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Diversification of AID/APOBEC-Like Deaminases in Metazoa: Multiplicity

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Diversification of AID/APOBEC-Like Deaminases in Metazoa: Multiplicity Diversification of AID/APOBEC-like deaminases in PNAS PLUS metazoa: multiplicity of clades and widespread roles in immunity Arunkumar Krishnana, Lakshminarayan M. Iyera, Stephen J. Hollandb, Thomas Boehmb, and L. Aravinda,1 aNational Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894; and bDepartment of Developmental Immunology, Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany Edited by Anjana Rao, La Jolla Institute and University of California San Diego, La Jolla, CA, and approved February 23, 2018 (received for review November 30, 2017) AID/APOBEC deaminases (AADs) convert cytidine to uridine in viruses and retrotransposons through hypermutation of DNA during single-stranded nucleic acids. They are involved in numerous muta- reverse transcription (APOBEC3s) (21). genic processes, including those underpinning vertebrate innate and The deaminase superfamily displays a conserved β-sheet with adaptive immunity. Using a multipronged sequence analysis strategy, five β-strands arranged in 2-1-3-4-5 order interleaved with three we uncover several AADs across metazoa, dictyosteliida, and algae, α-helices forming an α/β-fold (the deaminase fold) (22), which it including multiple previously unreported vertebrate clades, and shares with JAB/RadC, AICAR transformylase, formate de- versions from urochordates, nematodes, echinoderms, arthropods, hydrogenase accessory subunit (FdhD), and Tm1506 superfamilies lophotrochozoans, cnidarians, and porifera. Evolutionary analysis sug- of proteins. The active site consists of two zinc (Zn)-chelating gests a fundamental division of AADs early in metazoan evolution into motifs, respectively typified by the signatures HxE/CxE/DxE at secreted deaminases (SNADs) and classical AADs, followed by diver- the end of helix 2 and CxnC (where x is any amino acid and n is ≥2) sification into several clades driven by rapid-sequence evolution, gene located in loop 5 and the beginning of helix 3 (Fig. 1). The de- loss, lineage-specific expansions, and lateral transfer to various algae. aminase superfamily contains two major divisions. In the so-called Most vertebrate AADs, including AID and APOBECs1–3, diversified in helix-4 division, which includes the Tad2/TadA, ADAR, and AID/ the vertebrates, whereas the APOBEC4-like clade has a deeper origin APOBEC-like deaminases (AADs), the helix 4 precedes the ter- INFLAMMATION IMMUNOLOGY AND in metazoa. Positional entropy analysis suggests that several AAD minal strand, resulting in strand 5 being parallel to the rest of the clades are diversifying rapidly, especially in the positions predicted sheet (Fig. 1). In the C-terminal hairpin division, containing families to interact with the nucleic acid target motif, and with potential viral such as the CDD-like, blasticidin-S–like, and DYW, strands 4 and inhibitors. Further, several AADs have evolved neomorphic metal- 5 immediately follow each other, forming a β-hairpin (22). binding inserts, especially within loops predicted to interact with the The best-known AADs are APOBEC1, AID, APOBEC2, target nucleic acid. We also observe polymorphisms, driven by alter- APOBEC3s (3A–3D; 3F–3H), and APOBEC4 (13). AID plays a native splicing, gene loss, and possibly intergenic recombination be- critical role in gnathostome (jawed vertebrate) adaptive immunity: tween paralogs. We propose that biological conflicts of AADs with viruses and genomic retroelements are drivers of rapid AAD evolution, Significance suggesting a widespread presence of mutagenesis-based immune- “ defense systems. Deaminases like AID represent versions institution- Mutagenic AID/APOBEC deaminases (AADs) are central to ” alized from the broader array of AADs pitted in such arms races for processes such as generation of antibody diversity and antiviral mutagenesis of self-DNA, and similar recruitment might have inde- defense in vertebrates. Their presence and role outside verte- pendently occurred elsewhere in metazoa. brates are poorly characterized. We report the discovery of several AADs, including some that are secreted, across diverse DNA/RNA editing | immunity | arms race | biological conflicts | metazoan, dictyosteliid, and algal lineages. They appear to retroelements have emerged from an early transfer of an AAD from bacterial toxin systems, followed by extensive diversification into multi- he deaminase superfamily encompasses zinc-dependent en- ple eukaryotic clades, showing dramatic structural innovation, Tzymes catalyzing the deamination of bases in free nucleotides rapid divergence, gene loss, polymorphism, and lineage-specific and nucleic acids across diverse biological contexts (1–3). These expansions. We uncover evidence for their divergence in arms- include enzymes that are (i) primarily involved in the salvage of race scenarios with viruses and genomic retroelements and bases in free nucleotides, such as the cytidine deaminases (CDD/ show that AAD-based nucleic acid mutagenesis as a basis of CDA) (4), deoxycytidylate monophosphate deaminases (dCMP) immune defense is widespread across metazoa, slime molds, (5), and guanine deaminase (GuaD) (6); (ii) engaged in the bio- and algae. synthesis of modified nucleotide-derived compounds (e.g., blasticidin- Author contributions: A.K., L.M.I., S.J.H., T.B., and L.A. designed research; A.K., L.M.I., and S deaminase) (7) and the RibD deaminase domain (8); and (iii)active L.A. performed research; S.J.H., T.B., and L.A. contributed new reagents/analytic tools; in in situ modifications of bases in nucleic acids, such as tRNA A.K., L.M.I., and L.A. analyzed data; and A.K., L.M.I., and L.A. wrote the paper. adenosine deaminases (Tad2/TadA and Tad1) (9), RNA-specific The authors declare no conflict of interest. adenosine deaminase (ADAR) (10), RNA-editing cytidine deami- This article is a PNAS Direct Submission. nases such as DYW (11, 12), and members of the AID (activation- This open access article is distributed under Creative Commons Attribution-NonCommercial- induced deaminase)/APOBEC family, which modify both DNA and NoDerivatives License 4.0 (CC BY-NC-ND). RNA (13, 14). This last group of deaminases is implicated in the Data deposition: The sequence reported in this paper has been deposited in the Sequence Read Archive at the NCBI (accession nos. SAMN08013505, SAMN08013506,and generation of degenerate codons for decoding during translation SAMN08013507). – (Tad2/TadA) (9, 15); stabilization of codon anti-codon interactions 1To whom correspondence should be addressed. Email: [email protected]. (Tad1) (16, 17); editing mRNAs, siRNAs, and miRNA precursors; This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. inactivation of RNA viruses by hypermutation (ADAR) (10, 18, 19); 1073/pnas.1720897115/-/DCSupplemental. diversification of antibodies (AID) (20); and defense against retro- www.pnas.org/cgi/doi/10.1073/pnas.1720897115 PNAS Latest Articles | 1of10 Downloaded by guest on September 28, 2021 A helix-1 helix-2 FINAL NP_065712.1_AID_Hsap 4LLMNR R K F LYQ FKN 9 T Y L C YVV FGYLR N K 3 H V E L L F L R Y I S D WD 6 NP_663745.1_APOBEC3_Hsap 11 H LMDPH I FTSN FNN 6 T Y L C YEV RGFLH N Q 11H A E L R F L D L VPS L Q6 NP_001635.2_APOBEC1_Hsap 16 R RIEPWE FDVF C L L YEI N T 2 H V E VNF I K K F T S E R7 NP_006780.1_APOBEC2_Hsap 45 E RLPAN F F KFQ FRN 9 T F L C YVV RGYLE D E 4 H A E EAFFN T ILPAF5 XP_018105362.1_NAD1_Xlae 17 K LVSF E D FNGN FNN 6 T L A C FN WGFAY N N 4 H A E Q I I L Q E LYT F L10 GFIP01022257.1_NAD1_Pbuc 35 K QIPE D I F Y Q E FNN 6 T L L F FGLGQ WGYTF N R 3 H A E I R L LGFI K G F L10 H3B7Z9_LATCH_NAD1_Lcha 3KQLSK E E F EAE FNN 6 T L L C FSL Q Q WGYAH N N 4 H A E I L V L R E I E K Y L10 GECV01074881.1_NAD2_Mfis 23 I QMTPS I F ISH YAT 6 T H L C YEV N T 3 H A E EVF IGE RFR D E3 ABO15149.1_PmCDA1_Pmar 11 E KLDIYT F KKQ FFN 5 S HRC YVL WGYAV N K 9 H A E I FSI R K V E E Y L6 AIY70103.1_LcCDA1l_Lcam 7KKLPL N T F LFE FNN C YIF WGYAT N K 17H T E E L L L D E M T R HV 7 ABO15150.1_PmCDA2_Pmar 22RVAFL R C FAAPSQK 3 T V I L FYV VNY N K 5 H A E V L L L S A V R AAL15 AAGJ05003720.1_Spur 11 G EEIL N I FVKS GLH V C L VTF IKQ-- N R 3 H A E RDI I E F L R FNI3 GAGS01028218.1_Bsia 14 N LQLF T D ITNAGVH 7 T S A V N G3H A E IAL I E Q L T S F F9 AAGJ05065417.1_Spur 1 - - D I L K N F IHS GLH 13 T V V C LIV N I4H V E Q I L I E Y I N S K L5 GDJY01027842.1_Lana 134 A T D I M D T F ERS GPH 7 T DSY CVF RSFIF N D 4 H A E E Q A V N F LAK N I5 AKZP01034351.1_Pmin 10 I QEDI E T F IKS A V LL S T 3 H A E MNA VPS IFE L L3 GBYC01056953.1_Aele 22KNEIVR S F LVT SMY 9 T V V V CEI KVYR- N D 3 H A E I K L IGYL K D DS 7 APKA01034104.1_Bgla 19TTDDF D M F WRT HLM11 T I L Y WN RREG- T P2H AAAAVAR D LMT Q V8 NP_982279.1_APOBEC4_Hsap 3PIYEEYLANHGTIV11C SNCPYH ----32T F YE Q KGHAS S C 5 H P E S M LFE MNGYLD 9 XP_001622116.1_Nvec 59 V LGNK K E F C GAFYH 7CLDKQ S----C12T A V A LVK N C 5 H A E E F F LMD I D C Q L18 XP_005783540.1_Ehux 77 L LGTTAQ F C S S FYH 12CLSVAAGGPPC 3T V I C VARL Q LYI 4N C 9 H A E Q F L L Q D E D L RS33 GAWS02034135.1_Pame 12HSYFF R R M WNE Q S C VV Q K 4 H A E V K A L Q H V Q E K E6 KDR09461.1_Znev 46IVSTSK D I WTA C IT EISY- S H 4 H A E I K V L R N I K A R E7 XP_002637598.1_Cbri 148CTNGAS K FSVPKHV10 APOBEC4 S SGL IVT RGDFY 2S K 3 H V E E Q L VAAIYD L I7 GFAV01000705.1_SNAD4_Htub 217 E RELQ VVHIAC AED 2 T H L LYR-- S A8H A E M E F I R S R K Q T- GFAV01006376.1_SNAD4_Htub 14 L MKLNE ATKIACTT 3 Cnidaria-algae Zn T I L L LVL FYY-- N T 3 H A E MVM I D N Q S S D K1 XP_005947721.1_SNAD3_Hbur 236PSVNAN
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