Table 1 Classification, domain architectures, gene-neighborhoods and other salient features of HEPN proteins
Family (with any Pfam names/id) | Conservation of Rx4-6H | Salient Architecture and operons | Phyletic pattern, available structures and comments |
|---|---|---|---|
Nucleotidyltransferase (NT-) associated HEPN families | |||
HEPN-T (PF05168) | D replaces conserved H in several cases | Standalone versions and fusions to MNT; In the case of Sacsin it is part of a multi-domain protein with vertebrates showing a further fusion to an Ubiquitin-like domain and some animals showing a fusion to a Death domain. Several instances of genomic clustering with R-M system operons | Bacteria, Archaea, Eukaryotes |
pdb: 1wwp, 2hsb, 1o3u. | |||
Proteins with conserved D in place of H have a conserved H elsewhere which could contribute to activity | |||
HEPN-T(Parep1/8) | Lacks R but H is conserved | Fused to inactive LAF-1/Vasa-like RNA helicase N-terminal ATPase domain in Caenorhabditis. In operon with genes encoding Parep in tandem repeats or with genes encoding proteins with MNT and REase (DUF1626) | Archaea. Has two distinct families PAE0096 and PaREP1. PDB:2q00 |
HEPN-T (Cpin_6617) | No | Fusions to a dyad of ferredoxin domains (gi: 381187024, Bacteroidetes, Nitrospirae) | Mostly Bacteria |
HEPN-M (PF08780/DUF86-PF01934) | Mostly conserved (83%) | Occasionally fused to MNT, a previously undetected archaeal Holliday junction resolvase-like REase (Additional file 1), and nucleic acid methylase domains. In operon with a HAD phosphoesterase gene | PDB: 1ylm, 1jog-A. Bacteria, Archaea |
HEPN-M (SAV_6107) | No | - | actinobacteria |
Aminoglycoside_NT_C (PF07827/DUF4037) | No | Found at the C-termini of aminoglycoside nucleotidyltransferase and related proteins (gi: 15923025). Occasionally fused to TPRs (gi: 296454793) | PDB:1kny, 3jyy, 3jz0, 2pbe Bacteria |
GlnD/GlnE (PF08335)/ DUF294_C (PF10335) | No | Fused to GlnD/E-like nucleotidyltransferase. Usually part of the glutamine synthetase modifying complex. DrrA is a secreted toxin in Legionella. | PDB:1v4a, 3l0i Bacteria |
DUF4145-like | |||
DUF4145 (PF13643) | Mostly conserved (80%) | Fused to Restriction Endonuclease (REase, SF-II-Helicase); Sel1, Zinc Ribbon, TM and SH3 (Firmicutes), UvrD Helicase (endoV alpha subunit), TIR and ATPase (Thiorhodococcus drewsii AZ1); SIGMA-HTH; DpnII/MboI-NTD; AbiJ-NTD1. | Bacteria > Archaeaa, dsDNA viruses; |
In operon with R-M, TerD, McrB/C and symE toxin | |||
c2405 | Conserved H but lacks R | Fused to N-terminal AbiTii domain and in a few cases to a C-terminal Helix-hairpin-helix domain | Bacteria |
MtlR | 60% | Most often a part of mannitol operon with other mannitol utilization genes | gamma proteobacteria pdb:3c8g, 3brj |
Abi2/Swt1 | |||
Abi2/AbiF/AbiD | Yes | Abi2/AbiF/AbiD and jhp1408 families | Bacteria |
Embedded in R-M operons and also a protein with DNase domains ParB and HNH (Victivallis, Fusobacterium); | |||
Swt1-like | Partly conserved | Swt1 - Dyad of HEPN domains fused to a PIN domain, with an additional fusion to WW in some; Inactive. | Swt1 - Eukaryotes |
Ava_2192 - HEPN fused to a novel AAA + −ATPase. The Pfam profile DUF499 overlaps with this AAA + −ATPase (See Table 2); In operon with R-M components, where the SNF2-Helicase is fused to DUF3883, which is a novel REase domain. Active. | Ava_2192 - Bacterial with transfer to Naegleria, Dictyosteliida, Daphnia (expansion). All eukaryotes are solos. | ||
Cxorf38 - Zn ribbon inserted into HEPN, DSRBD, NACHT, Ankyrin, CARD and DEATH, Active. | Cxorf38 - Vertebrates, Saccoglossus, | ||
PY00838 – Fusion to Aegerolysin (Apicomplexa, Inactive) | Branchiostoma, Ciona, Nematostella. The Human gene is highly expressed in B lymphoblasts and CD56+ NK cells suggesting that this group might be involved in RNA virus defense. | ||
Other Fusions to TM (STY4199), active; Phospholipase D Nuclease (SAV_2148 ), inactive; ParB (Saro_3948), mostly active; and ParB (DUF262) with HNH(DUF2081) (VNG7073 ), active; Transglutaminase, SF-I- | |||
Helicase, Vsr REase and 2 wHTH (MTES_1575), active; CBS and HD (alr3009), active; RNASEIII and DSRBD (Cyanobacteria), active; STAND-ATPase, TPR, S1 (Npun_F6454, MED222_16016, Desac_1927), mostly active; SWI2/SNF2-ATPase (WQE_15321), active; Zinc Ribbon (Npun_R5629); ZnR with two TMs (Plim_2023), active. | |||
Ribo L-PSP-HEPN | Yes | Fused to endoRNase L-PSP(gi: 166363853) ; operon with ParB | Bacteria. Distantly related AbiF and AbiD |
Other Abi | |||
AbiU2 | Yes | In operon with a gene encoding protein with Sel1 repeats; R-M operons; | Bacteria |
AbiV | No | - | Bacteria; Has an alternative conserved H at the same position as the first HEPN-T family; hence, could be related to that family |
AbiJ | Yes | Fused to various novel N terminal domains labeled AbiJ-NTD1 to 5; Some of the solos occur in operon with R-M system | Bacteria |
AbiA-CTD | Yes | Fused to Reverse Transcriptase ; in operon with R-M system | Bacteria |
MAE_28990 | |||
MAE_28990 | Yes | In operon with a ParB nuclease and DNA methylase genes | Bacteria |
MAE_18760 | Yes | Fused to HEPN/RES-NTD1, HEPN/Toprim-NTD1, Schlafen and a novel beta rich domain. In operon with ParA/Soj ATPase of SIMIBI-type GTPase fold | Bacteria |
CRISPR-Cas | |||
Csx1( MJ1666) | Yes | A dyad of HEPN domains fused to a Rossmann fold domain (PF09455) | Archaea > Bacteria; PDB:2i71, 4EOG |
Csx1(TM1812) | Yes | HEPN fused to a Rossmann fold (PF09455), and a few other novel domains | Bacteria; |
Csm6 | Yes | HEPN fused to Csm6 (PF09659) and a helical domain | bacteria; |
Csm6 (Cas_Cas02710) | Yes | HEPN fused to Csm6 (PF09670) | Bacteria > Archaea; |
Other families | |||
Ymh (PF09509) | Yes | Solos and fusions to pMORC, AbiJ-NTD1 and AbiTii domain. | Bacteria > Archaea |
In operon with R-M | |||
C6orf70 | Yes | Fused to TPR; WD40 (Dictyostelium). | Bacteria > Eukaryotes. Overlaps with DUF4209 (PF13910). This family can be traced to LECA |
Occurs in R-M related operons | |||
DUF2526 (PF10735) | Yes | None detected | Gammaproteobacteria |
KEN (RnaseL/Ire1) | Mostly conserved (95%) | Fused to S/T/Y-Kinase, along with ankyrin repeats, CCCH in some. Also found fused to UBI (gi:125543109) and BRCT (gi: 218187285) | Eukaryotes. pdb:3lj2; solo RNase L in Oikopleura and an independent LSE of the same is also seen Plants (mainly monocots) |
Las1 | Yes | Mainly Solos. Sometimes fused to Metallo-beta-lactamase and EF-HAND (Ascomycota) and to family specific globular domains | Eukaryotes |
Rnase LS | Yes | Fused to RNase H (gi: 300902643), along with Caulimovirus viroplasmin domain (gi: 222100146). In some a TATA-binding protein (TBP)-like domain replaces the RNase H fold domain. In operon with antitoxin RnlB | Bacteria |
DZIP3/ hRUL138 | Mostly conserved | Fusion to TPR, Zn-ribbon, RING, Ankyrin, CARD, NACHT ATPase, DEATH and LRR in various animal lineages | Eukaryotes. Mainly animal lineage: LSEs in Nematostella, and the oyster and Capsaspora |
PrrC/RloC/ APECO1_4465 | Yes | Fused to ABC-ATPase. Often found in R-M operon and with genes for RhuM-like or Fic/Doc-like toxins. APECO1_4465 is also found in prophages | Bacteria |
ERFG_01251 | Yes | Fused to ABC-ATPase and HEPN/TOPRIM-NTD1 | Bacteria |
ApeA/BMEI1217 | Yes | In epsilonproteobacteria embedded in R-M operons | Bacteria > Archaea; |
EC042_2821 | Yes | Fused to wHTH, REase and ZnR domains. Occurs in R-M system operons | Bacteria overlaps with DUF3644 |
Integron cassette HEPN | Yes | Part of mobile integron element | PDB:3jrt Gammaproteobacteria |
pEK499_p136_Ecoli like (B) | Yes | Some in operon with R-M genes, ADP-ribosyltransferase-like enzymes (ART), and Macro. Also found in operon with NamA-like RNase H fold nuclease and with the Pgl components | NamA toxin / RlfA Replication in Phage P1 has a RnaseH fold |
LA2681 | Yes | Fused to TPR, and in operon with TPR | Bacteria > Archaea |
Cthe_2314 | Yes | None detected | Bacteria |
Bxe_C0808 | Yes | In operon with AbiU2 | Bacteria |