TY - JOUR
TI - Can ERAP1 and ERAP2 Form Functional Heterodimers? A Structural Dynamics Investigation
AU - Papakyriakou, A.
AU - Mpakali, A.
AU - Stratikos, E.
JO - Frontiers in Immunology
PY - 2022
VL - 13
TODO - null
SP - null
PB - Frontiers Media S.A
SN - null
TODO - 10.3389/fimmu.2022.863529
TODO - aminopeptidase;  endoplasmic reticulum aminopeptidase 1;  endoplasmic reticulum aminopeptidase 2;  major histocompatibility antigen class 1;  unclassified drug;  aminopeptidase;  antigen;  minor histocompatibility antigen;  peptide, amino acid sequence;  antigen presentation;  Article;  binding affinity;  conformational transition;  crystal structure;  dimerization;  disulfide bond;  enzyme active site;  exon;  heterodimerization;  homodimerization;  immune response;  innate immunity;  missense mutation;  molecular docking;  molecular dynamics;  molecular interaction;  protein protein interaction;  protein structure;  sequence homology;  tumor immunity;  X ray crystallography;  genetics;  metabolism;  protein domain, Aminopeptidases;  Antigens;  Minor Histocompatibility Antigens;  Peptides;  Protein Domains
TODO - Endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and ERAP2) play important roles in the generation of antigenic peptides presented by Major Histocompatibility Class I (MHCI) molecules and indirectly regulate adaptive immune responses. Although the discrete function of these enzymes has been extensively characterized, recent reports have suggested that they can also form heterodimers with functional consequences. However, lack of structural characterization of a putative ERAP1/ERAP2 dimer has limited our understanding of its biological role and significance. To address this, we employed computational molecular dynamics calculations to explore the topology of interactions between these two, based on experimentally determined homo-dimerization interfaces observed in crystal structures of ERAP2 or homologous enzymes. Our analysis of 8 possible dimerization models, suggested that the most likely ERAP1/ERAP2 heterodimerization topology involves the exon 10 loop, a non-conserved loop previously implicated in interactions between ERAP1 and the disulfide-bond shuffling chaperone ERp44. This dimerization topology allows access to the active site of both enzymes and is consistent with a previously reported construct in which ERAP1 and ERAP2 were linked by Fos/Jun zipper tags. The proposed model constitutes a tentative structural template to help understand the physiological role and significance of ERAP1/ERAP2 molecular interactions. Copyright © 2022 Papakyriakou, Mpakali and Stratikos.
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