Can ERAP1 and ERAP2 Form Functional Heterodimers? A Structural Dynamics Investigation

被引:5
|
作者
Papakyriakou, Athanasios
Mpakali, Anastasia
Stratikos, Efstratios
机构
[1] Institute of Biosciences and Applications, National Centre for Scientific Research “Demokritos”, Athens
[2] Laboratory of Biochemistry, Department of Chemistry, National and Kapodistrian University of Athens, Athens
来源
FRONTIERS IN IMMUNOLOGY | 2022年 / 13卷
关键词
aminopeptidase; antigen processing; antigen presentation; enzyme mechanism; molecular dynamics; binding free energy; adaptive immunity; MHC class I; INSULIN-REGULATED AMINOPEPTIDASE; MHC CLASS-I; CRYSTAL-STRUCTURE; BINDING-AFFINITY; AMBER; RECOGNITION; SPECIFICITY; INSIGHTS; REVEALS; SERVER;
D O I
10.3389/fimmu.2022.863529
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
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页数:13
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