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Molecular Mechanism for Regulating APOBEC3G DNA Editing Function by the Non-catalytic Domain

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Journal bioRxiv
Date 2024 Apr 1
PMID 38559028
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Abstract

APOBEC3G (A3G) belongs to the AID/APOBEC cytidine deaminase family and is essential for antiviral immunity. It contains two zinc-coordinated cytidine-deaminase (CD) domains. The N-terminal CD1 domain is non-catalytic but has a strong affinity for nucleic acids, whereas the C-terminal CD2 domain catalyzes C-to-U editing in single-stranded DNA. The interplay between the two domains in DNA binding and editing is not fully understood. Here, our studies on rhesus macaque A3G (rA3G) show that the DNA editing function in linear and hairpin loop DNA is greatly enhanced by AA or GA dinucleotide motifs present downstream (in the 3'-direction) but not upstream (in the 5'-direction) of the target-C editing sites. The effective distance between AA/GA and the target-C sites depends on the local DNA secondary structure. We present two co-crystal structures of rA3G bound to ssDNA containing AA and GA, revealing the contribution of the non-catalytic CD1 domain in capturing AA/GA DNA and explaining our biochemical observations. Our structural and biochemical findings elucidate the molecular mechanism underlying the cooperative function between the non-catalytic and the catalytic domains of A3G, which is critical for its antiviral role and its contribution to genome mutations in cancer.

References
1.
Yu Q, Konig R, Pillai S, Chiles K, Kearney M, Palmer S . Single-strand specificity of APOBEC3G accounts for minus-strand deamination of the HIV genome. Nat Struct Mol Biol. 2004; 11(5):435-42. DOI: 10.1038/nsmb758. View

2.
Wong L, Sami A, Chelico L . Competition for DNA binding between the genome protector replication protein A and the genome modifying APOBEC3 single-stranded DNA deaminases. Nucleic Acids Res. 2022; 50(21):12039-12057. PMC: 9757055. DOI: 10.1093/nar/gkac1121. View

3.
Kouno T, Silvas T, Hilbert B, Shandilya S, Bohn M, Kelch B . Crystal structure of APOBEC3A bound to single-stranded DNA reveals structural basis for cytidine deamination and specificity. Nat Commun. 2017; 8:15024. PMC: 5414352. DOI: 10.1038/ncomms15024. View

4.
Xiao X, Li S, Yang H, Chen X . Crystal structures of APOBEC3G N-domain alone and its complex with DNA. Nat Commun. 2016; 7:12193. PMC: 4974639. DOI: 10.1038/ncomms12193. View

5.
Green A, Weitzman M . The spectrum of APOBEC3 activity: From anti-viral agents to anti-cancer opportunities. DNA Repair (Amst). 2019; 83:102700. PMC: 6876854. DOI: 10.1016/j.dnarep.2019.102700. View