The Role of Conformational Dynamics in Antigen Trimming by Intracellular Aminopeptidases

Abstract

Antigenic peptides presented by the major histocompatibility complex class I (MHC-I) molecules for recognition by cytotoxic T-lymphocytes are processed by members of the oxytocinase sub-family of M1 aminopeptidases ERAP1, ERAP2, and IRAP. These three homologous zinc metallopeptidases trim N-terminally extended precursor antigenic peptides down to the correct length for loading onto the MHC-I but can also destroy some antigenic peptides by over-trimming, therefore, influencing the antigenic peptide repertoire and immunodominance hierarchy. Polymorphic variation has been found to affect their trimming function and predispose to human disease in complex and poorly understood patterns. Structural and biochemical analysis have pointed toward a complicated trimming mechanism that involves a major conformational transition during each catalytic cycle. Here, we provide an overview of current knowledge on the structure and mechanism of action of those enzymes with a focus on the proposed key role of conformational dynamics in their function.

A systematic re-examination of processing of MHCI-bound antigenic peptide precursors by endoplasmic reticulum aminopeptidase 1

“…This was recently demonstrated with a series of extended peptides bound onto HLA-B08 (37). In contrast, formation of a transient ERAP1/MHCI trimming complex would necessitate conformations not before observed experimentally, but simulated computationally (31,51). To date, no direct ERAP1/MHCI protein-protein interactions have been demonstrated (26).…”

The genetics, structure and function of the M1 aminopeptidase oxytocinase subfamily and their therapeutic potential in immune-mediated disease

“…The role of conformational flexibility in the function of the M1 aminopeptidases has also been explored through molecular dynamics simulations of both IRAP [23] and ERAP1 [25]. are accessible, in the absence of ligand, with very low energy barriers for transition between the conformations.…”

“…A 'wide-open' conformation of ERAP1 was shown to be potentially accessible, in which the angle between Domain IV and the rest of the protein increases to a degree that provides room for the insertion of a peptide-MHC-I complex. The complex can pack close enough to the active site to bring the N-terminal end of the peptide into the active site pocket [25]. Whether trimming of MHC-I bound peptides by ERAP1 or 2 occurs in vivo remains controversial, particularly in light of the structure of the MHC-I peptideloading complex (PLC) where the MHC-I-peptide is significantly enclosed by the components of the PLC [27].…”

Aminobenzosuberone Scaffold as a Modular Chemical Tool for the Inhibition of Therapeutically Relevant M1 Aminopeptidases

“…In the present work, we focused on subtle amino acid sequence differences in the active site that may explain the various inhibition values experimentally determined for the selected M1 aminopeptidases. In addition, conformational dynamics have been considered for some members of this family among the structures captured during various crystallization processes [ 20 , 21 , 24 , 70 ]. Data remain scarce due to the small number of solved 3D structures and no general statements could be outlined, nevertheless our SAR studies enabled to precise the structural environment required for potent inhibition by the aminobenzosuberone derivatives of a given enzyme within the M1 family.…”