RNA-dependent oligomerization of APOBEC3G is required for restriction of HIV-1.

The human cytidine deaminase APOBEC3G (A3G) is a potent inhibitor of retroviruses and transposable elements and is able to deaminate cytidines to uridines in single-stranded DNA replication intermediates. A3G contains two canonical cytidine deaminase domains (CDAs), of which only the C-terminal one...

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Autores principales:	Hendrik Huthoff, Flavia Autore, Sarah Gallois-Montbrun, Franca Fraternali, Michael H Malim
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2009
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/2e8cc2ed05354ef5a01c755cd8568ceb
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spelling	oai:doaj.org-article:2e8cc2ed05354ef5a01c755cd8568ceb2021-12-02T19:59:48ZRNA-dependent oligomerization of APOBEC3G is required for restriction of HIV-1.1553-73661553-737410.1371/journal.ppat.1000330https://doaj.org/article/2e8cc2ed05354ef5a01c755cd8568ceb2009-03-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19266078/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374The human cytidine deaminase APOBEC3G (A3G) is a potent inhibitor of retroviruses and transposable elements and is able to deaminate cytidines to uridines in single-stranded DNA replication intermediates. A3G contains two canonical cytidine deaminase domains (CDAs), of which only the C-terminal one is known to mediate cytidine deamination. By exploiting the crystal structure of the related tetrameric APOBEC2 (A2) protein, we identified residues within A3G that have the potential to mediate oligomerization of the protein. Using yeast two-hybrid assays, co-immunoprecipitation, and chemical crosslinking, we show that tyrosine-124 and tryptophan-127 within the enzymatically inactive N-terminal CDA domain mediate A3G oligomerization, and this coincides with packaging into HIV-1 virions. In addition to the importance of specific residues in A3G, oligomerization is also shown to be RNA-dependent. Homology modelling of A3G onto the A2 template structure indicates an accumulation of positive charge in a pocket formed by a putative dimer interface. Substitution of arginine residues at positions 24, 30, and 136 within this pocket resulted in reduced virus inhibition, virion packaging, and oligomerization. Consistent with RNA serving a central role in all these activities, the oligomerization-deficient A3G proteins associated less efficiently with several cellular RNA molecules. Accordingly, we propose that occupation of the positively charged pocket by RNA promotes A3G oligomerization, packaging into virions and antiviral function.Hendrik HuthoffFlavia AutoreSarah Gallois-MontbrunFranca FraternaliMichael H MalimPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 5, Iss 3, p e1000330 (2009)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Hendrik Huthoff Flavia Autore Sarah Gallois-Montbrun Franca Fraternali Michael H Malim RNA-dependent oligomerization of APOBEC3G is required for restriction of HIV-1.
description	The human cytidine deaminase APOBEC3G (A3G) is a potent inhibitor of retroviruses and transposable elements and is able to deaminate cytidines to uridines in single-stranded DNA replication intermediates. A3G contains two canonical cytidine deaminase domains (CDAs), of which only the C-terminal one is known to mediate cytidine deamination. By exploiting the crystal structure of the related tetrameric APOBEC2 (A2) protein, we identified residues within A3G that have the potential to mediate oligomerization of the protein. Using yeast two-hybrid assays, co-immunoprecipitation, and chemical crosslinking, we show that tyrosine-124 and tryptophan-127 within the enzymatically inactive N-terminal CDA domain mediate A3G oligomerization, and this coincides with packaging into HIV-1 virions. In addition to the importance of specific residues in A3G, oligomerization is also shown to be RNA-dependent. Homology modelling of A3G onto the A2 template structure indicates an accumulation of positive charge in a pocket formed by a putative dimer interface. Substitution of arginine residues at positions 24, 30, and 136 within this pocket resulted in reduced virus inhibition, virion packaging, and oligomerization. Consistent with RNA serving a central role in all these activities, the oligomerization-deficient A3G proteins associated less efficiently with several cellular RNA molecules. Accordingly, we propose that occupation of the positively charged pocket by RNA promotes A3G oligomerization, packaging into virions and antiviral function.
format	article
author	Hendrik Huthoff Flavia Autore Sarah Gallois-Montbrun Franca Fraternali Michael H Malim
author_facet	Hendrik Huthoff Flavia Autore Sarah Gallois-Montbrun Franca Fraternali Michael H Malim
author_sort	Hendrik Huthoff
title	RNA-dependent oligomerization of APOBEC3G is required for restriction of HIV-1.
title_short	RNA-dependent oligomerization of APOBEC3G is required for restriction of HIV-1.
title_full	RNA-dependent oligomerization of APOBEC3G is required for restriction of HIV-1.
title_fullStr	RNA-dependent oligomerization of APOBEC3G is required for restriction of HIV-1.
title_full_unstemmed	RNA-dependent oligomerization of APOBEC3G is required for restriction of HIV-1.
title_sort	rna-dependent oligomerization of apobec3g is required for restriction of hiv-1.
publisher	Public Library of Science (PLoS)
publishDate	2009
url	https://doaj.org/article/2e8cc2ed05354ef5a01c755cd8568ceb
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RNA-dependent oligomerization of APOBEC3G is required for restriction of HIV-1.

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