6P2S

Structure of a nested set of N-terminally extended MHC I-peptides provide novel insights into antigen processing and presentation

Summary for 6P2S

• Entry DOI: 10.2210/pdb6p2s/pdb
• Descriptor: MHC class I antigen, Beta-2-microglobulin, MHC I-peptide, ... (4 entities in total)
• Functional Keywords: mhc i antigen processing, mhc i antigen presentation, mhc i structure, mhc i immunopeptide, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 45021.92

Authors

Li, L.,Batliwala, M.,Bouvier, M. (deposition date: 2019-05-22, release date: 2019-10-16, Last modification date: 2024-10-16)

Primary citation

Li, L.,Batliwala, M.,Bouvier, M.
ERAP1 enzyme-mediated trimming and structural analyses of MHC I-bound precursor peptides yield novel insights into antigen processing and presentation.
J.Biol.Chem., 294:18534-18544, 2019

PubMed 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 ( 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) 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 Å resolutions revealed that the residue extensions (RA) 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.

PubMed: 31601650
DOI: 10.1074/jbc.RA119.010102

Experimental method

X-RAY DIFFRACTION (1.65 Å)