| Structural highlights
Function
ABC3A_HUMAN DNA deaminase (cytidine deaminase) with restriction activity against viruses, foreign DNA and mobility of retrotransposons. Exhibits antiviral activity against adeno-associated virus (AAV) and human T-cell leukemia virus type 1 (HTLV-1) and may inhibit the mobility of LTR and non-LTR retrotransposons. Selectively targets single-stranded DNA and can deaminate both methylcytosine and cytosine in foreign DNA. Can induce somatic hypermutation in the nuclear and mitochondrial DNA. May also play a role in the epigenetic regulation of gene expression through the process of active DNA demethylation.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]
Publication Abstract from PubMed
APOBEC3A (A3A) deaminates deoxycytidine in target motif TC in a single-stranded DNA (we termed it as TC DNA), which mortally mutates viral pathogens and immunoglobulins, and leads to the diversification and lethality of cancers. The crystal structure of A3A-DNA revealed a unique U-shaped recognition mode of target base dC(0) . However, when TC DNA was titrated into (15) N-labeled A3A solution, we observed two sets of (1) H-(15) N cross-peaks of A3A in HSQC spectra, and two sets of (1) H-(1) H cross-peaks of DNA in two-dimensional (13) C,(15) N-filtered TOCSY spectra, indicating two different kinds of conformers of either A3A or TC DNA existing in solution. Here, mainly by NMR, we demonstrated that one DNA conformer interacted with one A3A conformer, forming a specific complex A3A(S) -DNA(S) in a way almost similar to that observed in the reported crystal A3A-DNA structure, where dC(0) inserted into zinc ion binding center. While the other DNA conformer bound with another A3A conformer, but dC(0) did not extend into the zinc-binding pocket, forming a nonspecific A3A(NS) -DNA(NS) complex. The NMR solution structure implied three sites Asn(61) , His(182) and Arg(189) were necessary to DNA recognition. These observations indicate a distinctive way from that reported in X-ray crystal structure, suggesting an unexpected mode of deaminase APOBEC3A to identify target motif TC in DNA in solution.
Two different kinds of interaction modes of deaminase APOBEC3A with single-stranded DNA in solution detected by nuclear magnetic resonance.,Liu Y, Lan W, Wang C, Cao C Protein Sci. 2022 Feb;31(2):443-453. doi: 10.1002/pro.4242. Epub 2021 Nov 26. PMID:34792260[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Mariani R, Chen D, Schrofelbauer B, Navarro F, Konig R, Bollman B, Munk C, Nymark-McMahon H, Landau NR. Species-specific exclusion of APOBEC3G from HIV-1 virions by Vif. Cell. 2003 Jul 11;114(1):21-31. PMID:12859895
- ↑ Chen H, Lilley CE, Yu Q, Lee DV, Chou J, Narvaiza I, Landau NR, Weitzman MD. APOBEC3A is a potent inhibitor of adeno-associated virus and retrotransposons. Curr Biol. 2006 Mar 7;16(5):480-5. PMID:16527742 doi:10.1016/j.cub.2006.01.031
- ↑ Narvaiza I, Linfesty DC, Greener BN, Hakata Y, Pintel DJ, Logue E, Landau NR, Weitzman MD. Deaminase-independent inhibition of parvoviruses by the APOBEC3A cytidine deaminase. PLoS Pathog. 2009 May;5(5):e1000439. doi: 10.1371/journal.ppat.1000439. Epub 2009, May 22. PMID:19461882 doi:10.1371/journal.ppat.1000439
- ↑ Thielen BK, McNevin JP, McElrath MJ, Hunt BV, Klein KC, Lingappa JR. Innate immune signaling induces high levels of TC-specific deaminase activity in primary monocyte-derived cells through expression of APOBEC3A isoforms. J Biol Chem. 2010 Sep 3;285(36):27753-66. doi: 10.1074/jbc.M110.102822. Epub 2010, Jul 8. PMID:20615867 doi:10.1074/jbc.M110.102822
- ↑ Stenglein MD, Burns MB, Li M, Lengyel J, Harris RS. APOBEC3 proteins mediate the clearance of foreign DNA from human cells. Nat Struct Mol Biol. 2010 Feb;17(2):222-9. doi: 10.1038/nsmb.1744. Epub 2010 Jan , 10. PMID:20062055 doi:10.1038/nsmb.1744
- ↑ Guo JU, Su Y, Zhong C, Ming GL, Song H. Hydroxylation of 5-methylcytosine by TET1 promotes active DNA demethylation in the adult brain. Cell. 2011 Apr 29;145(3):423-34. doi: 10.1016/j.cell.2011.03.022. Epub 2011 Apr, 14. PMID:21496894 doi:10.1016/j.cell.2011.03.022
- ↑ Landry S, Narvaiza I, Linfesty DC, Weitzman MD. APOBEC3A can activate the DNA damage response and cause cell-cycle arrest. EMBO Rep. 2011 May;12(5):444-50. doi: 10.1038/embor.2011.46. Epub 2011 Apr 1. PMID:21460793 doi:10.1038/embor.2011.46
- ↑ Bulliard Y, Narvaiza I, Bertero A, Peddi S, Rohrig UF, Ortiz M, Zoete V, Castro-Diaz N, Turelli P, Telenti A, Michielin O, Weitzman MD, Trono D. Structure-function analyses point to a polynucleotide-accommodating groove essential for APOBEC3A restriction activities. J Virol. 2011 Feb;85(4):1765-76. doi: 10.1128/JVI.01651-10. Epub 2010 Dec 1. PMID:21123384 doi:10.1128/JVI.01651-10
- ↑ Suspene R, Aynaud MM, Guetard D, Henry M, Eckhoff G, Marchio A, Pineau P, Dejean A, Vartanian JP, Wain-Hobson S. Somatic hypermutation of human mitochondrial and nuclear DNA by APOBEC3 cytidine deaminases, a pathway for DNA catabolism. Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):4858-63. doi:, 10.1073/pnas.1009687108. Epub 2011 Mar 2. PMID:21368204 doi:10.1073/pnas.1009687108
- ↑ Carpenter MA, Li M, Rathore A, Lackey L, Law EK, Land AM, Leonard B, Shandilya SM, Bohn MF, Schiffer CA, Brown WL, Harris RS. Methylcytosine and normal cytosine deamination by the foreign DNA restriction enzyme APOBEC3A. J Biol Chem. 2012 Oct 5;287(41):34801-8. doi: 10.1074/jbc.M112.385161. Epub 2012 , Aug 15. PMID:22896697 doi:10.1074/jbc.M112.385161
- ↑ Ooms M, Krikoni A, Kress AK, Simon V, Munk C. APOBEC3A, APOBEC3B, and APOBEC3H haplotype 2 restrict human T-lymphotropic virus type 1. J Virol. 2012 Jun;86(11):6097-108. doi: 10.1128/JVI.06570-11. Epub 2012 Mar 28. PMID:22457529 doi:10.1128/JVI.06570-11
- ↑ Liu Y, Lan W, Wang C, Cao C. Two different kinds of interaction modes of deaminase APOBEC3A with single-stranded DNA in solution detected by nuclear magnetic resonance. Protein Sci. 2022 Feb;31(2):443-453. PMID:34792260 doi:10.1002/pro.4242
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