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Molecular modelling of the HCMV IL-10 protein isoforms and analysis of their interaction with the human IL-10 receptor

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Pantaleao_2022_PLoS_ONE_Molecular_modelling_CC.pdf (1.742Mb)
Date
28/11/2022
Author
Pantaleão, Simone Queiroz
Camillo, Lívia de Moraes Bomediano
Neves, Tainan Cerqueira
Menezes, Isabela de Godoy
Stangherlin, Lucas Matheus
Batista, Helena Beatriz de Carvalho Ruthner
Poole, Emma
Nevels, Michael
Philot, Eric Alisson
Scott, Ana Ligia
Carlan da Silva, Maria Cristina
Keywords
QH426 Genetics
DAS
MCC
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Abstract
The human cytomegalovirus (HCMV) UL111A gene encodes several homologs of the cellular interleukin 10 (cIL-10). Alternative splicing in the UL111A region produces two relatively well-characterized transcripts designated cmvIL-10 (isoform A) and LAcmvIL-10 (isoform B). The cmvIL-10 protein is the best characterized, both structurally and functionally, and has many immunosuppressive activities similar to cIL-10, while LAcmvIL-10 has more restricted biological activities. Alternative splicing also results in five less studied UL111A transcripts encoding additional proteins homologous to cIL-10 (isoforms C to G). These transcripts were identified during productive HCMV infection of MRC-5 cells with the high passage laboratory adapted AD169 strain, and the structure and properties of the corresponding proteins are largely unknown. Moreover, it is unclear whether these protein isoforms are able to bind the cellular IL-10 receptor and induce signalling. In the present study, we investigated the expression spectrum of UL111A transcripts in fully permissive MRC-5 cells and semi permissive U251 cells infected with the low passage HCMV strain TB40E. We identified a new spliced transcript (H) expressed during productive infection. Using computational methods, we carried out molecular modelling studies on the three-dimensional structures of the HCMV IL-10 proteins encoded by the transcripts detected in our work (cmvIL-10 (A), LAcmvIL-10 (B), E, F and H) and on their interaction with the human IL-10 receptor (IL-10R1). The modelling predicts clear differences between the isoform structures. Furthermore, the in silico simulations (molecular dynamics simulation and normal-mode analyses) allowed us to evaluate regions that contain potential receptor binding sites in each isoform. The analyses demonstrate that the complexes between the isoforms and IL-10R1 present different types of molecular interactions and consequently different affinities and stabilities. The knowledge about structure and expression of specific viral IL-10 isoforms has implications for understanding of their properties and role in HCMV immune evasion and pathogenesis.
Citation
Pantaleão , S Q , Camillo , L D M B , Neves , T C , Menezes , I D G , Stangherlin , L M , Batista , H B D C R , Poole , E , Nevels , M , Philot , E A , Scott , A L & Carlan da Silva , M C 2022 , ' Molecular modelling of the HCMV IL-10 protein isoforms and analysis of their interaction with the human IL-10 receptor ' , PLoS ONE , vol. 17 , no. 11 , e0277953 . https://doi.org/10.1371/journal.pone.0277953
Publication
PLoS ONE
Status
Peer reviewed
DOI
https://doi.org/10.1371/journal.pone.0277953
ISSN
1932-6203
Type
Journal article
Rights
Copyright: © 2022 Pantaleão et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Description
Funding: Funder 01: Grant number: 2020/08527-1 Fundação de Amparo a Pesquisa do Estado de São Paulo, Brazil (FAPESP) - https://fapesp.br/ Author: Maria Cristina Carlan da Silva - Maria Cristina Carlan Silva Funder 02: Grant number: 2020/07767-9 Fundação de Amparo a Pesquisa do Estado de São Paulo, Brazil (FAPESP) - https://fapesp.br/ Author: Tainan Cerqueira Neves - Neves, Tainan C. Funder 03: Grant number: 164052/2020-8 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) - https://www.gov.br/cnpq/pt-br Author: Simone Queiroz Pantaleão - Pantaleão, Simone Queiroz.
Collections
  • University of St Andrews Research
URI
http://hdl.handle.net/10023/26515

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