6P2C

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

6P2C の概要

• エントリーDOI: 10.2210/pdb6p2c/pdb
• 分子名称: HLA class I histocompatibility antigen, B-8 alpha chain, Beta-2-microglobulin, MHC I-peptide, ... (4 entities in total)
• 機能のキーワード: mhc i antigen processing, mhc i antigen presentation, mhc i structure, mhc i immunopeptide, immune system
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 45961.01

構造登録者

Li, L.,Batliwala, M.,Bouvier, M. (登録日: 2019-05-21, 公開日: 2019-10-16, 最終更新日: 2024-10-23)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.396 Å)