PMID- 31601650
OWN - NLM
STAT- MEDLINE
DCOM- 20200615
LR  - 20230106
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 294
IP  - 49
DP  - 2019 Dec 6
TI  - ERAP1 enzyme-mediated trimming and structural analyses of MHC I-bound precursor 
      peptides yield novel insights into antigen processing and presentation.
PG  - 18534-18544
LID - S0021-9258(20)30408-7 [pii]
LID - 10.1074/jbc.RA119.010102 [doi]
AB  - 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) (n) 
      AAKKKYCL 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 A 
      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.
CI  - (c) 2019 Li et al.
FAU - Li, Lenong
AU  - Li L
AD  - Department of Microbiology and Immunology, University of Illinois, Chicago, 
      Illinois 60612.
FAU - Batliwala, Mansoor
AU  - Batliwala M
AD  - Department of Microbiology and Immunology, University of Illinois, Chicago, 
      Illinois 60612.
FAU - Bouvier, Marlene
AU  - Bouvier M
AD  - Department of Microbiology and Immunology, University of Illinois, Chicago, 
      Illinois 60612. Electronic address: mbouvier@uic.edu.
LA  - eng
SI  - PDB/1AGD
SI  - PDB/1AGB
SI  - PDB/6P2S
SI  - PDB/6P23
SI  - PDB/6P27
SI  - PDB/6P2C
SI  - PDB/6P2F
GR  - R01 AI045070/AI/NIAID NIH HHS/United States
GR  - R01 AI108546/AI/NIAID NIH HHS/United States
GR  - R01 AI114467/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20191010
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (HLA-B*08:01 antigen)
RN  - 0 (HLA-B8 Antigen)
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (Minor Histocompatibility Antigens)
RN  - EC 3.4.11.- (Aminopeptidases)
RN  - EC 3.4.11.- (ERAP1 protein, human)
RN  - EC 3.4.11.- (ERAP2 protein, human)
SB  - IM
MH  - Adaptive Immunity/physiology
MH  - Amino Acid Sequence
MH  - Aminopeptidases/chemistry/*metabolism
MH  - Antigen Presentation/physiology
MH  - CD8-Positive T-Lymphocytes/metabolism
MH  - Crystallography, X-Ray
MH  - HLA-B8 Antigen/metabolism
MH  - Histocompatibility Antigens Class I/chemistry/*metabolism
MH  - Humans
MH  - Minor Histocompatibility Antigens/chemistry/*metabolism
MH  - Protein Binding
MH  - X-Ray Diffraction
PMC - PMC6901306
OTO - NOTNLM
OT  - CD8+ T cells
OT  - HLA-B*0801
OT  - adaptive immunity
OT  - antigen presentation
OT  - antigen processing
OT  - endoplasmic reticulum (ER)
OT  - endoplasmic reticulum aminopeptidase (ERAP)
OT  - immunology
OT  - immunopeptidome
OT  - major histocompatibility complex I (MHC I)
OT  - structural biology
COIS- The authors declare that they have no conflicts of interest with the contents of 
      this article
EDAT- 2019/10/12 06:00
MHDA- 2020/06/17 06:00
PMCR- 2019/10/10
CRDT- 2019/10/12 06:00
PHST- 2019/07/08 00:00 [received]
PHST- 2019/09/20 00:00 [revised]
PHST- 2019/10/12 06:00 [pubmed]
PHST- 2020/06/17 06:00 [medline]
PHST- 2019/10/12 06:00 [entrez]
PHST- 2019/10/10 00:00 [pmc-release]
AID - S0021-9258(20)30408-7 [pii]
AID - RA119.010102 [pii]
AID - 10.1074/jbc.RA119.010102 [doi]
PST - ppublish
SO  - J Biol Chem. 2019 Dec 6;294(49):18534-18544. doi: 10.1074/jbc.RA119.010102. Epub 
      2019 Oct 10.