.CO;2-I	journal	October 1998
Structure of the human MHC-I peptide-loading complex Blees, Andreas; Januliene, Dovile; Hofmann, Tommy Nature, Vol. 551, Issue 7681 https://doi.org/10.1038/nature24627	journal	November 2017
XDS Kabsch, Wolfgang Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2 https://doi.org/10.1107/S0907444909047337	journal	January 2010
The impact of human leukocyte antigen (HLA) micropolymorphism on ligand specificity within the HLA-B*41 allotypic family Bade-Doding, C.; Theodossis, A.; Gras, S. Haematologica, Vol. 96, Issue 1 https://doi.org/10.3324/haematol.2010.030924	journal	October 2010
A Structural Basis for LCMV Immune Evasion Achour, Adnane; Michaëlsson, Jakob; Harris, Robert A. Immunity, Vol. 17, Issue 6 https://doi.org/10.1016/S1074-7613(02)00478-8	journal	December 2002
Conformational Flexibility of the MHC Class I α1-α2 Domain in Peptide Bound and Free States: A Molecular Dynamics Simulation Study Zacharias, Martin; Springer, Sebastian Biophysical Journal, Vol. 87, Issue 4 https://doi.org/10.1529/biophysj.104.044743	journal	October 2004
The first step of peptide selection in antigen presentation by MHC class I molecules Garstka, Malgorzata A.; Fish, Alexander; Celie, Patrick H. N. Proceedings of the National Academy of Sciences, Vol. 112, Issue 5 https://doi.org/10.1073/pnas.1416543112	journal	January 2015
Present Yourself! By MHC Class I and MHC Class II Molecules Rock, Kenneth L.; Reits, Eric; Neefjes, Jacques Trends in Immunology, Vol. 37, Issue 11 https://doi.org/10.1016/j.it.2016.08.010	journal	November 2016
ERAAP Synergizes with MHC Class I Molecules to Make the Final Cut in the Antigenic Peptide Precursors in the Endoplasmic Reticulum Kanaseki, Takayuki; Blanchard, Nicolas; Hammer, Gianna Elena Immunity, Vol. 25, Issue 5 https://doi.org/10.1016/j.immuni.2006.09.012	journal	November 2006
Large Scale Mass Spectrometric Profiling of Peptides Eluted from HLA Molecules Reveals N-Terminal-Extended Peptide Motifs Escobar, Hernando; Crockett, David K.; Reyes-Vargas, Eduardo The Journal of Immunology, Vol. 181, Issue 7 https://doi.org/10.4049/jimmunol.181.7.4874	journal	September 2008
Antigen processing influences HIV-specific cytotoxic T lymphocyte immunodominance Tenzer, Stefan; Wee, Edmund; Burgevin, Anne Nature Immunology, Vol. 10, Issue 6 https://doi.org/10.1038/ni.1728	journal	May 2009
Conformational Restraints and Flexibility of 14-Meric Peptides in Complex with HLA-B*3501 Probst-Kepper, Michael; Hecht, Hans-Jürgen; Herrmann, Hanne The Journal of Immunology, Vol. 173, Issue 9 https://doi.org/10.4049/jimmunol.173.9.5610	journal	October 2004
Two Polymorphisms Facilitate Differences in Plasticity between Two Chicken Major Histocompatibility Complex Class I Proteins Bailey, Alistair; van Hateren, Andy; Elliott, Tim PLoS ONE, Vol. 9, Issue 2 https://doi.org/10.1371/journal.pone.0089657	journal	February 2014
Concerted peptide trimming by human ERAP1 and ERAP2 aminopeptidase complexes in the endoplasmic reticulum Saveanu, Loredana; Carroll, Oliver; Lindo, Vivian Nature Immunology, Vol. 6, Issue 7 https://doi.org/10.1038/ni1208	journal	May 2005
The Length Distribution of Class I–Restricted T Cell Epitopes Is Determined by Both Peptide Supply and MHC Allele–Specific Binding Preference Trolle, Thomas; McMurtrey, Curtis P.; Sidney, John The Journal of Immunology, Vol. 196, Issue 4 https://doi.org/10.4049/jimmunol.1501721	journal	January 2016
HLA-A2-peptide complexes: refolding and crystallization of molecules expressed in Escherichia coli and complexed with single antigenic peptides. Garboczi, D. N.; Hung, D. T.; Wiley, D. C. Proceedings of the National Academy of Sciences, Vol. 89, Issue 8 https://doi.org/10.1073/pnas.89.8.3429	journal	April 1992
Structure of the TAPBPR–MHC I complex defines the mechanism of peptide loading and editing Thomas, Christoph; Tampé, Robert Science, Vol. 358, Issue 6366 https://doi.org/10.1126/science.aao6001	journal	October 2017
Crystal structure of a TAPBPR–MHC I complex reveals the mechanism of peptide editing in antigen presentation Jiang, Jiansheng; Natarajan, Kannan; Boyd, Lisa F. Science, Vol. 358, Issue 6366 https://doi.org/10.1126/science.aao5154	journal	October 2017
Structural basis for antigenic peptide precursor processing by the endoplasmic reticulum aminopeptidase ERAP1 Nguyen, Tina T.; Chang, Shih-Chung; Evnouchidou, Irini Nature Structural & Molecular Biology, Vol. 18, Issue 5 https://doi.org/10.1038/nsmb.2021	journal	April 2011
Coot model-building tools for molecular graphics Emsley, Paul; Cowtan, Kevin Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132 https://doi.org/10.1107/S0907444904019158	journal	November 2004
An Endogenous HIV Envelope-derived Peptide without the Terminal NH 3 + Group Anchor Is Physiologically Presented by Major Histocompatibility Complex Class I Molecules Samino, Yolanda; López, Daniel; Guil, Sara Journal of Biological Chemistry, Vol. 279, Issue 2 https://doi.org/10.1074/jbc.M305343200	journal	October 2003
Selective loading of high-affinity peptides onto major histocompatibility complex class I molecules by the tapasin-ERp57 heterodimer Wearsch, Pamela A.; Cresswell, Peter Nature Immunology, Vol. 8, Issue 8 https://doi.org/10.1038/ni1485	journal	July 2007
PHENIX: a comprehensive Python-based system for macromolecular structure solution Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 2, p. 213-221 https://doi.org/10.1107/S0907444909052925	journal	January 2010
Cellular peptide composition governed by major histocompatibility complex class I molecules Falk, Kirsten; Rötzschke, Olaf; Rammensee, Hans-Georg Nature, Vol. 348, Issue 6298 https://doi.org/10.1038/348248a0	journal	November 1990
The aminopeptidase ERAAP shapes the peptide repertoire displayed by major histocompatibility complex class I molecules Hammer, Gianna Elena; Gonzalez, Federico; Champsaur, Marine Nature Immunology, Vol. 7, Issue 1 https://doi.org/10.1038/ni1286	journal	November 2005
The Three-Dimensional Structure of Peptide-MHC Complexes Madden, Dean R. Annual Review of Immunology, Vol. 13, Issue 1 https://doi.org/10.1146/annurev.iy.13.040195.003103	journal	April 1995
Macromolecular TLS Refinement in REFMAC at Moderate Resolutions Winn, Martyn D.; Murshudov, Garib N.; Papiz, Miroslav Z. Methods in Enzymology https://doi.org/10.1016/S0076-6879(03)74014-2	book	January 2003
Antagonist HIV-1 Gag Peptides Induce Structural Changes in HLA B8 Reid, Scott W.; McAdam, Steve; Smith, Kathrine J. The Journal of Experimental Medicine, Vol. 184, Issue 6 https://doi.org/10.1084/jem.184.6.2279	journal	December 1996
Importance of peptide amino and carboxyl termini to the stability of MHC class I molecules Bouvier, M.; Wiley, D. Science, Vol. 265, Issue 5170 https://doi.org/10.1126/science.8023162	journal	July 1994
ERAAP and Tapasin Independently Edit the Amino and Carboxyl Termini of MHC Class I Peptides Kanaseki, Takayuki; Lind, Kristin Camfield; Escobar, Hernando The Journal of Immunology, Vol. 191, Issue 4 https://doi.org/10.4049/jimmunol.1301043	journal	July 2013
Naturally Occurring ERAP1 Haplotypes Encode Functionally Distinct Alleles with Fine Substrate Specificity Reeves, Emma; Edwards, Christopher J.; Elliott, Tim The Journal of Immunology, Vol. 191, Issue 1 https://doi.org/10.4049/jimmunol.1300598	journal	June 2013
Proofreading of Peptide—MHC Complexes through Dynamic Multivalent Interactions Thomas, Christoph; Tampé, Robert Frontiers in Immunology, Vol. 8 https://doi.org/10.3389/fimmu.2017.00065	journal	February 2017
NMRPipe: A multidimensional spectral processing system based on UNIX pipes Delaglio, Frank; Grzesiek, Stephan; Vuister, GeertenW. Journal of Biomolecular NMR, Vol. 6, Issue 3 https://doi.org/10.1007/BF00197809	journal	November 1995
The Energetic Basis Underpinning T-cell Receptor Recognition of a Super-bulged Peptide Bound to a Major Histocompatibility Complex Class I Molecule Liu, Yu Chih; Chen, Zhenjun; Burrows, Scott R. Journal of Biological Chemistry, Vol. 287, Issue 15 https://doi.org/10.1074/jbc.M112.344689	journal	February 2012
ERAP1–ERAP2 Dimerization Increases Peptide-Trimming Efficiency Evnouchidou, Irini; Weimershaus, Mirjana; Saveanu, Loredana The Journal of Immunology, Vol. 193, Issue 2 https://doi.org/10.4049/jimmunol.1302855	journal	June 2014
Peptide trimming by endoplasmic reticulum aminopeptidases: Role of MHC class I binding and ERAP dimerization Evnouchidou, Irini; van Endert, Peter Human Immunology, Vol. 80, Issue 5 https://doi.org/10.1016/j.humimm.2019.01.003	journal	May 2019
Have we cut ourselves too short in mapping CTL epitopes? Burrows, Scott R.; Rossjohn, Jamie; McCluskey, James Trends in Immunology, Vol. 27, Issue 1 https://doi.org/10.1016/j.it.2005.11.001	journal	January 2006
Direct Interrogation of Viral Peptides Presented by the Class I HLA of HIV-Infected T Cells Yaciuk, J. C.; Skaley, M.; Bardet, W. Journal of Virology, Vol. 88, Issue 22 https://doi.org/10.1128/JVI.01914-14	journal	August 2014
Human Leukocyte Antigen F Presents Peptides and Regulates Immunity through Interactions with NK Cell Receptors Dulberger, Charles L.; McMurtrey, Curtis P.; Hölzemer, Angelique Immunity, Vol. 46, Issue 6 https://doi.org/10.1016/j.immuni.2017.06.002	journal	June 2017
How ERAP1 and ERAP2 Shape the Peptidomes of Disease-Associated MHC-I Proteins López de Castro, José A. Frontiers in Immunology, Vol. 9 https://doi.org/10.3389/fimmu.2018.02463	journal	October 2018
Phaser crystallographic software McCoy, Airlie J.; Grosse-Kunstleve, Ralf W.; Adams, Paul D. Journal of Applied Crystallography, Vol. 40, Issue 4 https://doi.org/10.1107/S0021889807021206	journal	July 2007
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 Abualrous, Esam Tolba; Saini, Sunil Kumar; Ramnarayan, Venkat Raman PLOS ONE, Vol. 10, Issue 8 https://doi.org/10.1371/journal.pone.0135421	journal	August 2015
[20] Processing of X-ray diffraction data collected in oscillation mode Otwinowski, Zbyszek; Minor, Wladek Macromolecular Crystallography Part A, 307-326 https://doi.org/10.1016/S0076-6879(97)76066-X	book	January 1997
Cavin1 intrinsically disordered domains are essential for fuzzy electrostatic interactions and caveola formation Tillu, Vikas A.; Rae, James; Gao, Ya Nature Communications, Vol. 12, Issue 1 https://doi.org/10.1038/s41467-021-21035-4	journal	February 2021
Multi-functionality of a tryptophan residue conserved in substrate-binding groove of GH19 chitinases Nagata, Takuya; Shinya, Shoko; Ohnuma, Takayuki Scientific Reports, Vol. 11, Issue 1 https://doi.org/10.1038/s41598-021-81903-3	journal	January 2021
Overview of the CCP4 suite and current developments. Winn, Martyn D.; Ballard, Charles C.; Cowtan, Kevin D. Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.52322	text	January 2011
PHENIX: a comprehensive Python-based system for macromolecular structure solution. Adams, Paul D.; Afonine, Pavel V.; Bunkóczi, Gábor Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.45787	text	January 2010
Structural Basis For Antigenic Peptide Precursor Processing by the Endoplasmic Reticulum Aminopeptidase ERAP1 Nguyen, Tina T.; Chang, Shih‐Chung; Evnouchidou, Irini The FASEB Journal, Vol. 25, Issue S1 https://doi.org/10.1096/fasebj.25.1_supplement.lb72	journal	April 2011

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59 BASIC BIOLOGICAL SCIENCES
immunology
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major histocompatibility complex I (MHC I)
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Title: ERAP1 enzyme-mediated trimming and structural analyses of MHC I–bound precursor peptides yield novel insights into antigen processing and presentation

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