title: ERAP1-ERAP2 dimers trim MHC I-bound precursor peptides; implications for understanding peptide editing.
abstract: The processing of MHC class I antigenic precursor peptides by the endoplasmic reticulum aminopeptidase 1 (ERAP1) and ERAP2 is an important event in the cell biology of antigen presentation. To date, the molecular context by which the ERAP enzymes trim precursor peptides, and how ERAPs shape peptide repertoires, remain open questions. Using ERAP1 and ERAP2 heterodimers (ERAP1/2), and N-terminally extended model and natural peptides in their free and HLA-B*0801-bound forms, we characterized the mode of action of ERAPs. We provide evidence that ERAP1/2 can trim MHC I-bound precursor peptides to their correct and final lengths, albeit more slowly than the corresponding free precursors. Trimming of MHC I-bound precursors by ERAP1/2 increases the conformational stability of MHC I/peptide complexes. From the data, we propose a molecular mechanistic model of ERAP1/2 as peptide editors. Overall, our study provides new findings on a significant issue of the ERAP-mediated processing pathway of MHC class I antigens.
authors: Department of Microbiology and Immunology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612 USA.
authors: Hanna
authors: H
authors: Chen
authors: Department of Microbiology and Immunology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612 USA.
authors: Lenong
authors: L
authors: Li
authors: INSERM, Unité 1151; CNRS, Unité 8352; Université Paris Descartes, 75015 Paris, France.
authors: Mirjana
authors: M
authors: Weimershaus
authors: INSERM, Unité 1151; CNRS, Unité 8352; Université Paris Descartes, 75015 Paris, France.
authors: Irini
authors: I
authors: Evnouchidou
authors: INSERM, Unité 1151; CNRS, Unité 8352; Université Paris Descartes, 75015 Paris, France.
authors: Peter
authors: P
authors: van Endert
authors: Department of Microbiology and Immunology, University of Illinois at Chicago, College of Medicine, Chicago, IL 60612 USA.
authors: Marlene
authors: M
authors: Bouvier
mesh_terms: D000626:Aminopeptidases / Q000737:chemistry*; D002942:Circular Dichroism; D004220:Disulfides; D000939:Epitopes / Q000737:chemistry; D015395:Histocompatibility Antigens Class I / Q000737:chemistry*; D006358:Hot Temperature; D006801:Humans; D015778:Minor Histocompatibility Antigens / Q000737:chemistry*; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry*; D011485:Protein Binding; D000072417:Protein Domains; D055503:Protein Multimerization; D013379:Substrate Specificity; D013820:Thermolysin / Q000737:chemistry
chemical_list: D004220:Disulfides; D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D015778:Minor Histocompatibility Antigens; D010455:Peptides; D000626:Aminopeptidases; C464841:ERAP1 protein, human; C503944:ERAP2 protein, human; D013820:Thermolysin