A computational analysis of the structural determinants of APOBEC3's catalytic activity and vulnerability to HIV-1 Vif
Department of Biochemistry and Molecular Pharmacology
Medical Subject Headings
Amino Acid Sequence; Cytosine Deaminase; Gene Expression Regulation; Humans; Membrane Potentials; Protein Binding; Protein Conformation; Protein Structure, Tertiary; Sequence Alignment; Static Electricity; vif Gene Products, Human Immunodeficiency Virus
Biochemistry | Structural Biology | Virology
APOBEC3s (A3) are Zn(2+) dependent cytidine deaminases with diverse biological functions and implications for cancer and immunity. Four of the seven human A3s restrict HIV by 'hypermutating' the reverse-transcribed viral genomic DNA. HIV Virion Infectivity Factor (Vif) counters this restriction by targeting A3s to proteasomal degradation. However, there is no apparent correlation between catalytic activity, Vif binding, and sequence similarity between A3 domains. Our comparative structural analysis reveals features required for binding Vif and features influencing polynucleotide deaminase activity in A3 proteins. All Vif-binding A3s share a negatively charged surface region that includes residues previously implicated in binding the highly-positively charged Vif. Additionally, catalytically active A3s share a positively charged groove near the Zn(2+) coordinating active site, which may accommodate the negatively charged polynucleotide substrate. Our findings suggest surface electrostatics, as well as the spatial extent of substrate accommodating region, are critical determinants of substrate and Vif binding across A3 proteins with implications for anti-retroviral and anti-cancer therapeutic design.
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Citation: Virology. 2014 Dec;471-473:105-16. doi: 10.1016/j.virol.2014.09.023. Epub 2014 Oct 29. Link to article on publisher's site
Shandilya, Shivender; Bohn, Markus-Frederik; and Schiffer, Celia A., "A computational analysis of the structural determinants of APOBEC3's catalytic activity and vulnerability to HIV-1 Vif" (2014). University of Massachusetts Medical School Faculty Publications. 638.