No 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.

No abstract

Schizophrenia (SZ) is an inheritable complex mental disease. There have been several genome-wide association studies (GWASs) of SZ to identify novel genetic susceptibility factors. To further interpret SZ GWASs, pathway-based analysis (PBA), which considers the combined effect of variants and identifies pathways associated with traits, provides a feasible solution to discover the biological function and mechanism of SZ. Furthermore, to investigate the common pathways between SZ and bipolar disorder (BD) will help explore common mechanism between psychiatric phenotypes. We performed a PBA, called improved gene set enrichment analysis (i-GSEA), on 3 independent GWASs of SZ to identify pathways associated with SZ. The results were further compared to the BD-associated pathways identified by i-GSEA for 2 BD GWASs and from literature reports. Our analysis identified a highly statistically significant association between SZ and pathway 'substrate specific channel activity' in all 3 SZ GWASs (false discovery rate (FDR) < 0.05). This association has not been reported elsewhere before. This pathway was also identified by PBA for 2 independent BD GWASs. Our results suggest that pathway 'substrate specific channel activity' is statistically significantly associated with SZ, and SZ and BD share the common biological function and mechanism represented by this pathway.