Table 2 Phyletic distribution, export pathways, and contextually-associated domains and proteins of polymorphic toxin domains

DNase toxins

Tox-NucA

HNH/EndoVII fold; GH, N, N, E

Actinobacteria, α,β,γ,δ-proteobacteria, bacteroidetes, chloroflexi, firmicutes, spirochaetes, verrucomicrobia

T2SS, T5SS, T6SS, T7SS (WXG,LXG,LDXD), PVC

Imm36, Imm-SUKH, Imm-NTF2

Proteases: PVC-Metallopeptidase, Caspase; Repeats: FilH, RHS, Tail-fiber

Tox-ColE7

HNH/EndoVII fold (PDB: 1zns);HH, H, H

Bacteroidetes, α,γ,δ,ϵ-proteobacteria, firmicutes

T2SS, T5SS, T6SS, T7SS (WXG,LXG), PyocinS

Imm-ColE7, Imm-SUKH

Repeats: FilH, RHS

Tox-HNH (including Tox-HNH-CIDE)

HNH/EndoVII fold; A DHxxE characterizes the Tox-HNH-CIDE clade.

Acidobacteria, actinobacteria, bacteroidetes, chlorobi, firmicutes, proteobacteria, Eukaryotes :metazoa

T2SS, T5SS, T7SS (WXG,LXG, LDXD), PVC, TcdB/TcaC

Imm-SUKH, Imm-SuFu, Imm14, Imm18, Imm24, Imm33,

Proteases: PVC-Metallopeptidase, HINT, Tox-PLOTU, ZU5; Repeats: FilH, RHS

Tox-AHH

HNH/EndoVII fold; [AG]HH, N, H, H, Y motif and residues

Actinobacteria, α,β,γ,δ,ϵ-proteobacteria, bacteroidetes, cyanobacteria, firmicutes, fusobacteria, lentisphaerae, planctomycetes, spirochaetes, verrucomicrobia, eukaryotes: hexapoda, Viruses: Ostreococcus lucimarinus virus, Bathycoccus sp. RCC1105 virus

T2SS, T5SS, T6SS, T7SS (LXG, WXG, LDxD), TcdB/TcaC

Imm-PA2201, Imm-ank, Imm11, Imm20, Imm23, Imm24, Imm43

Proteases: HINT; Repeats: RHS, FilH

Tox-DHNNK

HNH/EndoVII fold; DH, N, N, N, K motif and residues

Acidobacteria, actinobacteria α,β,γ,δ,ϵ-proteobacteria, firmicutes, fusobacteria, planctomycetes, spirochaetes, archaea: euryarchaeota, eukaryotes: fungi(ascomycota, basidiomycota)

T2SS, T6SS, T7SS (LXG, LDXD,WXG), PVC

Imm-SUKH, Imm-SuFu, Imm33

Proteases: PVC-Metallopeptidase, HINT

Tox-EHHH

HNH/EndoVII fold; [ED]H, H, H

Actinobacteria, bacteroidetes, β,γ,δ-proteobacteria, firmicutes

T2SS, T5SS T6SS, T7SS (WXG, LxG), TcdB/TcaC

Imm8, Imm50

Repeats: FilH, RHS

Tox-GH-E

HNH/EndoVII fold; GH, E, N, E motif and residues

Actinobacteria, bacteroidetes, β,γ,δ,ϵ-proteobacteria, chloroflexi, firmicutes, planctomycete, spirochaetes, archaea: euryarchaeota

T2SS (MafBN), T5SS, T6SS, T7SS (WXG, LxG, LDXD), PVC

Imm-SuFu, Imm-ank

Proteases: HINT, PVC-Metallopeptidase; Repeats: RHS, FilH, Tail Fiber

Tox-GHH

HNH/EndoVII fold; WxxE, W, G[HQ]H, NIxF, [DE]H; Eukaryotic versions lack the conserved histidines and a C-terminal helix

Acidobacteria, bacteroidetes, firmicutes, γ-proteobacteria, planctomycete, eukaryotes: metazoa

T2SS, T6SS, T7SS (LXG), TcdB/TcaC

Imm-SUKH

Repeats: RHS

Tox-GHH2

HNH/EndoVII fold; s[AGP]HH, HxxxH

β,γ-proteobacteria, bacteroidetes, firmicutes

T2SS, T6SS

-

Repeats: RHS

Tox-HHH

HNH/EndoVII fold; N, s[GD]xxR, HHH, H

Actinobacteria, bacteroidetes, γ-proteobacteria, firmicutes

T2SS, T5SS,T6SS, T7SS (LXG,LDXD), PVC

Imm-SUKH

Proteases: PVC-Metallopeptidase; Repeats: FilH, RHS

Tox-LHH

HNH/EndoVII fold; N, LHH, E, H, H, W

Actinobacteria, α,β,γ,δ,ϵ-proteobacteria, bacteroidetes, firmicutes, fusobacteria, planctomycetes

T2SS, T5SS, T6SS, T7SS (WXG,LXG), PVC

Imm-SUKH

Proteases: PVC-Metallopeptidase, HINT; Repeats: FilH, RHS, Tail-fiber

Tox-SHH

HNH/EndoVII fold; [SG]HH, H motif and residue

Actinobacteria, α,β,γ,δ-proteobacteria, bacteroidetes, cyanobacteria, firmicutes, planctomycetes, eukaryotes: crustacea, viruses : caudovirales

T2SS, T5SS, T6SS, T7SS (LDXD, LXG, WXG)

Imm-SUKH, Imm11, Imm24, Imm30, Imm55

Proteases: HINT Repeats: FilH, RHS, ALF

NGO1392-like (Also known as Tox-SuFu-Nuc)

HNH/EndoVII fold; CxxC, DH, CXXC, Q

Actinobacteria, α,β,γ,δ-proteobacteria, chlorobi, chloroflexi, cyanobacteria, firmicutes, spirochaetes, eukaryotes: alveolata(apicomplexa), choanoflagellida, metazoa, stramenopiles, viridiplantae, Viruses: several Mycobacteriophages, caudovirales

T2SS (MafBN), T5SS, TcdB/TcaC, PVC

Imm-SuFu, Imm13, Imm21, Imm33, Imm38

Proteases: HINT, PVC-Metallopeptidase, ZU5; Repeats: FilH, RHS, Tail fiber

Tox-WHH

HNH/EndoVII fold; WHH, L, H, HxG

Actinobacteria, α,β,γ,δ,ϵ-proteobacteria, bacteroidetes, chloroflexi, firmicutes, fusobacteria, planctomycete, synergistetes

T2SS, T5SS, T6SS, T7SS (WXG, LXG, LDXD), PVC, TcdB/TcaC

Imm-SUKH, Imm28, Imm37

Proteases: HINT, PVC-Metallopeptidase; Repeats: RHS, ALF, FilH

Tox-REase-1

Restriction endonuclease fold; E, D, ExK, Q

Actinobacteria, bacteroidetes, β,γ,ϵ-proteobacteria, cyanobacteria, fusobacteria, firmicutes, gemmatimonadetes, planctomycetes, eukaryotes: alveolata, heterolobosea

T2SS,T5SS, T6SS, T7S (WXG,LXG), TcdB/TcaC

Imm-PA2201, Imm49

Proteases: HINT, Caspase, ZU5; Repeats: FilH, RHS, Tail-fiber

Tox-REase-2

Restriction endonuclease fold; E, DG, [DE]xK, T, W

Actinobacteria

T2SS, T7SS (WXG), PrsW

-

Proteases: PrsW-peptidase

Tox-REase-3

Restriction endonuclease fold; [KR]ExD, K, ExQxK

β,γ-proteobacteria, firmicutes

T2SS (MafBN), T6SS, T7SS (WXG), PrsW

Imm-SUKH, Imm7

Proteases: PrsW-peptidase; Repeats: RHS

Tox-REase-4

Restriction endonuclease fold; D, ExK

Actinobacteria, α,β,γ,δ-proteobacteria, bacteroidetes, cyanobacteria, firmicutes, planctomycetes, spirochaetes, eukaryotes: stramenopiles

T2SS, T5SS, T6SS, T7SS (WXG,LDXD), PrsW

Imm-SUKH, Imm22, Imm54

Proteases: PrsW-peptidase; HINT; Repeats: FilH, RHS, Tail fiber

Tox-REase-5

Restriction endonuclease fold; Y, FDG, EAK, Y, Q,W

Actinobacteria, α,β,γ,δ-proteobacteria, firmicutes, fusobacteria, Viruses: caudovirales

T2SS, T5SS, T6SS, PrsW

Imm52

Proteases: PrsW-peptidase; Repeats: FilH, RHS

Tox-REase-6

Restriction endonuclease fold; E, D, ExK, Q, Y

Actinobacteria, α,β,γ-proteobacteria, bacteroidetes, cyanobacteria, firmicutes, eukaryotes: heterolobosea

T2SS, T5SS, T6SS, T7SS (WXG), PrsW

Imm49

Proteases: PrsW-peptidase; Repeats: RHS, Tail fiber

Tox-REase-7

Restriction endonuclease fold; GxxxE, IxD, ExK, Q

Actinobacteria, α,γ,ϵ-proteobacteria, bacteroidetes, cyanobacteria, firmicutes, planctomycetes, verrucomicrobia

T2SS, T5SS, T6SS, T7SS (WXG)

ImmHEAT, Imm23, Imm54

Proteases: HINT; Repeats: FilH, RHS, Tail-fiber

Tox-REase-8

Restriction endonuclease fold; GxxxQ, DD, QxK

Actinobacteria, α,β,γ,δ-proteobacteria, bacteroidetes, chlorobi, chloroflexi, firmicutes, spirochaetes, verrucomicrobia, eukaryotes: metazoa(crustacea, hexapoda,placozoa)

T2SS (APD1)

-

Repeats: Ankyrin repeats, TPR repeats, RHS

Tox-Rease-9

Restriction endonuclease fold; GxxxH, E, D, ELKP, YxxE

Actinobacteria, γ-proteobacteria, bacteroidetes, chlamydiae, firmicutes

T2SS, T7SS (LxG)

Imm54

Proteases: HINT; Repeats: RHS

Tox-Rease-10

Restriction endonuclease fold; E, Q, [DE], ExKNY, R, DxRG

β,γ,ϵ-proteobacteria, firmicutes, fusobacteria, spirochaetes

T2SS, T5SS, T7SS (WXG, LXG),

Imm54, Imm70

Repeats: FilH

Tox-URI1

URI nuclease fold; Y, YxG, R, [RK]xxE, N

Actinobacteria, α,β,γ,δ-proteobacteria, bacteroidetes, chlamydiae, chloroflexi, firmicutes, lentisphaerae, nitrospirae, verrucomicrobia, archaea: euryarchaeota, v iruses: Ostreococcus lucimarinus virus , eukaryotes: fungi

T2SS, T5SS, T6SS, TcdB/TcaC

Imm14, Imm26, Imm44, Imm51

Proteases: HINT; Repeats: RHS, FilH, Tail fiber

Tox-URI2

URI nuclease fold; Y, KxG, [EQ]

Actinobacteria, α,β,γ-proteobacteria, bacteroidetes, firmicutes

T2SS, T6SS

Imm9, Imm39, Imm12, Imm44

Proteases: HINT; Repeats: RHS, Tail fiber

RNase toxins of known fold

Tox-Barnase

Barnase-EndoU-ColicinE5/D-RelE like nuclease (BECR) fold (α + β); H, H, [ST], FP, [STD]

Actinobacteria, bacteroidetes, β,γ,δ,ϵ-proteobacteria, chlamydiae, chloroflexi, cyanobacteria, deinococci, fibrobacteres, firmicutes, fusobacteria, nitrospirae, planctomycetes archaea: euryarchaeota

T2SS, T6SS, T7SS (WXG), TcdB/TcaC, MuF, PVC

Imm-Barstar

Proteases: PVC-Metallopeptidase; Repeats: RHS

Tox-Colicin D

BECR fold (α + β); (PDB: 1v74); [KH]K, Hxx[ED], [ST], [TS]xxK; Of the conserved residues in ColicinD (PDB: 1v74), K607, K608, H611, D614, and S677 are essential for activity

β,γ,δ-proteobacteria, chloroflexi, firmicutes, spirochaetes, archaea: euryarchaeota, eukaryotes: fungi (ascomycota)

T2SS, T5SS, Cloacin, TcdB/TcaC, PVC, MuF

ImmD, Imm64; ImmD is the major immunity protein share with plasmid borne colicin systems

Proteases: PVC-Metallopeptidase; Repeats: RHS, FilH

Tox-ColicinC/E5 tRNase

BECR fold (α + β, PDB: 2dfx); K, W, Y, Y, Q, [RK], W; Of the conserved residues in Colicin E5 (PDB: 2dfx), Y81 and S95 are predicted to be involved in catalysis

β,γ-proteobacteria, firmicutes, Plasmid ColE5-099

T2SS, T5SS, T7SS (LXG), Cloacin/PyocinS, TcdB/TcaC

ImmE5

Repeats: RHS, FilH

Tox-EndoU (including XendoU)

BECR fold (α + β, PDB: 2c1w); H, H, [SNT],[SNT]; This structural core contains two BECR fold units, where the N-terminal unit has lost strand-4, while the helix in the C-terminal unit has flipped to the opposite end. In 2c1w, H162 and T278 form one pair of catalytic residues and H178 and S229 form the other. Some members use a Mn²⁺ probably as a transition state stabilizer

Actinobacteria, α,β,γ-proteobacteria, bacteroidetes, chlamydiae, cyanobacteria, fibrobacteres, firmicutes, fusobacteria, tenericutes, eukaryotes: hemichordata, viridiplantae, stramenopiles, metazoa

T2SS (MafBN), T5SS, T6SS, T7SS (WXG,LXG)

Imm-SUKH, Imm-SuFu, Imm28

Proteases: HINT; Repeats: FilH, RHS

Tox-RelE

BECR fold (α + β); [KR], R; The active site residues in the classical RelE (PDB: 3kha) correspond to residues R61 and R81

Actinobacteria, α, γ, -proteobacteria, bacteroidetes, cyanobacteria, firmicutes, fusobacteria

T2SS

Imm54

Proteases: HINT; Repeats: RHS

Ntox7

Predicted BECR fold (α + β); DGx + xhR, N motif

Actinobacteria, bacteroidetes, β,γ, δ- proteobacteria, chlamydiae, chloroflexi, firmicutes

T2SS (MafBN), T2SS (APD1), T5SS, T7SS, TcdB/TcaC

Imm8, Imm31, Imm32, Imm-NMB0513, Imm-SuFu; Imm8 is the predominant immunity protein across a wide phyletic range

Proteases : HINT, ZU5; Repeats: FilH, RHS

Ntox19

Predicted BECR fold (α + β); D,H,DxxxR,E,HxxF; Also found in mimivirus, where it is fused to ankyrin repeats,

β,γ,δ- proteobacteria, firmicutes, fusobacteria, bacteroidetes, Viruses: Acanthamoeba polyphaga mimivirus

T2SS (MafBN), T5SS, T7SS (LxG and WxG), TcdB/TcaC

Imm38, Imm40. These associations are seen across many different bacterial lineages

Repeats: FilH, RHS

Ntox21; Also referred to as the E. clocae CdiAC; Shown to be a tRNAse

Predicted BECR fold (α + β); K, [DS]xDxxxH, K, RxG[ST], RxxD

Actinobacteria, α,β,γ-proteobacteria bacteroidetes, firmicutes

T2SS (MafBN), T5SS, T4SS, T7SS

Imm-Barstar, Imm41

Proteases : HINT; Repeats: RHS, FilH

Ntox35

Predicted BECR fold (α + β); H, KH

Actinobacteria, bacteroidetes, β-proteobacteria, chlamydiae, chloroflexi, firmicutes, planctomycetes

T2SS (MafBN)

-

Repeats: RHS

Ntox36

Predicted BECR fold (α + β); N, [RY], [DE]

Acidobacteria, actinobacteria, β,γ-proteobacteria, cyanobacteria, elusimicrobia, firmicutes

T2SS, T5SS

-

Proteases: HINT; Repeats: RHS, FilH

Ntox41

Predicted BECR fold (α + β); [RK]H, [KR], [ST]xxP

Actinobacteria, α,β,γ-proteobacteria, bacteroidetes, firmicutes, planctomycetes

T2SS, T5SS, T7SS (WXG,LXG)

-

Proteases: HINT; Repeats: RHS, FilH, ALF

Ntox47

Predicted BECR fold (α + β); D, [HRK], RT, E, D, PH, H, [DE], R

β,γ-proteobacteria, firmicutes

T2SS, T6SS, T7SS (LXG,WXG)

-

Proteases: HINT; Repeats: RHS

Ntox48

Predicted BECR fold (α + β); R, [RK], Q, Q

Acidobacteria, actinobacteria, α,β,γ,δ-proteobacteria, bacteroidetes, cyanobacteria, firmicutes, fusobacteria, planctomycetes

T2SS, T5SS, T6SS T7SS (WXG,LXG),

Imm60, Imm62, Imm66, Imm71

Proteases: HINT; Repeats: RHS, FilH

Ntox49

Predicted BECR fold (α + β); H, [KR]

Actinobacteria, α,β,γ,δ-proteobacteria, bacteroidetes, chlamydiae, chloroflexi, cyanobacteria, firmicutes, thermotogae, archaea: euryarchaeota, eukaryotes: stramenopiles, viridiplantae, viruses: caudovirales

T2SS (MafBN), T5SS, T7SS (WXG,LXG), MuF, PVC

Imm22

Proteases: PVC-Metallopeptidase, HINT, ZU5; Repeats: RHS

Ntox50

Predicted BECR fold (α + β); H, S, K, T, H, K, HxVP

Actinobacteria, β,γ,δ-proteobacteria, chlamydiae, firmicutes, fusobacteria, viruses: caudovirales

T2SS (MafBN), T6SS, T7SS (WXG,LXG), MuF

-

Proteases: HINT

Predicted metal-independent RNase toxins

Tox-CdiAC

All-β; N, [DSN],E

β,γ,δ-proteobacteria

T2SS, T5SS, T6SS, TcdB/TcaC

Imm-CdiI, Imm5 + Imm36. Imm-CdiI is the most prominent immunity protein to this toxin

Repeats: RHS, FilH

Tox-ColE3

All-β; ColE3 cytotoxic ribonuclease fold, R, Dxx + [HK], E, H

Actinobacteria, α,β,γ-proteobacteria, bacteroidetes, cyanobacteria, firmicutes, fusobacteria

T2SS (MafBN), T5SS, T7SS (WXG,LXG)

Imm-Cloacin, Imm45

Proteases: HINT; Repeats: RHS, FilH

Tox-RES; PF08808 in Pfam. Also found in toxin-antitoxin systems (see text);

α + β; R, R, E, S

Acidobacteria, actinobacteria, α,β,γ,δ,ϵ-proteobacteria, bacteroidetes, chlorobi, chloroflexi, cyanobacteria, deinococci, firmicutes, nitrospirae, spirochaetes, synergistetes, verrucomicrobia, Viruses: caudovirales

T2SS, T5SS, T6SS

Imm51, Antitoxin-DUF2384(in AT system)

Repeats: RHS, FilH

Ntox2

α + β + α-helical C-terminus; GEsH motif and conserved E, RE, H and K; Multiple copies in the same gene neighborhood in Microscilla

Microscilla marina (Bacteroidetes)

PVC

-

Proteases: PVC-Metallopeptidase

Ntox4

α + β; Several charged residues

Nitrosococcus, Frankia

PVC

-

Proteases : PVC-Metallopeptidase

Ntox5

α + β; Several charged residues

Streptomyces, Nitrobacter

PVC

-

Proteases : PVC-Metallopeptidase

Ntox9

Mostly β; RxY, E, WxE and H; Catalytic mechanism likely to be similar to that of Colicin-E3

Actinobacteria, α,β,γ-proteobacteria bacteroidetes, chlamydiae, fusobacteria

T2SS (MafBN), T5SS, T6SS

-

Proteases: PrsW peptidase; Repeats: RHS

Ntox12

All-β; D, D, H

Actinobacteria, chlamydiae, firmicutes, α,β,γ- proteobacteria

T2SS, T5SS T6SS, T7SS (WxG and LxG), TcdB/TcaC

Imm32; Note immunity protein also present in intracellular parasite Odyssella

Proteases: OUT; Repeats: RHS, FilH

Ntox13

β/α, KxxxxxxE motif

Firmicutes, β-proteobacteria

T2SS

Imm59

Repeats: RHS

Proteases: Transglutaminase

Ntox15

Mostly α, HxxD motif

Actinobacteria, firmicutes, α,β,γ- proteobacteria

T2SS, T6SS, T7SS (LDxD and LxG), PVC

Imm-SUKH

Proteases: PVC-Metallopeptidase, HINT

Ntox16

α-helical domain; R, [DNE]xxH; part of polytoxin in Xanthomonas fuscans

Cyanobacteria, β,γ, δ proteobacteria, verrucomicrobia

T2SS, T6SS, PVC

-

Proteases: PVC-Metallopeptidase; Repeats: RHS

Ntox17

Mostly β; ExD, H, several charged residues

α,β,γ proteobacteria, firmicutes

T2SS (MafB), TcdB/TcaC, T7SS

Imm31; association widespread several lineages

Repeats: RHS

Ntox20

Mostly β; conserved R

Acidobacteria, α,β,γ,ϵ-proteobacteria

T2SS (MafBN), T5SS

Imm-NMB0513, Imm-SUKH Imm28

Repeats: FilH

Ntox23

All-β;

Bacteroidetes

T2SS, TcdB/TcaC

-

Repeats: RHS

ND, DxxR, H

Ntox24

All-β; Y, H, H; Also found in Toxin-Antitoxin systems (see text)

Actinobacteria, α,β,γ-proteobacteria, chlamydiae, chloroflexi, firmicutes, fusobacteria

T2SS, T5SS T7SS (WXG,LXG), MuF

Imm50, Imm53

Proteases: HINT; Repeats: RHS, FilH

Ntox25

Mostly β; FGPY motif

α,γ-proteobacteria, bacteroidetes

T2SS, T5SS

-

Repeats: FilH

Ntox27

α + β; D, E, RxW

Actinobacteria, bacteroidetes, fusobacteria

T2SS, T7SS (WXG)

-

Proteases: HINT; Repeats: ALF, RHS

Ntox28

All-α; D,K[DE], [DN]HxxE, E

Actinobacteria, α,γ-proteobacteria, firmicutes

T2SS, T5SS T7SS (WXG)

-

Repeats: FilH

Ntox31

α + β; K, E, E

Actinobacteria, α,γ-proteobacteria, bacteroidetes, firmicutes, eukaryotes: ciliophora

T2SS, T5SS, T6SS, T7SS (WXG, LXG)

Imm62

Repeats: RHS, FilH

Ntox32

All-α; H, [KR], [ED], [DE]

Bacteroidetes, α,γ-proteobacteria, firmicutes, eukaryotes: insects

T2SS

-

Proteases: Peptidase S8 (Subtilisin family); Repeats: RHS

Ntox34

All-α; GNxxD, K, C, C, K, WxCxH and other charged residues

γ,δ,ϵ-proteobacteria, firmicutes

T2SS, T6SS

Imm-HEAT

Repeats: RHS

Ntox37

All-β; E, [KR] Hx[DH]

Actinobacteria, γ-proteobacteria, chlamydiae, chloroflexi, firmicutes

T2SS, T7SS(WXG)

Imm32

Proteases: Tox-PLOTU; Repeats: RHS

Ntox39

All-β; Several basic residues

Firmicutes

T2SS

-

Repeats: RHS

Ntox40

All-β; DRxxG, R, Y

Acidobacteria, actinobacteria, α,β,γ,ϵ-proteobacteria, bacteroidetes, firmicutes, planctomycetes, synergistetes, eukaryotes: fungi

T2SS, T5SS, T6SS, T7SS (WXG,LXG,LDXD), TcdB/TcaC

Imm35, Imm36, Imm59, Imm60, Imm61, Imm63

Repeats: RHS, FilH

Ntox42

α + β; GK, ExxxH, DxYxF[ED]

Firmicutes (negativicutes)

T5SS

-

Repeats: FilH

Ntox44

All-α; DxK, GNxxxG, and DxxxD.

Actinobacteria, α,β,γ,δ-proteobacteria, bacteroidetes, chloroflexi, firmicutes, proteobacteria, spirochaetes, eukaryotes: fungi (microsporidia)

T2SS, T6SS, T7SS(WXG,LXG)

-

Proteases: Papain-like protease; Repeats: RHS, ALF

Predicted RNase toxins with two conserved histidine residues

Tox-EDA39C

α + β; H, Sx[HS]Y; Present in a wide range of eukaryotes where it might be a defensive RNAse

Acidobacteria, actinobacteria, α,β,γ,δ-proteobacteria, bacteroidetes, chlamydiae, chloroflexi, firmicutes, gemmatimonadetes, planctomycetes, verrucomicrobia, eukaryotes: plants, chlorophytes, fungi, dictyosteliida, stramenopiles

T2SS, T5SS, T6SS, T7SS (LXG)

Imm-SuFu

Proteases: HINT; Repeats: RHS

Ntox18

α/β; H, S, H

α,β,γ- proteobacteria, bacteroidetes, chloroflexi, cyanobacteria, firmicutes, eukaryotes: metazoan: Lateral transfer to Branchiostoma

T2SS (MafBN), T2SS

Imm29, Imm42; Imm29 association is widespread across bacteria

Proteases: HINT; Repeats: RHS, FilH

Ntox22

Mostly β, D, D, H, E, H

Ralstonia, Burkholderia phymatum

T5SS

-

Repeats: FilH

Ntox26

α + β; KHxx[DE], Q, W, H

Actinobacteria, α,β,γ-proteobacteria, firmicutes, fusobacteria

T2SS, T5SS T7SS (LXG)

-

Proteases: HINT; Repeats: RHS, FilH, Tail fiber

Ntox30

All-β; RxH, R THIP

Actinobacteria, bacteroidetes, α,γ-proteobacteria, firmicutes, spirochaetes

T2SS, T6SS, T7SS (WXG, LXG), TcdB/TcaC

-

Repeats: RHS

Ntox43; Pseudomonas RhsT-C belongs to this clade

α + β; with two conserved H

Actinobacteria, γ,δ-proteobacteria, firmicutes, verrucomicrobia

T2SS, TcdB/TcaC

-

Repeats: RHS

Tox-JAB-1

Deaminase fold (α + β); NxxxE, HxH, S, D

Bacteroidetes

T2SS

Imm65

Repeats: RHS

Tox-JAB-2 (DUF4329 in Pfam)

Deaminase fold (α + β); E, H[ST]H, S, D

α,γ,δ-proteobacteria bacteroidetes, cyanobacteria, firmicutes, eukaryotes: fungi (ascomycota), viruses: caudovirales

T2SS, T6SS, T7SS (WXG), TcdB/TcaC

Imm-NTF2 family 2

Repeats: RHS

Tox-ComI

α + β fold; DE motif

Actinobacteria, α,β,γ-proteobacteria, bacteroidetes, firmicutes, verrucomicrobia, eukaryotes: dictyosteliida, fungi (ascomycota, basidiomycota), viruses: Bacillus phage SP10

T2SS, T6SS

Imm-ComJ, Imm-SUKH

Proteases: HINT; Repeats: RHS

Tox-HET-C

All-α; H, [DE], HxD, HxxxDxxxH, Nxx[DE], [ST]G; We predict that the Het-C domain is related to phospholipase C and the S1-P1 nuclease and shares a common active site and fold (see text)

Actinobacteria, cyanobacteria, γ,δ-proteobacteria, dictyoglomi, eukaryotes: fungi (ascomycota, basidiomycota), metazoa

T2SS, T6SS, PVC

-

Proteases: PVC-Metallopeptidase

Ntox29

All-β; D,D, HxE, D, K, R residues

β,γ-proteobacteria, firmicutes

T2SS, T5SS,T7SS (LXG)

Imm41

Proteases: HINT; Repeats: RHS, FilH

Predicted RNase toxins with uncertain metal dependence

Ntox1

α + β fold; C, C, H, E

Acidobacteria, α-proteobacteria

PVC

Proteases: PVC-Metallopeptidase

Ntox3

All-β; several charged residues including as D, R, H, C; associated with Annexin domain in Haliangium

Haliangium (δ-proteobacteria), Microscilla (Bacteroidetes)

PVC

-

Proteases: PVC- Metallopeptidase; Repeats: Annexin

Ntox6

α + β; several charged residues;

Microcoleus(Cyanobacteria), Haliangium(δ-proteobacteria)

PVC

-

Proteases: PVC- Metallopeptidase

Ntox8

α + β fold; HxR and HxxxH motifs

β-proteobacteria, bacteroidetes, firmicutes, eukaryotes: dictyosteliida

T2SS, T6SS

Imm16

Repeats: RHS

Ntox10

α + β; Several charged residues

Bacteroidetes, verrucomicrobia

T2SS

Imm27, Imm53; Imm27 primary immunity protein across most lineages

Repeats: RHS

Proteases: Transglutaminase

Ntox11

α/β followed by β rich C-terminus; N-terminal GxR, RxxxoH motif, C-terminal domain has H, GxE, GxxH and an acidic residues; Naegleria possibly secreted

Actinobacteria, cyanobacteria, firmicutes α, δ,γ-proteobacteria, eukaryotes: Trichoplax, Naegleria

PVC

-

Proteases: PVC- Metallopeptidase

Ntox14

α + β; Several charged residues

Desulfobacca, Pelobacter (δ-proteobacteria)

PVC

Imm22

Proteases: PVC-Metallopeptidase

Ntox33

α + β; [DN]xHxxK, DxxxD

Actinobacteria, cyanobacteria, firmicutes, γ-proteobacteria, verrucomicrobia

T2SS

-

-

Ntox45

α + β; DxD motif

Actinobacteria, α-proteobacteria, bacteroidetes

T2SS

-

Proteases: HINT; Repeats: RHS

Other toxins that act on nucleic acids

Tox-Deaminase

Deaminase fold (α + β); [HCD]xE, CxxC; As previously reported, nine distinct families of deaminase belonging to two distinct clades are present in polymorphic toxin systems as toxins. We report two additional families below

Acidobacteria, actinobacteria, bacteroidetes, chlorobi, cyanobacteria, firmicutes, α,β,γ,δ,-proteobacteria Eukaryotes : See text and previous publication

T2SS (MafBN), T5SS, T6SS, T7SS (WXG, LDXD, LXG), PVC, TcdB/TcaC

Imm1, Imm2, Imm3, Imm4, Imm5,

Proteases: PVC-Metallopeptidase, HINT, CPD, PrsW peptidase, Caspase; Repeats: RHS, FilH, ALF, PPR

Imm6, Imm10, Imm18, Imm-SUKH, Imm-ank

Tox-Deaminase (sce3516-like)

Deaminase fold (α + β); H[occasionally D]xE, CxxC; Toxins of this family belong to the strand-hairpin clade of deaminases

Actinobacteria, β,γ,δ,-proteobacteria

T2SS, T5SS, T6SS T7SS, TcdB/TcaC

Imm-SUKH

Proteases: HINT

Repeats: RHS, FilH

Tox-Deaminase (WD0512-like)

Deaminase fold (α + β); CxE, CxxC; Toxins of this family belong to the Helix-4 clade of deaminases. These proteins additionally contain a C-terminal toxin, the Tox-Latrotoxin-CTD

α- proteobacteria (Wolbachia)

T2SS

-

Repeats: RHS

Tox-ParB

ParB fold (α + β); R

Actinobacteria, α,β,γ,δ-proteobacteria, bacteroidetes, firmicutes

T2SS (MafBN), T5SS, T6SS, T7SS (WXG), PVC

Imm20, Imm27, Imm-SuFu

Proteases: PVC-Metallopeptidase, HINT; Repeats: RHS, FilH

Tox-ParBL1

Predicted ParB fold (α + β); [ST], [NT][RT][RT]; note the latter two residues of this motif are mostly R

Actinobacteria,α,β,γ-proteobacteria, firmicutes, euryarchaea, eukaryotes: stramenopiles, viridiplantae, ascomycota, chlorophyta, choanoflagellida,metazoa,ciliophora, kinetoplastida

T2SS (MafBN), T5SS, T6SS, T7SS (WXG, LXG)

Imm-SUKH, Imm44

Proteases: HINT; Repeats: FilH, RHS

Tox-HTH

HTH fold; RxxY, R, [ST]

Acidobacteria, actinobacteria, α,β,γ,δ,ϵ-proteobacteria, bacteroidetes, cyanobacteria, firmicutes, proteobacteria, archaea, eukaryotes: ascomycota, viridiplantae,

T2SS, T5SS, T6SS, T7SS (LXG, WXG, LDXD), PVC, MuF

-

Proteases: PVC-Metallopeptidase; Repeats: FilH

Peptidase toxins

Tox-ALFMetallopeptidase(Anthrax lethal factor)

metallopeptidase fold (α + β); HExxH

Actinobacteria, bacteroidetes, δ-proteobacteria, firmicutes, fibrobacteres

PVC, T2SS

Imm-SuFu

Proteases: PVC-Metallopeptidase

Repeats: FilH

Tox-HopH1

metallopeptidase fold (α + β); HExxH, [DE]N

Actinobacteria, α,β,γ-proteobacteria bacteroidetes, planctomycetes

T2SS,T3SS,T5SS, T6SS,T7SS (WXG), PVC, TcdB/TcaC

-

Proteases: PVC-Metallopeptidase, ZU5, caspase; Repeats: RHS

Tox-MPTase1

metallopeptidase fold (α + β); HExxH

Actinobacteria, α,β,γ,δ-proteobacteria, bacteroidetes, chlorobi, cyanobacteria, deinococci, planctomycetes, spirochaetes, thermotogae

T2SS,T7SS (WXG), TcdB/TcaC

-

Repeats: RHS

Tox-MPTase2

metallopeptidase fold (α + β); Y, HExxH,

Bacteroidetes

TcdB/TcaC

-

Proteases: ZU5; Repeats: RHS

Tox-MPTase3

metallopeptidase fold (α + β); K, HExxH, F[DE]

α-proteobacteria, bacteroidetes

T2SS, PVC

-

Proteases: PVC-Metallopeptidase; Repeats: RHS

Tox-MPTase4

metallopeptidase fold (α + β); F[DN], [RK], HExxH

γ-proteobacteria, fusobacteria, firmicutes, planctomycetes

T2SS, T6SS, T7SS (WXG,LDXD,LXG)

-

Repeats: RHS

Tox-MPTase5

metallopeptidase fold (α + β); HEELH

Actinobacteria, γ-proteobacteria

T2SS

-

Repeats: RHS

PVC-Metallopeptidase

metallopeptidase fold (α + β); HExxH; Most versions of this domain are releasing peptidases in polymorphic toxins. However, some versions, often present at the C-terminal end of polymorphic toxins, are likely to additionally function as toxins

Acidobacteria, actinobacteria, α,β,γ,δ-proteobacteria, bacteroidetes, chlorobi, chloroflexi, cyanobacteria, deinococci, firmicutes, nitrospirae, verrucomicrobia, archaea: euryarchaeota, eukaryotes: fungi(ascomycota)

PVC

-

Proteases: PVC-Metallopeptidase; Repeats: RHS

Tox-MCF1-SHE

All-α; S, T, HSxxE

Actinobacteria, α,β,γ,δ-proteobacteria, bacteroidetes, chlamydiae, viruses: Acanthamoeba polyphaga mimivirus

T2SS, T7SS(WXG), PVC

-

Proteases: PVC-Metallopeptidase, Caspase, Tox-PLOTU

Tox-SerPeptidase

α + β; H, R, R

Actinobacteria, α,β,γ,δ,ϵ-proteobacteria

T2SS, T7SS (WXG)

-

Proteases: Tox-PLOTU

Tox-YabG

α + β; HxD, Y, E, [DE], GHD, Y, R

Bacteroidetes, firmicutes

PVC

DUF1021(antitoxin in toxin-antitoxin systems), Imm-SUKH

Proteases: PVC-Metallopeptidase

Tox-LD-peptidase

LD-peptidase (PDB: 1ZAT); H, S, C

Actinobacteria, bacteroidetes, β,γ,δ-proteobacteria, chloroflexi, firmicutes

T2SS,T6SS, TcdB/TcaC

Imm16, Imm57

Proteases: ZU5; Repeats: RHS

Tox-Caspase

Caspase-like fold (α/β); H, C; Most versions of this domain are releasing peptidases in polymorphic toxins. However, some versions, often present at the C-terminal end of polymorphic toxins, are likely to additionally function as toxins

Actinobacteria, α,β,γ,δ,ϵ-proteobacteria, bacteroidetes, chloroflexi, cyanobacteria, firmicutes, viruses: caudovirales

T2SS,T6SS, T7SS (WXG,PPE), PVC

Imm36

Proteases: PVC-Metallopeptidase; Repeats: RHS

Tox-HDC

α + β; H, D, C

β,γ-proteobacteria, viruses: caudovirales

T2SS

-

Proteases: Caspase; Repeats: RHS

Tox-NLPC/P60

Papain-like peptidase fold (α + β); C, H, D

Bacteroidetes, δ-proteobacteria

T6SS, PVC, TcdB/TcaC

-

Proteases: PVC-Metallopeptidase, ZU5; Repeats: RHS

Tox-PL1

Papain-like peptidase fold (α + β); NC, H, D; Most versions of this domain are toxins in polymorphic toxins. However, some versions are, additionally, likely to be releasing peptidases

Actinobacteria, bacteroidetes, γ,δ-proteobacteria, firmicutes, fusobacteria, gemmatimonadetes

T2SS, T3SS, T6SS, T7SS (WXG), MuF

-

Proteases: Tox-Caspase, HINT; Repeats: RHS

Tox-PL-2

Papain-like peptidase fold (α + β); C, NxxH, DN

β,δ-proteobacteria, cyanobacteria, firmicutes

T2SS, TcdB/TcaC

Imm73

Proteases: HINT, PLOTU, ZU5; Repeats: RHS

Tox-PL3

Papain-like peptidase fold (α + β); C, [DE]H, [DE], R

Bacteroidetes, fibrobacteres, δ,ϵ-proteobacteria

T2SS, TcdB/TcaC

-

Proteases: ZU5; Repeats: RHS

Tox-PLOTU

Papain-like peptidase fold (α + β); C, H, D; Most versions of this domain are releasing peptidases in polymorphic toxins. However, some versions, often present at the C-terminal end of polymorphic toxins, are likely to additionally function as toxins

Actinobacteria, α,γ-proteobacteria, bacteroidetes, chlamydiae, eukaryotes: fungi (ascomycota), metazoa, viridiplantae, viruses: Invertebrate iridescent virus 3, Wiseana iridescent virus

T2SS (APD1), T7SS (WXG)

-

Repeats: Ankyrin, Sel1, FilH

Tox-PLC39

Papain-like peptidase fold (α + β); C, H, D

Bacteroidetes, chloroflexi, firmicutes

T2SS, T6SS, PVC

-

Proteases: PVC-Metallopeptidase; Repeats: RHS

Tox-PLDMTX

Papain-like peptidase fold (α + β); C, W, H, D, Q

α,β,γ-proteobacteria

T2SS

-

-

Tox-TGase

Papain-like fold (α + β); C, H, D

β,γ,δ-proteobacteria, bacteroidetes, cyanobacteria

T2SS, T3SS, PVC

-

Proteases: PVC-Metallopeptidase

Tox-UCH

Papain-like fold (α + β) C, H, D

β-proteobacteria

PVC

-

Proteases: PVC-Metallopeptidase

Tox-OmpA

α + β;

α,β,γ-proteobacteria, cyanobacteria

PVC

-

Proteases: PVC-Metallopeptidase

Protein-modifying toxins

Tox-ART-RSE;

ADP-ribosyltransferase fold (α + β); RxDxR, S, [DN]xN, E

Actinobacteria, α,β,γ,δ-proteobacteria, bacteroidetes, chloroflexi, firmicutes, planctomycetes, spirochaetes, tenericutes, eukaryotes: fungi (ascomycota, basidiomycota), metazoan (hexapoda, mollusca), viridiplantae, viruses: Vibrio phage CTX

T2SS, T6SS, T7SS (WXG, LXG, LDXD)

Imm41, Imm-ADP-RGHD (ADP-ribosyl glycohydrolase)

Proteases: HINT, Caspase, MCF1-SHE Repeats: RHS, Tail-fiber

Tox-ART-PARP

ADP-ribosyltransferase fold (α + β); HG[ST], Y, K, E

Actinobacteria

PVC

-

Proteases: PVC-Metallopeptidase

Tox-ART-HYE1

ADP-ribosyltransferase fold (α + β); H, Y, E

γ-proteobacteria

TcdB/TcaC?

-

Repeats: RHS

Tox-ART-HYD1

ADP-ribosyltransferase fold (α + β); H,[RK], [FY], [DE]

Actinobacteria, β,γ-proteobacteria, bacteroidetes, firmicutes

T2SS, T6SS, T7SS

Imm-My6CBD;

Proteases: HINT; Repeats: RHS

Tox-ART-HYD2

ADP-ribosyltransferase fold (α + β); H, D, GFY, W, R

Actinobacteria, bacteroidetes, deinococci, fibrobacteres, firmicutes, fusobacteria, γ-proteobacteria, lentisphaerae, spirochaetes, synergistetes, eukaryotes: choanoflagellida, Capsaspora, fungi, cnidaria

T2SS, PVC

-

Proteases: HINT, PVC-Metallopeptidase; Repeats: RHS, Tail-Fiber

Tox-ARC (ADP-Ribosyl cyclase)

Flavodoxin fold (α/β); [ST] [DE], S, E

Actinobacteria, bacteroidetes, cyanobacteria, firmicutes, β, γ- proteobacteria, spirochaetes eukaryotes: fungi (ascomycota, basidiomycota), Capsaspora , choanoflagellida, metazoa; This domain appears to have independently been acquired by the fungi and the animals from the bacteria.

T2SS, T5SS, T6SS, T7SS (LXG, WXG)

Imm74, Imm63; Imm74 is the primary immunity protein across wide phyletic range

Repeats: RHS, FilH

Tox-Doc

Doc/Fic fold (PDB: 2f6s, All-α); HxFx[DE]GNxR; (See Pfam PF02661)

Actinobacteria, γ-proteobacteria

T5SS, T7SS (WXG)

Imm23, Imm-SUKH, Imm13

Proteases: Caspase; Repeats: FilH

Tox-CNF (Cytotoxic necrotizing factor)

CNF1/YfiH fold (α + β, PDB: 1hzg); D, C, H; See Pfam PF05785

γ-proteobacteria

T6SS

-

Repeats: RHS

Tox-Glycosyltransferase

Nucleotide diphospho-sugar transferase fold (α/β); [DNE]xxR, YxDxD; See Pfam PF04488

Actinobacteria

T7SS (WXG), PVC

-

Proteases: PVC-Metallopeptidase

Tox-Peptide Kinase

α + β; DxH, YKP[KR], DxHxEN, DxE, S, R; Related to the kinase domain found in lantibiotic synthetases

Firmicutes

PVC

-

Proteases: PVC-Metallopeptidase

Pore-forming toxins

Tox-WTIP

Two membrane spanning α-helices; RxxR, Wx[ST]IP

α,β,γ-proteobacteria

T2SS, PVC

-

Proteases: PVC-Metallopeptidase; Repeats: RHS

Toxins that act on carbohydrates

Tox-Aldo-ketoreductase

Rossmann (α/β);

Bacteroidetes, cyanobacteria

PVC

-

Proteases: PVC-Metallopeptidases;

Tox-Glucosaminidase

Lysozyme-like fold (α + β); E, N, Y (See Pfam PF01832)

Firmicutes

T6SS, PVC

-

Proteases: PVC-Metallopeptidase

Toxins that act on lipids

Tox-AB hydrolase1 (Pfam DUF2235)

α/β hydrolase (α/β); DG, [ST]N, [KR], D, ExE, GxHxD

Acidobacteria, actinobacteria, α,β,γ,δ,ϵ-proteobacteria, bacteroidetes, cyanobacteria, nitrospirae planctomycetes, verrucomicrobia, eukaryotes: fungi(ascomycota, basidiomycota), rhodophyta, viridiplantae

T2SS, T6SS

-

Repeats: RHS

Tox- AB hydrolase3

α/β hydrolase (α/β); G[ST], GHSxG

Actinobacteria, α,β,γ-proteobacteria, bacteroidetes, firmicutes

T2SS, T6SS,T7SS (WXG), TcdB/TcaC

Imm66, Imm69

Repeats: RHS, FilH

Tox-PLA2

Phospholipase A2 fold (All-α, PDB: 1kp4); DxC[ST], CxxHxxxYxN, C

Actinobacteria, α,β,γ,δ-proteobacteria, aquificae, bacteroidetes, chlorobi, chloroflexi, cyanobacteria, deinococci, firmicutes, fusobacteria, nitrospirae, planctomycetes, spirochaetes, eukaryotes: fungi(ascomycota), heterolobosea, metazoa, stramenopiles, viridiplantae, Viruses: Campylobacter phage

T2SS

-

Repeats: RHS, ALF

Tox-CDP-alcohol phosphatidyltransferase

All-α; DxxDGxxxR, DxxxD; See Pfam PF01066

β-proteobacteria (mainly Neisseria species)

PVC

-

Proteases: PVC-Metallopeptidase

Tox-Glycerophosphoryl diester phosphodiesterase (GDPD)

TIM Barrel (PDB: 1VD6; α/β); HRG, E, ExD, D, H; See Pfam PF03009

Cyanothece sp. (Cyanobacteria)

PVC

-

Proteases: PVC-Metallopeptidase

Miscellaneous toxins

Tox-AB hydrolase2

α/β hydrolase superfamily (α/β); NG, [DE], [KR], HSxG, D, H

acidobacteria, α,β,γ,δ,ϵ-proteobacteria, chlamydiae, fusobacteria, verrucomicrobia, eukaryotes: fungi(ascomycota, basidiomycota), stramenopiles

T2SS, T5SS, T6SS

Imm-SUKH

Repeats: FilH, RHS

Tox-ODYAM1

All-α; Several charged residues

α-proteobacteria, bacteroidetes

T2SS (APD1)

-

Proteases: Tox-PLOTU; Repeats: Sel1

Tox-LatrotoxinCTD

Two conserved α-helices; D, [ST], Y, E

α,γ-proteobacteria, eukaryotes: metazoa ( Latrodectus hasseltii, Latrodectus tredecimguttatus )

T2SS

-

Proteases: Tox-PLOTU; Repeats: ankyrin

Tox-SGS (salivary gland secreted protein)

α + β; C, C, C, C, [DE}xx[ND]

Eukaryotes: metazoan (crustacea, hexapoda)

T2SS

-

Repeats: RHS

Ntox38

All-β; PXhhG and several hydrophobic residues

Actinobacteria

T2SS, T7SS (WXG)

Imm56

Proteases: Mycosin (Subtilisin)-like protease in the neighborhood

Ntox46

α + β; [KR]STxxPxxDxx[ST], Q

α,γ,δ-proteobacteria, bacteroidetes

T2SS, T6SS

-

Repeats: RHS, FilH