| 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
Nucleic acid editing enzymes are essential components of the immune system that lethally mutate viral pathogens and somatically mutate immunoglobulins, and contribute to the diversification and lethality of cancers. Among these enzymes are the seven human APOBEC3 deoxycytidine deaminases, each with unique target sequence specificity and subcellular localization. While the enzymology and biological consequences have been extensively studied, the mechanism by which APOBEC3s recognize and edit DNA remains elusive. Here we present the crystal structure of a complex of a cytidine deaminase with ssDNA bound in the active site at 2.2 A. This structure not only visualizes the active site poised for catalysis of APOBEC3A, but pinpoints the residues that confer specificity towards CC/TC motifs. The APOBEC3A-ssDNA complex defines the 5'-3' directionality and subtle conformational changes that clench the ssDNA within the binding groove, revealing the architecture and mechanism of ssDNA recognition that is likely conserved among all polynucleotide deaminases, thereby opening the door for the design of mechanistic-based therapeutics.
Crystal structure of APOBEC3A bound to single-stranded DNA reveals structural basis for cytidine deamination and specificity.,Kouno T, Silvas TV, Hilbert BJ, Shandilya SMD, Bohn MF, Kelch BA, Royer WE, Somasundaran M, Kurt Yilmaz N, Matsuo H, Schiffer CA Nat Commun. 2017 Apr 28;8:15024. doi: 10.1038/ncomms15024. PMID:28452355[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Madsen P, Anant S, Rasmussen HH, Gromov P, Vorum H, Dumanski JP, Tommerup N, Collins JE, Wright CL, Dunham I, MacGinnitie AJ, Davidson NO, Celis JE. Psoriasis upregulated phorbolin-1 shares structural but not functional similarity to the mRNA-editing protein apobec-1. J Invest Dermatol. 1999 Aug;113(2):162-9. PMID:10469298 doi:10.1046/j.1523-1747.1999.00682.x
- ↑ 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
- ↑ Kouno T, Silvas TV, Hilbert BJ, Shandilya SMD, Bohn MF, Kelch BA, Royer WE, Somasundaran M, Kurt Yilmaz N, Matsuo H, Schiffer CA. Crystal structure of APOBEC3A bound to single-stranded DNA reveals structural basis for cytidine deamination and specificity. Nat Commun. 2017 Apr 28;8:15024. doi: 10.1038/ncomms15024. PMID:28452355 doi:http://dx.doi.org/10.1038/ncomms15024
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