Model Structure of Human APOBEC3G

Alejandro Aballay,Kun-Lin Zhang,Amalio Telenti,Olivier Michielin,Bastien Mangeat,Millan Ortiz,Vincent Zoete,Didier Trono

doi:10.1371/journal.pone.0000378

Abstract

BackgroundAPOBEC3G (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G) has antiretroviral activity associated with the hypermutation of viral DNA through cytosine deamination. APOBEC3G has two cytosine deaminase (CDA) domains; the catalytically inactive amino-terminal domain of APOBEC3G (N-CDA) carries the Vif interaction domain. There is no 3-D structure of APOBEC3G solved by X-ray or nuclear magnetic resonance.Methodology/Principal FindingsWe predicted the structure of human APOBEC3G based on the crystal structure of APOBEC2. To assess the model structure, we evaluated 48 mutants of APOBEC3G N-CDA that identify novel variants altering ΔVif HIV-1 infectivity and packaging of APOBEC3G. Results indicated that the key residue D128 is exposed at the surface of the model, with a negative local electrostatic potential. Mutation D128K changes the sign of that local potential. In addition, two novel functionally relevant residues that result in defective APOBEC3G encapsidation, R122 and W127, cluster at the surface.Conclusions/SignificanceThe structure model identifies a cluster of residues important for packaging of APOBEC3G into virions, and may serve to guide functional analysis of APOBEC3G.

Highlights

Primate APOBEC3G has antiretroviral activity associated with the hypermutation of viral DNA through cytosine deamination
We modeled the huAPOBEC3G N-cytosine deaminase (CDA) based on the outer monomer of APOBEC2 to resolve the structure between residues 22 and 33 of huAPOBEC3G
The outer monomer of APOBEC2 is more suitable as template because the middle monomer coordinates the Zn2+ with E60, a residue not present at the corresponding position in huAPOBEC3G N-CDA

Summary

Introduction

Primate APOBEC3G has antiretroviral activity associated with the hypermutation of viral DNA through cytosine deamination (for recent review see [1,2,3]). APOBEC3G has a duplicated catalytic deaminase domain (CDA); the amino-terminal domain (N-CDA) of APOBEC3G is required for viral encapsidation but not cytosine deamination [9,10,11]. Recent comparative modeling work for APOBEC1 and AID [12,13,14,15,16,17] led to the proposition of a secondary structure alignment between APOBEC3G and cytidine deaminase [18]. APOBEC3G (apolipoprotein B mRNA-editing enzyme, catalytic polypeptide-like 3G) has antiretroviral activity associated with the hypermutation of viral DNA through cytosine deamination. The structure model identifies a cluster of residues important for packaging of APOBEC3G into virions, and may serve to guide functional analysis of APOBEC3G

Methods

Results

Conclusion