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APOBEC3C Tandem Domain Proteins Create Super Restriction Factors against HIV-1

Humans encode proteins, called restriction factors, that inhibit replication of viruses such as HIV-1. The members of one family of antiviral proteins, apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3; shortened here to A3), act by deaminating cytidines to uridines during t...

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Autores principales: McDonnell, Mollie M., Crawford, Kate H. D., Dingens, Adam S., Bloom, Jesse D., Emerman, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188997/
https://www.ncbi.nlm.nih.gov/pubmed/32345636
http://dx.doi.org/10.1128/mBio.00737-20
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author McDonnell, Mollie M.
Crawford, Kate H. D.
Dingens, Adam S.
Bloom, Jesse D.
Emerman, Michael
author_facet McDonnell, Mollie M.
Crawford, Kate H. D.
Dingens, Adam S.
Bloom, Jesse D.
Emerman, Michael
author_sort McDonnell, Mollie M.
collection PubMed
description Humans encode proteins, called restriction factors, that inhibit replication of viruses such as HIV-1. The members of one family of antiviral proteins, apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3; shortened here to A3), act by deaminating cytidines to uridines during the reverse transcription reaction of HIV-1. The A3 locus encodes seven genes, named A3A to A3H. These genes have either one or two cytidine deaminase domains, and several of these A3s potently restrict HIV-1. A3C, which has only a single cytidine deaminase domain, however, inhibits HIV-1 only very weakly. We tested novel double domain protein combinations by genetically linking two A3C genes to make a synthetic tandem domain protein. This protein created a “super restriction factor” that had more potent antiviral activity than the native A3C protein, which correlated with increased packaging into virions. Furthermore, disabling one of the active sites of the synthetic tandem domain protein resulted in an even greater increase in the antiviral activity—recapitulating a similar evolution seen in A3F and A3G (double domain A3s that use only a single catalytically active deaminase domain). These A3C tandem domain proteins do not have an increase in mutational activity but instead inhibit formation of reverse transcription products, which correlates with their ability to form large higher-order complexes in cells. Finally, the A3C-A3C super restriction factor largely escaped antagonism by the HIV-1 viral protein Vif.
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spelling pubmed-71889972020-05-07 APOBEC3C Tandem Domain Proteins Create Super Restriction Factors against HIV-1 McDonnell, Mollie M. Crawford, Kate H. D. Dingens, Adam S. Bloom, Jesse D. Emerman, Michael mBio Research Article Humans encode proteins, called restriction factors, that inhibit replication of viruses such as HIV-1. The members of one family of antiviral proteins, apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3; shortened here to A3), act by deaminating cytidines to uridines during the reverse transcription reaction of HIV-1. The A3 locus encodes seven genes, named A3A to A3H. These genes have either one or two cytidine deaminase domains, and several of these A3s potently restrict HIV-1. A3C, which has only a single cytidine deaminase domain, however, inhibits HIV-1 only very weakly. We tested novel double domain protein combinations by genetically linking two A3C genes to make a synthetic tandem domain protein. This protein created a “super restriction factor” that had more potent antiviral activity than the native A3C protein, which correlated with increased packaging into virions. Furthermore, disabling one of the active sites of the synthetic tandem domain protein resulted in an even greater increase in the antiviral activity—recapitulating a similar evolution seen in A3F and A3G (double domain A3s that use only a single catalytically active deaminase domain). These A3C tandem domain proteins do not have an increase in mutational activity but instead inhibit formation of reverse transcription products, which correlates with their ability to form large higher-order complexes in cells. Finally, the A3C-A3C super restriction factor largely escaped antagonism by the HIV-1 viral protein Vif. American Society for Microbiology 2020-04-28 /pmc/articles/PMC7188997/ /pubmed/32345636 http://dx.doi.org/10.1128/mBio.00737-20 Text en Copyright © 2020 McDonnell et al. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
McDonnell, Mollie M.
Crawford, Kate H. D.
Dingens, Adam S.
Bloom, Jesse D.
Emerman, Michael
APOBEC3C Tandem Domain Proteins Create Super Restriction Factors against HIV-1
title APOBEC3C Tandem Domain Proteins Create Super Restriction Factors against HIV-1
title_full APOBEC3C Tandem Domain Proteins Create Super Restriction Factors against HIV-1
title_fullStr APOBEC3C Tandem Domain Proteins Create Super Restriction Factors against HIV-1
title_full_unstemmed APOBEC3C Tandem Domain Proteins Create Super Restriction Factors against HIV-1
title_short APOBEC3C Tandem Domain Proteins Create Super Restriction Factors against HIV-1
title_sort apobec3c tandem domain proteins create super restriction factors against hiv-1
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188997/
https://www.ncbi.nlm.nih.gov/pubmed/32345636
http://dx.doi.org/10.1128/mBio.00737-20
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