SII-SWORD/CoKE huggingface dataset:
Bcl-2 family (Bcl-2_fam)
Type: Family

B cell CLL/lymphoma-2 (Bcl-2) and related proteins comprise the Bcl-2 family. Bcl-2 proteins are central regulators of caspase activation, and play a key role in cell death by regulating the integrity of the mitochondrial and endoplasmic reticulum (ER) membranes . Though originally characterised with respect to their roles in controlling outer mitochondrial membrane integrity and apoptosis, the members of the Bcl-2 family are involved in numerous cellular pathways .

Bcl-2 and its relatives are functionally classified as either antiapoptotic or proapoptotic. All members contain at least one of four conserved motifs, termed Bcl-2 Homology (BH) domains. Antiapoptotic BCL-2 proteins contain four Bcl-2 homology domains (BH1-4). The major antiapoptotic proteins are Bcl-2-related gene A1 (A1), Bcl-2, Bcl-2-related gene, long isoform (Bcl-xL), Bcl-w, and myeloid cell leukemia 1 (MCL-1). They preserve outer mitochondrial membrane (OMM) integrity by directly inhibiting the proapoptotic Bcl-2 proteins .

The proapoptotic Bcl-2 members are divided into the effector proteins and the BH3-only proteins. The effector proteins Bcl-2 antagonist killer 1 (BAK) and Bcl-2-associated x protein (BAX) were originally described to contain only BH1-3; however, structure-based alignments revealed a conserved BH4 motif . Upon activation BAK and BAX homo-oligomerise into proteolipid pores within the OMM to promote MOMP (mitochondrial outer membrane permeabilisation). The BH3-only proteins function in distinct cellular stress scenarios and are subdivided based on their ability to interact with the antiapoptotic or both the antiapoptotic and the effector proteins .
Mitochondrial 28S ribosomal protein S31 (MRP-S31)
Type: Family

mS31 (also known as MRPS31) proteins are components of the mitochondrial ribosome small subunit (28S) which comprises a 12S rRNA and about 30 distinct proteins .
CWF11 family (CWF11_fam)
Type: Family

This family includes Aquarius, which is a pre-mRNA splicing factor and has RNA helicase activity. It is responsible for coupling snoRNP (small nucleolar ribonucleoprotein) assembly to intron excision . Aquarius also contributes to the maintenance of genomic stability via regulation of homologous recombination by CtIP-dependent and -independent pathways . This family also includes pre-mRNA-splicing factor cwf11, which associates with cdc5 and the other cwf proteins as part of the spliceosome and is involved in mRNA splicing .
NEDD4-binding protein 2-like 1/3 (NEDD4-bd_p2)
Type: Family

NEDD4-binding protein 2 has 5'-polynucleotide kinase and nicking endonuclease activity. It may play a role in DNA repair or recombination .
RSBN1/Dpy-21/CEP530 (RSBN1/Dpy-2/CEP530)
Type: Family

This entry represents RSNB1 proteins, Dpy-21 and Centrosome-associated protein CEP530.

Dosage compensation protein dpy-21 from C. elegans. Dpy-21 is required for X chromosome dosage compensation by reducing X-linked gene transcription in hermaphrodites throughout development .

Lysine-specific demethylase 9 (Round spermatid basic protein 1, RSBN1 or Rosbin) is a homeobox-like protein that is located in the nucleus and is expressed exclusively in haploid round spermatids. It modulates chromosome architecture by demethylating dimethylated 'Lys-20' of histone H4 (H4K20me2) .

CEP530 from Toxoplasma gondii is required for proper nuclei segregation during cell division . It plays a role in the coordination of karyokinesis and cytokinesis during the tachyzoite cell cycle.
Transmembrane protein 132 (TMEM132)
Type: Family

The transmembrane protein 132 family (TMEM132) consists of TMEM132A, TMEM132B, TMEM132C, TMEM132D, TMEM132E. These are transmembrane proteins that regulate neuronal structure and function. In mammalian cells, they may regulate NAP1 in the WAVE regulatory complex (WRC) to finely modulate actin nucleation, cellular cytoskeletal and morphological changes . TMEM132 members have been associated with panic disorders, anxiety and major depressive disorders .

TMEM132A may play a role in embryonic and postnatal development of the brain. It increased resistance to cell death induced by serum starvation in cultured cells. It regulates cAMP-induced GFAP gene expression via STAT3 phosphorylation .

These proteins consist of six globular domains: N-terminal

, 2nd

, 3rd

, 4th

, 5th

and 6th

. The latter three are a tandem of Ig-like domains .

represents the C-terminal region which includes a single transmembrane helix.
YLP motif-containing protein 1 (YLP_motif_con_p1)
Type: Family

YLP motif-containing protein 1 plays a role in the reduction of telomerase activity during differentiation of embryonic stem cells by binding to the core promoter of TERT and controlling its down-regulation .
Out at first protein (Oaf)
Type: Family

This entry represents Out at first protein from Drosophila melanogaster (Oaf) and similar animal proteins. Oaf is vital in for proper neuronal development and hatchin .
KAT8 regulatory NSL complex subunit 2 (NSL2)
Type: Family

The nonspecific lethal (NSL) complex associates with the histone acetyltransferase MOF (KAT8) in both Drosophila and mammals . KAT8 regulatory NSL complex subunit 2 (KANSL2 or NSL2) is part of the NSL complex , which is involved in acetylation of nucleosomal histone H4 on several lysine residues and therefore may be involved in the regulation of transcription .
Protein C10 (P_C10)
Type: Family

The function of this protein family is unknown. Mutations in protein C (C12orf57) are implicated in the pathogenesis of colobomatous microphthalmia .
Zinc finger C2HC domain-containing protein 1A/B-like (ZC2HC1A/B-like)
Type: Family

Proteins in this family contain Zinc finger C2HC domains. The function of this family is unknown.
Proline-rich protein 14 (PRR14)
Type: Family

The function of this family is unclear.
Coiled-coil domain-containing protein 134 (CC134)
Type: Family

This coiled-coil domain-containing protein 134 (CCDC134) is a secretory protein that regulates the mitogen activated protein kinase (MAPK) pathway . Overexpression of CCDC134 inhibits transcriptional activity of Elk1 and phosphorylation of Erk and JNK/SAPK but not p38 MAPK . In humans, CCDC134 interacts with a transcription adaptor hADA2a .
Geopeptide radical SAM maturase, putative (Geopep_mat_rSAM)
Type: Family

This family is the radical SAM/SPASM domain-containing putative peptide maturase for the geopeptide described by

. The SPASM domain frequently marks peptide-modifying radical SAM enzymes.
Exosortase-related protein XrtF (Exosortase-related_prot_XrtF)
Type: Family

This entry represents a family of exosortase-related proteins. Exosortases are proposed transpeptidases with a cysteine active site (3.4.22.-), but usually are associated with specific C-terminal target motifs (PEP-CTERM, PEF-CTERM, PGF-CTERM, etc) .
Haem oxygenase, HugZ (Haem_oxygenase_HugZ)
Type: Family

Members of this protein family are HugZ, a class of heme oxygenase that belongs to the PPOX family and lacks homology to the HmuO family. This enzyme releases iron during the conversion of heme to biliverdin .
Protein of unknown function DUF932 (DUF932)
Type: Family

This entry represents a family of prokaryotic proteins with unknown function. They contain a number of highly conserved polar residues that could suggest an enzymatic activity.
Probable tRNA pseudouridine synthase B, archaeal (TruB_arch)
Type: Family

This entry represents archaeal probable tRNA pseudouridine synthase B. It may be responsible for synthesis of pseudouridine from uracil-55 in the psi GC loop of transfer RNAs.
Methyl-coenzyme M reductase, protein C-like (Me_CoM_Rdtase_prot-C-like)
Type: Family

Members of this protein family include protein C, a non-structural protein of the operon for methyl coenzyme M reductase . The function of this protein is unknown . Other uncharacterised archaeal family members may be linked to methanogenesis or a process closely connected to it.
Formylmethanofuran dehydrogenase, subunit E (FmdE)
Type: Family

Formylmethanofuran dehydrogenases (

), found in methanogenic archaea, are molybdenum or tungsten iron-sulphur proteins containing a pterin dinucleotide cofactor. Formylmethanofuran dehydrogenase catalyses the reversible reduction of CO
2
and methanofuran via N-carboxymethanofuran (carbamate) to N-formylmethanofuran, the first and second steps in methanogenesis from CO
2
. There are two isoenzymes of formylmethanofuran dehydrogenase: a tungsten-containing isoenzyme (Fwd) and a molybdenum-containing isoenzyme (Fmd). The tungsten isoenzyme is constitutively transcribed, whereas transcription of the molybdenum operon is induced by molybdate .

This entry represents subunit E of formylmethanofuran dehydrogenase (FmdE). It has been shown that FmdE is not present in the purified enzyme in Methanosarcina barkeri , so the exact role of this subunit is unclear.
Succinylornithine transaminase (SOAT)
Type: Family

Succinylornithine transaminase catalyzes the transamination of N(2)-succinylornithine and alpha-ketoglutarate into N(2)-succinylglutamate semialdehyde and glutamate. It can also act as an acetylornithine aminotransferase .
Integrating conjugative element protein PFL_4710 (PFL_4710)
Type: Family

Members of this protein family are found in genomic regions associated with conjugative transfer and integrated TOL-like plasmids. The specific function is unknown.
Anaerobilin synthase HutW (HutW)
Type: Family

HutW is a radical SAM enzyme distinct from HemN and more similar to the class C RSMTs (radical SAM methyltransferases). It is an anaerobic heme-degrading enzyme that uses a mechanism similar to what has been reported for other RSMTs .
ATP-dependent DNA ligase, PP_1105 family (ATP_dep_DNA_lig_pp_1105_fam)
Type: Family

This entry represents a family of ATP-dependent DNA ligases. It occurs as part of a four-gene system with an exonuclease, a helicase and a phosphoesterase, with all four genes clustered or at least the first two and last two paired. This family resembles DNA ligase I, and its presumed function may be in DNA repair, replication, or recombination.
FxSxx-COOH family (FxSxx-COOH)
Type: Family

Members of this family are very short (~60 residue) polypeptides, among which the fifth and third to last residues are an invariant Phe and invariant Ser, respectively (FXS motif). This motif is a substrate for the modifications introduced by a radical SAM enzyme. The radical SAM enzyme-catalyses the cyclisation by cross-linking the side chains of the first and third residues of tripeptides such as WXN, WXR, FXN or FXS .
Radical SAM/SPASM domain, FxsB family (rSAM_SPASM_FxsB)
Type: Family

This entry represents a radical SAM/SPASM domain fusion subfamily, distinct from PqqE, MftC, anaerobic sulfatase maturases, and other peptide maturases. Some family members are fused to another domain, such as HEXXH motif domain

. Members occurring in the same cassette as a member of the FXSXX-COOH family (

) should be designated FxsB. The post-translational modifications introduced by these radical SAM enzymes are implicated in cyclophane formation, which is the crosslinking of an aromatic amino acid side chain to another side chain two residues away to form a strained cyclophane moiety .
Ligase-associated DNA damage response endonuclease PdeM-like (PdeM-like)
Type: Family

This entry represents putative DNA ligase-associated phosphodiesterases, including Ligase-associated DNA damage response endonuclease PdeM from the proteobacteria Derxia gummosa, a class III phosphodiesterase .
Alpha-ketoglutarate-HExxH-type peptide, beta-hydroxylase domain (AKG_HExxH)
Type: Domain

Sequences belonging to this entry include C-terminal extension regions shared by members of the FxsB family of radical SAM/SPASM proteins that perform post-translational modifications to FxSxx-COOH family RiPP precursor proteins, but also additional proteins from bacteria that lack an FxSxx-COOH modification system. Members of this entry that are not fused to a radical SAM domain, have a HEXXH motif that hinted at metalloprotease activity. However, the domain recently was shown instead to function as an alpha-ketoglutarate (aKG)-dependent non-heme iron beta-hydroxylase ('H') domain .
NDMA-dependent methanol dehydrogenase (NDMA_methanol_DH)
Type: Family

Members of this family belong to the iron-dependent alcohol dehydrogenase family. The NADP(H) cofactor is bound too tightly for exchange (although non-convalently), so enzymatic activity depends on a second substrate or electron carrier . The radical SAM-modified natural product mycofactocin is proposed to fill this role .
Corrinoid activation enzyme RamA (RamA_corrin_act)
Type: Family

Members of this family occur as paralogues in species capable of generating methane from mono-, di-, and tri-methylamine. Members include RamA (Reductive Activation of Methyltransfer, Amines) from Methanosarcina barkeri MS (DSM 800) . Member proteins have two C-terminal motifs with four Cys each, likely to bind one 4Fe-4S cluster per motif.
ThiI, thiazole biosynthesis domain (THII_Thiazole_biosynth_dom)
Type: Domain

The tRNA sulfurtransferase ThiI protein of Escherichia coli is a bifunctional protein in which most of the length of the protein is responsible for sulfurtransferase activity in 4-thiouridine modification to tRNA (

). This rhodanese-like C-terminal domain, by itself, is able to synthesize the thiazole moiety during thiamin biosynthesis . Note that the invariant Cys residue in this domain is unusual in being required for both activities of the bifunctional ThiI protein.
T9SS type B sorting domain (T9SS_type_B)
Type: Domain

This entry describes a C-terminal domain greatly expanded in proteins from Bacteriodetes, where Type IX secretions systems (T9SS) occur. This domain, known as Type B, is recognized as sorting signal by T9SS, whose targets are normally cleaved by a transpeptidase and then attached to a component of the outer membrane, but a few are released in soluble form. Species in this lineage include several, such as Cytophaga hutchinsonii and Flavobacterium johnsoniae, that exhibit a poorly understood rapid gliding phenotype. Several members of this protein family are found in operons with other genes whose loss leads to a loss of motility .
SynChlorMet cassette protein ScmD (SCM_PqqD-rel)
Type: Family

A biosynthesis cassette found in Syntrophobacter fumaroxidans MPOB, Chlorobium limicola DSM 245, Methanocella paludicola SANAE, and delta proteobacterium NaphS2 contains two PqqE-like radical SAM/SPASM domain proteins, a PqqD homologue, and a conserved hypothetical protein . These components suggest modification of a ribosomally produced peptide precursor, but the precursor has not been identified. Members of this family are the PqqD-like protein.
SynChlorMet cassette protein ScmC (SCM_chp_ScmC)
Type: Family

A biosynthesis cassette found in Syntrophobacter fumaroxidans MPOB, Chlorobium limicola DSM 245, Methanocella paludicola SANAE, and delta proteobacterium NaphS2 contains two PqqE-like radical SAM/SPASM domain proteins, a PqqD homologue, and a conserved hypothetical protein. These components suggest modification of a ribosomally produced peptide precursor, but the precursor has not been identified. Members of this family are designated ScmC.
SynChlorMet cassette radical SAM/SPASM protein ScmE (SCM_rSAM_ScmE)
Type: Family

A biosynthesis cassette found in Syntrophobacter fumaroxidans MPOB, Chlorobium limicola DSM 245, Methanocella paludicola SANAE, and delta proteobacterium NaphS2 contains two PqqE-like radical SAM/SPASM domain proteins, a PqqD homologue, and a conserved hypothetical protein. These components suggest modification of a ribosomally produced peptide precursor, but the precursor has not been identified. This entry represents one of the two PqqE homologues of this cassette. It is more closely related to PqqE than the other homologue.
Adhesin isopeptide-forming adherence domain (Adh_isopep-form_adh_dom)
Type: Domain

This entry represents a domain with a conserved Lys and Asn that form an intramolecular isopeptide bond . The domain is found in a variety of proteins, including cell-surface adhesins and members of the Antigen I/II family.
SynChlorMet cassette radical SAM/SPASM protein ScmF (SCM_rSAM_ScmF)
Type: Family

A biosynthesis cassette found in Syntrophobacter fumaroxidans MPOB, Chlorobium limicola DSM 245, Methanocella paludicola SANAE, and delta proteobacterium NaphS2 contains two PqqE-like radical SAM/SPASM domain proteins, a PqqD homologue, and a conserved hypothetical protein. These components suggest modification of a ribosomally produced peptide precursor, but the precursor has not been identified. This entry represents one of the two PqqE homologues of this cassette. It is more distantly related to PqqE than the other homologue.
2-methylfumaryl-CoA isomerase-like (Mct-like)
Type: Family

This entry represents 2-methylfumaryl-CoA isomerase from Chloroflexus aurantiacus (Mct) and similar bacterial proteins. Mct is involved in the glyoxylate assimilation cycle used to regenerate acetyl-CoA and produce pyruvate as universal precursor for biosynthesis. This reaction involves an intramolecular CoA transferase that catalyses the reversible transfer of the CoA moiety from the C1-carboxyl group of mesaconyl-CoA to the C4-carboxyl group. It does not require free mesaconate as CoA acceptor . Members of this protein family belong by homology to the family of CoA transferases.
Putative globular PEP-CTERM protein (Glob_PEP-CTERM)
Type: Family

Representatives of this family include a 13-member paralogous family of proteins about 215 amino acids in length from the termite gut bacterium Opitutaceae bacterium TAV2, a member of the Verrucomicrobia. Family members contain an N-terminal signal peptide and a C-terminal PEP-CTERM putative protein sorting signal. Conserved residues such as an invariant Arg and a lack of conspicuous low-complexity sequence suggest a globular structure and possible enzymatic activity. Members average about thirty percent sequence identify overall, but over seventy percent in the PEP-CTERM region. The function of this family is unknown.
Conserved hypothetical protein CHP04255 (CHP04255)
Type: Family

Members of this uncharacterised protein family are found broadly but sporadically among bacteria and archaea, including members of the genera Mycobacterium, Nostoc, Acinetobacter, Planctomyces, Geobacter, Streptomyces, Methanospirillum, etc. Their function is unknown.
GxxExxY protein (GxxExxY)
Type: Family

Members of this protein family average about 130 residues in length and include an almost perfectly conserved motif GxxExxY. Members occur in a wide range of prokaryotes, including Proteobacteria, Perrucomicrobia, Cyanobacteria, Bacteriodetes, Archaea, etc. They belong to the PD-(D/E)XK nuclease superfamily .
Arsenosugar biosynthesis radical SAM protein ArsS-like (rSAM_ArsS-like)
Type: Family

This entry represents a family of proteins predominantly found in bacteria that have an N-terminal radical SAM domain and a C-terminal domain whose function is unknown (see

). The C-terminal region has several conserved Cys residues, one of which is replaced by selenocysteine in at least five bacterial reference genomes. Slr0304 protein from Synechocystis sp. PCC 6803 (

) and Slr3097 protein from Nostoc sp. PCC 7120 (

), included in this family, have been named as ArsS, a radical SAM enzyme involved in arsenosugar biosynthesis .
C(7)-type cytochrome triheme domain (Nanowire_3heme)
Type: Domain

This domain binds three hemes, and itself occurs as a repeating unit. It occurs, for instance, four times in the dodecaheme c-type cytochrome protein GSU_1996 (

), whose crystal structure shows elongation and a nanowire-like arrangement of twelve hemes that could function in extracellular electron transport processes .
Hypoxanthine-DNA glycosylase (Hypoxan-DNA_Glyclase)
Type: Family

Members of this protein family represent family 6 of the uracil-DNA glycosylase superfamily, where the five previously described families all act as uracil-DNA glycosylase (

) per se. This family, instead, acts as a hypoxanthine-DNA glycosylase, where hypoxanthine results from deamination of adenine. Activity was shown directly for members from Methanosarcina barkeri and Methanosarcina acetivorans .
Four helix bundle suffix domain (4helix_suffix_dom)
Type: Domain

This domain occurs as a suffix domain to some members of the much broader four helix bundle protein family (

), a few of whose other members are encoded within intervening sequences of bacterial 23S ribosomal RNA. Some proteins with this domain, in turn, are followed by a predicted DNA topoisomerase type C4 zinc finger.
Oxalate/formate antiporter (Oxa/Form_antiport)
Type: Family

This entry represents a subfamily of the Major Facilitator transporter family. Family members include the known oxalate/formate antiporter of Oxalobacter formigenes, as well as transporter subunits co-clustered with the two genes of a system that decarboxylates oxalate into formate. In many of these cassettes, two subunits are found rather than one, suggesting the antiporter is sometimes homodimeric, sometimes heterodimeric.
GrrA/OscA1 cyclophane-containing rSAM-modified RiPP (GrrA/OscA1_RiPP)
Type: Family

Members of this protein family average 125 in length, roughly half of which is the repetitive and extremely Gly-rich C-terminal region. Virtually all members occur in the Cyanobacteria, in a neighbourhood that includes a radical SAM/SPASM domain, often a marker of peptide modification systems. A key feature in the C-terminal region is the presence of aromatic amino acids in repetitions of motifs such as WXN or FXN, modified by side chain crosslinking to form three-residue aromatic strained cyclophane moieties. The modified RiPP (ribosomally translated and post-translationally modified peptide) natural products are therefore classified as triceptides. Two specific members, recently, were given species-specific names OscA1 and OscA2 .
Radical SAM/SPASM domain, GrrM/OscB system (rSAM_SPASM_GrrM_OscB)
Type: Family

Members of this protein family are radical SAM/SPASM domain proteins, related to anaeroboic sulfatase maturating enzymes and the peptide modification enzyme PqqE. Members are found primarily in Cyanobacteria adjacent to a short protein, ~150 residues, in which the last ~60 residues tends to be repetitive and highly glycine-rich (see

). The post-translational modifications introduced by these radical SAM enzymes are implicated in cyclophane formation, which is the crosslinking of an aromatic amino acid side chain to another side chain two residues away to form a strained cyclophane moiety .
Substrate-binding orphan protein, GRRM family (Orph_peri_GRRM)
Type: Family

This subfamily belongs to bacterial extracellular solute-binding protein family 3. In that family, most members are ABC transporter periplasmic substrate-binding proteins. However, members of the present subfamily are orphans, in the sense of being adjacent to neither ABC transporter ATP-binding proteins or permease subunits. Instead, most members are encoded next to the two signature proteins of the proposed Glycine-Rich Repeat Modification (GRRM) system, a radical SAM/SPASM protein GrrM (

) and the Gly-rich repeat protein itself GrrA (

).
SasC/FmtB intercellular aggregation domain (SasC/FmtB_aggreg_dom)
Type: Domain

This domain, about 375 amino acids long on average, occurs mainly in Staphylococcus. It occurs as a non-repetitive N-terminal domain of LPXTG-anchored surface proteins, including SasC, Mrp, and FmtB. This region in SasC was shown to be involved in cell aggregation and biofilm formation, which may explain the methicillin resistance seen for Mrp and FmtB .
Putative exonuclease, DNA ligase-associated (Xnuc_lig_assoc)
Type: Family

Members of this protein family frequently are found annotated as a putative exonuclease involved in mRNA processing. They are associated with three other proteins: an ATP-dependent DNA ligase, a helicase, and putative phosphoesterase.