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Role of Electrostatic Hotspots in the Selectivity of Complement Control Proteins Toward Human and Bovine Complement Inhibition

Poxviruses are dangerous pathogens, which can cause fatal infection in unvaccinated individuals. The causative agent of smallpox in humans, variola virus, is closely related to the bovine vaccinia virus, yet the molecular basis of their selectivity is currently incompletely understood. Here, we exam...

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Autores principales: Narkhede, Yogesh B., Gautam, Avneesh K., Hsu, Rohaine V., Rodriguez, Wilson, Zewde, Nehemiah T., Harrison, Reed E. S., Arantes, Pablo R., Gaieb, Zied, Gorham, Ronald D., Kieslich, Chris, Morikis, Dimitrios, Sahu, Arvind, Palermo, Giulia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020814/
https://www.ncbi.nlm.nih.gov/pubmed/33829039
http://dx.doi.org/10.3389/fmolb.2021.618068
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author Narkhede, Yogesh B.
Gautam, Avneesh K.
Hsu, Rohaine V.
Rodriguez, Wilson
Zewde, Nehemiah T.
Harrison, Reed E. S.
Arantes, Pablo R.
Gaieb, Zied
Gorham, Ronald D.
Kieslich, Chris
Morikis, Dimitrios
Sahu, Arvind
Palermo, Giulia
author_facet Narkhede, Yogesh B.
Gautam, Avneesh K.
Hsu, Rohaine V.
Rodriguez, Wilson
Zewde, Nehemiah T.
Harrison, Reed E. S.
Arantes, Pablo R.
Gaieb, Zied
Gorham, Ronald D.
Kieslich, Chris
Morikis, Dimitrios
Sahu, Arvind
Palermo, Giulia
author_sort Narkhede, Yogesh B.
collection PubMed
description Poxviruses are dangerous pathogens, which can cause fatal infection in unvaccinated individuals. The causative agent of smallpox in humans, variola virus, is closely related to the bovine vaccinia virus, yet the molecular basis of their selectivity is currently incompletely understood. Here, we examine the role of the electrostatics in the selectivity of the smallpox protein SPICE and vaccinia protein VCP toward the human and bovine complement protein C3b, a key component of the complement immune response. Electrostatic calculations, in-silico alanine-scan and electrostatic hotspot analysis, as introduced by Kieslich and Morikis (PLoS Comput. Biol. 2012), are used to assess the electrostatic complementarity and to identify sites resistant to local perturbation where the electrostatic potential is likely to be evolutionary conserved. The calculations suggest that the bovine C3b is electrostatically prone to selectively bind its VCP ligand. On the other hand, the human isoform of C3b exhibits a lower electrostatic complementarity toward its SPICE ligand. Yet, the human C3b displays a highly preserved electrostatic core, which suggests that this isoform could be less selective in binding different ligands like SPICE and the human Factor H. This is supported by experimental cofactor activity assays revealing that the human C3b is prone to bind both SPICE and Factor H, which exhibit diverse electrostatic properties. Additional investigations considering mutants of SPICE and VCP that revert their selectivity reveal an “electrostatic switch” into the central modules of the ligands, supporting the critical role of the electrostatics in the selectivity. Taken together, these evidences provide insights into the selectivity mechanism of the complement regulator proteins encoded by the variola and vaccinia viruses to circumvent the complement immunity and exert their pathogenic action. These fundamental aspects are valuable for the development of novel vaccines and therapeutic strategies.
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spelling pubmed-80208142021-04-06 Role of Electrostatic Hotspots in the Selectivity of Complement Control Proteins Toward Human and Bovine Complement Inhibition Narkhede, Yogesh B. Gautam, Avneesh K. Hsu, Rohaine V. Rodriguez, Wilson Zewde, Nehemiah T. Harrison, Reed E. S. Arantes, Pablo R. Gaieb, Zied Gorham, Ronald D. Kieslich, Chris Morikis, Dimitrios Sahu, Arvind Palermo, Giulia Front Mol Biosci Molecular Biosciences Poxviruses are dangerous pathogens, which can cause fatal infection in unvaccinated individuals. The causative agent of smallpox in humans, variola virus, is closely related to the bovine vaccinia virus, yet the molecular basis of their selectivity is currently incompletely understood. Here, we examine the role of the electrostatics in the selectivity of the smallpox protein SPICE and vaccinia protein VCP toward the human and bovine complement protein C3b, a key component of the complement immune response. Electrostatic calculations, in-silico alanine-scan and electrostatic hotspot analysis, as introduced by Kieslich and Morikis (PLoS Comput. Biol. 2012), are used to assess the electrostatic complementarity and to identify sites resistant to local perturbation where the electrostatic potential is likely to be evolutionary conserved. The calculations suggest that the bovine C3b is electrostatically prone to selectively bind its VCP ligand. On the other hand, the human isoform of C3b exhibits a lower electrostatic complementarity toward its SPICE ligand. Yet, the human C3b displays a highly preserved electrostatic core, which suggests that this isoform could be less selective in binding different ligands like SPICE and the human Factor H. This is supported by experimental cofactor activity assays revealing that the human C3b is prone to bind both SPICE and Factor H, which exhibit diverse electrostatic properties. Additional investigations considering mutants of SPICE and VCP that revert their selectivity reveal an “electrostatic switch” into the central modules of the ligands, supporting the critical role of the electrostatics in the selectivity. Taken together, these evidences provide insights into the selectivity mechanism of the complement regulator proteins encoded by the variola and vaccinia viruses to circumvent the complement immunity and exert their pathogenic action. These fundamental aspects are valuable for the development of novel vaccines and therapeutic strategies. Frontiers Media S.A. 2021-03-16 /pmc/articles/PMC8020814/ /pubmed/33829039 http://dx.doi.org/10.3389/fmolb.2021.618068 Text en Copyright © 2021 Narkhede, Gautam, Hsu, Rodriguez, Zewde, Harrison, Arantes, Gaieb, Gorham, Kieslich, Morikis, Sahu and Palermo. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Biosciences
Narkhede, Yogesh B.
Gautam, Avneesh K.
Hsu, Rohaine V.
Rodriguez, Wilson
Zewde, Nehemiah T.
Harrison, Reed E. S.
Arantes, Pablo R.
Gaieb, Zied
Gorham, Ronald D.
Kieslich, Chris
Morikis, Dimitrios
Sahu, Arvind
Palermo, Giulia
Role of Electrostatic Hotspots in the Selectivity of Complement Control Proteins Toward Human and Bovine Complement Inhibition
title Role of Electrostatic Hotspots in the Selectivity of Complement Control Proteins Toward Human and Bovine Complement Inhibition
title_full Role of Electrostatic Hotspots in the Selectivity of Complement Control Proteins Toward Human and Bovine Complement Inhibition
title_fullStr Role of Electrostatic Hotspots in the Selectivity of Complement Control Proteins Toward Human and Bovine Complement Inhibition
title_full_unstemmed Role of Electrostatic Hotspots in the Selectivity of Complement Control Proteins Toward Human and Bovine Complement Inhibition
title_short Role of Electrostatic Hotspots in the Selectivity of Complement Control Proteins Toward Human and Bovine Complement Inhibition
title_sort role of electrostatic hotspots in the selectivity of complement control proteins toward human and bovine complement inhibition
topic Molecular Biosciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020814/
https://www.ncbi.nlm.nih.gov/pubmed/33829039
http://dx.doi.org/10.3389/fmolb.2021.618068
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