Functional analysis and structural modeling of human APOBEC3G reveal the role of evolutionarily conserved elements in the inhibition of human immunodeficiency virus type 1 infection and Alu transposition.

Details

Serval ID
serval:BIB_22A8D5FCCCA0
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Functional analysis and structural modeling of human APOBEC3G reveal the role of evolutionarily conserved elements in the inhibition of human immunodeficiency virus type 1 infection and Alu transposition.
Journal
Journal of Virology
Author(s)
Bulliard Y., Turelli P., Röhrig U.F., Zoete V., Mangeat B., Michielin O., Trono D.
ISSN
1098-5514[electronic]
Publication state
Published
Issued date
2009
Volume
83
Number
23
Pages
12611-12621
Language
english
Abstract
Retroelements are important evolutionary forces but can be deleterious if left uncontrolled. Members of the human APOBEC3 family of cytidine deaminases can inhibit a wide range of endogenous, as well as exogenous, retroelements. These enzymes are structurally organized in one or two domains comprising a zinc-coordinating motif. APOBEC3G contains two such domains, only the C terminal of which is endowed with editing activity, while its N-terminal counterpart binds RNA, promotes homo-oligomerization, and is necessary for packaging into human immunodeficiency virus type 1 (HIV-1) virions. Here, we performed a large-scale mutagenesis-based analysis of the APOBEC3G N terminus, testing mutants for (i) inhibition of vif-defective HIV-1 infection and Alu retrotransposition, (ii) RNA binding, and (iii) oligomerization. Furthermore, in the absence of structural information on this domain, we used homology modeling to examine the positions of functionally important residues and of residues found to be under positive selection by phylogenetic analyses of primate APOBEC3G genes. Our results reveal the importance of a predicted RNA binding dimerization interface both for packaging into HIV-1 virions and inhibition of both HIV-1 infection and Alu transposition. We further found that the HIV-1-blocking activity of APOBEC3G N-terminal mutants defective for packaging can be almost entirely rescued if their virion incorporation is forced by fusion with Vpr, indicating that the corresponding region of APOBEC3G plays little role in other aspects of its action against this pathogen. Interestingly, residues forming the APOBEC3G dimer interface are highly conserved, contrasting with the rapid evolution of two neighboring surface-exposed amino acid patches, one targeted by the Vif protein of primate lentiviruses and the other of yet-undefined function.
Keywords
Amino Acid Sequence, Animals, Conserved Sequence, Cytidine Deaminase/genetics, Cytidine Deaminase/immunology, Dimerization, HIV-1/immunology, Humans, Lentiviruses, Primate, Models, Molecular, Molecular Sequence Data, Mutagenesis, Site-Directed, Primates, Protein Binding, Protein Structure, Tertiary, RNA, Viral/metabolism, Sequence Homology, Amino Acid
Pubmed
Web of science
Open Access
Yes
Create date
08/01/2010 14:45
Last modification date
20/08/2019 13:00
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