Understanding the Structure, Multimerization, Subcellular Localization and mC Selectivity of a Genomic Mutator and Anti-HIV Factor APOBEC3H

Scientific Reports
Fumiaki ItoXiaojiang S Chen

Abstract

APOBEC3H (A3H) is a member of the APOBEC3 subfamily of DNA cytosine deaminases that are important for innate immune defense and have been implicated in cancer biogenesis. To understand the structural basis for A3H biochemical function, we determined a high-resolution structure of human A3H and performed extensive biochemical analysis. The 2.49 Å crystal structure reveals a uniquely long C-terminal helix 6 (h6), a disrupted β5 strand of the canonical five-stranded β-sheet core, and a long loop 1 around the Zn-active center. Mutation of a loop 7 residue, W115, disrupted the RNA-mediated dimerization of A3H yielding an RNA-free monomeric form that still possessed nucleic acid binding and deaminase activity. A3H expressed in HEK293T cells showed RNA dependent HMW complex formation and RNase A-dependent deaminase activity. A3H has a highly positively charged surface surrounding the Zn-active center, and multiple positively charged residues within this charged surface play an important role in the RNA-mediated HMW formation and deaminase inhibition. Furthermore, these positively charged residues affect subcellular localization of A3H between the nucleus and cytosol. Finally, we have identified multiple residues of loop 1 and 7 that c...Continue Reading

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Datasets Mentioned

BETA
ACK77776

Methods Mentioned

BETA
deamination
size exclusion chromatography
salt treatment
electrophoretic mobility shift assay
deaminase assay
PCR
gel
gel filtration
transfection
protein assay

Software Mentioned

PHENIX
ImageQuant
ImageQuant TL
MOLREP
GraphPad Prism
HKL2000
ImageJ
Quantity One
COOT

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