SII-SWORD/CoKE huggingface dataset:
Proteinase inhibitor I46, leech metallocarboxypeptidase inhibitor (Prot_inh_LCI)
Type: Homologous_superfamily

Leech carboxypeptidase inhibitor (LCI) is a novel protein inhibitor present in the medicinal leech Hirudo medicinalis. The structures of LCI free and bound to carboxypeptidase A2 (CPA2) have been determined by NMR and X-ray crystallography, respectively . The LCI structure has a motif that comprises a five-stranded antiparallel β-sheet and one short α-helix. This structure is preserved in the complex with human CPA2. The C-terminal tail of LCI becomes rigid upon binding the protease and it interacts with the carboxypeptidase in a substrate-like manner.

LCI shares sequence identity at its C terminus (-Thr-Cys-X-Pro-Tyr-Val-X) with carboxypeptidase inhibitors from family I37 - the potato carboxypeptidase inhibitors, this represents a striking example of convergent evolution dictated by the target protease .
FdhE-like superfamily (FdhE-like_sf)
Type: Homologous_superfamily

This superfamily represents a domain found in formate dehydrogenase accessory protein FdhE and homologues. It consists of an N-terminal five-helical bundle, a tandem repeat of two rubredoxin-like domains and a C-terminal helix packed together.
DNA topoisomerase V, catalytic domain superfamily (TopoV_catalytic_dom_sf)
Type: Homologous_superfamily

DNA topoisomerases regulate the number of topological links between two DNA strands (i.e. change the number of superhelical turns) by catalysing transient single-or double-strand breaks, crossing the strands through one another, then resealing the breaks . These enzymes have several functions: to remove DNA supercoils during transcription and DNA replication; for strand breakage during recombination; for chromosome condensation; and to disentangle intertwined DNA during mitosis . DNA topoisomerases are divided into two classes: type I enzymes (

; topoisomerases I, III and V) break single-strand DNA, and type II enzymes (

; topoisomerases II, IV and VI) break double-strand DNA .

Topoisomerases are involved in controlling and maintaining the topology of DNA and are present in all kingdoms of life. Unlike all other types of topoisomerases, similar type IB enzymes have only been identified in bacteria and eukarya. The only putative type IB topoisomerase in archaea is represented by Methanopyrus kandleri topoisomerase V. Uniquely, this topoisomerase also displays DNA repair activities . Despite several common functional characteristics, topoisomerase V shows no sequence similarity to other members of the same type. The topoisomerase V protein consists of an N-terminal catalytic domain followed by 24 tandem helix-hairpin-helix (HhH) motifs. The N-terminal domain can relax DNA in the absence of any HhH motifs, while the HhH motifs are required for stable protein-DNA complex formation .

This superfamily represents the catalytic domain of topoisomerase V.
RGS, subdomain 1/3 (RGS_subdom1/3)
Type: Homologous_superfamily

RGS (Regulator of G Protein Signalling) proteins are multi-functional, GTPase-accelerating proteins that promote GTP hydrolysis by the alpha subunit of heterotrimeric G proteins . Upon activation by GPCRs, heterotrimeric G proteins exchange GDP for GTP, are released from the receptor, and dissociate into free, active GTP-bound alpha subunit and beta-gamma dimer, both of which activate downstream effectors. Usually, the response is terminated upon GTP hydrolysis by the alpha subunit (

), which can then bind the beta-gamma dimer (

,

) and the receptor. However, in some cases, RGS proteins can have a positive effect on signal potentiation .

All RGS proteins contain an 'RGS-box' (or RGS domain), which is required for activity. Some small RGS proteins such as RGS1 and RGS4 are comprised of little more than an RGS domain, while others also contain additional domains that confer further functionality . RGS domains can be found in conjunction with a variety of domains, including: DEP for membrane targeting (

), PDZ for binding to GPCRs (

), PTB for phosphotyrosine-binding (

), RBD for Ras-binding (

), GoLoco for guanine nucleotide inhibitor activity (

), PX for phosphatidylinositol-binding (

), PXA that is associated with PX (

), PH for stimulating guanine nucleotide exchange (

), and GGL (G protein gamma subunit-like) for binding G protein beta subunits (

) . Those RGS proteins that contain GGL domains can interact with G protein beta subunits to form novel dimers that prevent G protein gamma subunit binding and G protein alpha subunit association, thereby preventing heterotrimer formation.

The RSG box in RSG4 corresponds to an array of α-helices that fold into two domains. Both are required for GAP (GTPase activating protein) activity . This superfamily represents the subdomains 1 and 3 of the RSG box.
Methylmalonyl-CoA mutase small subunit, N-terminal (Me-malonyl-CoA_mutase_sm_su_N)
Type: Homologous_superfamily

Methylmalonyl-CoA mutase (

) catalyses the isomerization of succinyl-CoA to methylmalonyl-CoA during the synthesis of propionate from tricarboxylic acid-cycle intermediates in propionic acid fermentation.

This entry represents the N-terminal portion of the catalytic domain found in methylmalonyl-CoA mutase small subunits.
Rotavirus NSP2, N-terminal (Rotavirus_NSP2_N)
Type: Homologous_superfamily

Rotavirus non-structural protein 2 (NSP2) is a basic protein which possesses RNA-binding activity and is essential for genome replication . It may also be important for viral RNA packaging.

This superfamily represents the N-terminal domain of Rotavirus NSP2.
AF2212-like domain superfamily (AF2212-like_dom_sf)
Type: Homologous_superfamily

This domain superfamily is found in protein AF2212 (also known as putative antitoxin VapB21) from the archaean Archaeoglobus fulgidus, and other uncharacterised proteins belonging to the UPF0165 family. The structure of AF2212 has been solved (2NWT) but not published. The AF2212-like domain is irregular with few secondary structures.
S-Me-THD, C-terminal domain superfamily (S-Me-THD_C_sf)
Type: Homologous_superfamily

This β-barrel domain is found at the C-terminal of S-methyl thiohydantoin desulfurase from Variovorax sp. (S-Me-THD) and similar sequences mainly found in bacteria and fungi. S-Me-THD catalyses the hydrolysis of S-methyl-thiohydantoin-5-propanoate into hydantoin-5-propanoate and methanethiol, the third step in S-methyl ergothioneine degradation .
Dihydrofolate reductase-like domain superfamily (DHFR-like_dom_sf)
Type: Homologous_superfamily

Dihydrofolate reductase (DHFR) catalyses the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate, an essential step in
de novo
synthesis both of glycine and of purines and deoxythymidine phosphate (the precursors of DNA synthesis) , and important also in the conversion of deoxyuridine monophosphate to deoxythymidine monophosphate.

This superfamily represents a structural domain found in dihydrofolate reductases, as well as in riboflavin biosynthesis proteins (usually as a C-terminal domain) and related enzymes.
Argininosuccinate synthetase mutimerisation domain, C-terminal tail (AS_multimer_C_tail)
Type: Homologous_superfamily

The argininosuccinate synthetase (AS) monomer is composed of a nucleotide binding domain and a catalytic/multimerisation domain. The catalytic/multimerisation domain possesses a C-terminal tail, which is involved in protein dimerisation and tetramerisation . The tail contains two α helices. In a subset of bacterial species, it also contains a short terminal β structure.

This superfamily represents the C-terminal tail containing the α helices and the β structure.
Argininosuccinate synthetase, catalytic/multimerisation domain body (AS_cat/multimer_dom_body)
Type: Homologous_superfamily

The argininosuccinate synthetase (AS) monomer is composed of a nucleotide binding domain and a catalytic/multimerisation domain. The catalytic/multimerisation domain can be subdivided in the body of the domain and a C-terminal tail involved in multimerisation, though this tail is not present in all sequences.

This entry represents the body of the catalytic/multimerisation domain. It is a mixed α/β fold consisting of two four-stranded antiparallel β sheets arranged end-to-end to form a cradle for a cluster of five α helices. In general, the α helices of the domain are responsible for multimerisation interactions, whereas the β sheets form the solvent-exposed surface .
DNA-directed RNA polymerase, helix hairpin domain superfamily (DNA-dir_RNA_pol_helix_hairp_sf)
Type: Homologous_superfamily

The single subunit DNA-directed RNA polymerase (RNAP) that is encoded by bacteriophage T7 is the prototype of a class of relatively simple RNAPs that includes the RNAPs of the related phages T3 and SP6, as well as the mitochondrial and chloroplastic RNAPs . This superfamily represents a helix hairpin structural domain found in this type of RNA polymerases.
Rotavirus NSP2, C-terminal (Rotavirus_NSP2_C)
Type: Homologous_superfamily

Rotavirus non-structural protein 2 (NSP2) is a basic protein which possesses RNA-binding activity and is essential for genome replication . It may also be important for viral RNA packaging.

This superfamily represents the C-terminal domain of the Rotavirus NSP2.
Neurolysin/Thimet oligopeptidase, domain 2 (Neurolysin/TOP_dom2)
Type: Homologous_superfamily

Thimet oligopeptidase and neurolysin are closely related zinc-dependent metallopeptidases that metabolize small bioactive peptides. They cleave many substrates at the same sites, but they recognise different positions on others .

This entry represents an α orthogonal bundle domain found in these and related peptidases.
Putative deacetylase LmbE-like domain superfamily (LmbE-like_dom_sf)
Type: Homologous_superfamily

This superfamily represents a domain which consists of a 3-layer (α/β/α) sandwich, and it is found in the enzymes 1D-myo-inositol 2-acetamido-2-deoxy-alpha-D-glucopyranoside deacetylase and N-acetylglucosaminyl-phosphatidylinositol de-N-acetylase, as well as in uncharacterised putative deacetylases.
Metallopeptidase, catalytic domain superfamily (MetalloPept_cat_dom_sf)
Type: Homologous_superfamily

This superfamily represents the catalytic domain of different metallopeptidases. It consists of a three layer α-β-α sandwich.
Neurolysin/Thimet oligopeptidase, N-terminal (Neurolysin/TOP_N)
Type: Homologous_superfamily

Thimet oligopeptidase and neurolysin are closely related zinc-dependent metallopeptidases that metabolize small bioactive peptides. They cleave many substrates at the same sites, but they recognise different positions on others .

This entry represents the up-down α bundle domain found at the N terminus of these and related M3 peptidases.
Proline dehydrogenase PutA, domain II (PRODH_PutA_dom_II)
Type: Domain

This entry represents domain II of PutA. It has been suggested that this domain may be involved in DNA binding .

The PutA flavoprotein from Escherichia coli plays multiple roles in proline catabolism by functioning as a membrane-associated bi-functional enzyme and a transcriptional repressor of proline utilisation genes .
Fumarase/histidase, N-terminal (Fumarase/histidase_N)
Type: Homologous_superfamily

This entry represents an N-terminal structural domain which forms an α-helical orthogonal bundle found in fumarate lyase (fumarase) and related proteins, as well as in histidine ammonia-lyase (or histidase) .

One member of the fumarate lyase family is L-aspartate ammonia-lyase (aspartase), which catalyses the reversible deamination of the amino acid L-aspartic acid, using a carbanion mechanism to produce fumaric acid and ammonium ion. Aspartases from different organisms show high sequence homology, and this homology extends to functionally related enzymes such as the class II fumarases, the argininosuccinate and adenylosuccinate lyases. The high-resolution structure of aspartase reveals a monomer that is composed of three domains oriented in an elongated S-shape .
Isopropylmalate dehydrogenase-like domain (IsoPropMal-DH-like_dom)
Type: Domain

The isocitrate and isopropylmalate dehydrogenases family includes isocitrate dehydrogenase (IDH), 3-isopropylmalate dehydrogenase (IMDH) and tartrate dehydrogenase.

IDH is an important enzyme of carbohydrate metabolism which catalyses the oxidative decarboxylation of isocitrate into alpha-ketoglutarate . IDH is either dependent on NAD
+
(

) or on NADP
+
(

). In eukaryotes there are at least three isozymes of IDH: two are located in the mitochondrial matrix (one NAD
+
-dependent, the other NADP
+
-dependent), while the third one (also NADP
+
-dependent) is cytoplasmic. In Escherichia coli, the activity of a NADP
+
-dependent form of the enzyme is controlled by the phosphorylation of a serine residue; the phosphorylated form of IDH is completely inactivated.

IMDH (

) catalyses the third step in the biosynthesis of leucine in bacteria and fungi, the oxidative decarboxylation of 3-isopropylmalate into 2-oxo-4-methylvalerate .

This entry represents a structural domain found in all types of isocitrate dehydrogenase, and in isopropylmalate dehydrogenase and tartrate dehydrogenase. The crystal structure of Escherichia coli isopropylmalate dehydrogenase has been described .
Phosphoglucosamine mutase, archaeal type (GlmM_arc-type)
Type: Family

The entry represents a group of phosphoglucosamine mutases (encoded by gene GlmM) from archea and bacteria. MMP1680 protein from Methanococcus maripaludis in this family has been characterised as the archaeal protein responsible for the second step of UDP-GlcNAc biosynthesis . MMP1680 protein catalyses the conversion of glucosamine-6-phosphate to glucosamine-1-phosphate. This entry also includes a number of sequences from non-archaea in the Bacteroides, Chlorobi, Chloroflexi, Planctomycetes and Spirochaetes lineages .

In some organisms including Leptospira, this archaeal GlmM is found adjacent to the GlmS as well as a putative GlmU non-orthologous homologue .

This family of phosphoglucosamine mutases and the bacterial family of phosphoglucosamine mutases represented by

are members of the larger phosphoglucomutase/phosphomannomutase family (characterised by three domains:

,

and

), but are not nearest neighbours to each other.
Creatininase-like superfamily (Creatininase-like_sf)
Type: Homologous_superfamily

Creatinase (

) catalyses the hydrolysis of creatinine to creatine, which can then be metabolised to urea and sarcosine by creatinase. Formamide hydrolase catalyzes the hydrolysis of the formamide of 2-amino-5-formylamino-6-ribosylamino-4(3H)-pyrimidinone 5'-monophosphate (FAPy) to form 2,5-diamino-6-ribosylamino-4(3H)-pyrimidinone 5'-phosphate (APy) (

).

Creatininase from Pseudomonas putida has a structure consisting of 3-layers, α/β/α, where the core consists of a parallel β-sheet of 4 strands. The enzyme is a typical Zn2+ enzyme with a binuclear metal centre .

This superfamily represents the structural domain found in creatininases and in formamide hydrolases.
Tyrosine-tRNA ligase, bacterial-type (Tyr-tRNA-ligase_bac-type)
Type: Family

Two main groups can be distinguished among tyrosine-tRNA ligases: one group contains bacterial and organellar eukaryotic proteins and the other archaeal and cytosolic eukaryotic proteins. This entry represents the bacterial and organellar eukaryotic tyrosine-tRNA ligases.

Tyrosine-tRNA ligases (TyrRS; also known as Tyrosyl-tRNA synthetases) (

) are widely distributed, being found in archaea, bacteria and eukaryotes. TyrRS is a homodimer which attaches Tyr to the appropriate tRNA. TyrRS is a class I tRNA synthetases, so it aminoacylates the 2'-OH of the nucleotide at the 3' end of the tRNA. The core domain is based on the Rossman fold and is responsible for the ATP-dependent formation of the enzyme bound aminoacyl-adenylate. It contains the class I characteristic 'HIGH' and 'KMSKS' motifs, which are involved in ATP binding. Studies have shown that the 'KMSKS' motif plays a role in the initial binding of tRNA(Tyr) to tyrosine-tRNA ligase .

The aminoacyl-tRNA synthetases (also known as aminoacyl-tRNA ligases) catalyse the attachment of an amino acid to its cognate transfer RNA molecule in a highly specific two-step reaction . These proteins differ widely in size and oligomeric state, and have limited sequence homology . The 20 aminoacyl-tRNA synthetases are divided into two classes, I and II. Class I aminoacyl-tRNA synthetases contain a characteristic Rossman fold catalytic domain and are mostly monomeric . Class II aminoacyl-tRNA synthetases share an anti-parallel β-sheet fold flanked by α-helices , and are mostly dimeric or multimeric, containing at least three conserved regions . However, tRNA binding involves an α-helical structure that is conserved between class I and class II synthetases. In reactions catalysed by the class I aminoacyl-tRNA synthetases, the aminoacyl group is coupled to the 2'-hydroxyl of the tRNA, while, in class II reactions, the 3'-hydroxyl site is preferred. The synthetases specific for arginine, cysteine, glutamic acid, glutamine, isoleucine, leucine, methionine, tyrosine, tryptophan, valine, and some lysine synthetases (non-eukaryotic group) belong to class I synthetases. The synthetases specific for alanine, asparagine, aspartic acid, glycine, histidine, phenylalanine, proline, serine, threonine, and some lysine synthetases (non-archaeal group), belong to class-II synthetases. Based on their mode of binding to the tRNA acceptor stem, both classes of tRNA synthetases have been subdivided into three subclasses, designated 1a, 1b, 1c and 2a, 2b, 2c .

The class Ia aminoacyl-tRNA synthetases consist of the isoleucyl, methionyl, valyl, leucyl, cysteinyl, and arginyl-tRNA synthetases; the class Ib include the glutamyl and glutaminyl-tRNA synthetases, and the class Ic are the tyrosyl and tryptophanyl-tRNA synthetases .
Proline dehydrogenase PutA, domain I/II (PRODH_PutA_dom_I/II)
Type: Homologous_superfamily

The PutA flavoprotein from Escherichia coli plays multiple roles in proline catabolism by functioning as a membrane-associated bi-functional enzyme and a transcriptional repressor of proline utilisation genes .

This entry spans domain I and II of PutA.
Proline dehydrogenase PutA, domain I (PRODH_PutA_dom_I)
Type: Homologous_superfamily

The PutA flavoprotein from Escherichia coli plays multiple roles in proline catabolism by functioning as a membrane-associated bi-functional enzyme and a transcriptional repressor of proline utilisation genes .

This entry represents domain I of PutA.
LnmK-like bifunctional acyltransferase/decarboxylase domain (LnmK-like_bifun_acyl/decarbox)
Type: Domain

The founding member of this family, LnmK from Streptomyces atroolivaceus, is a bifunctional enzyme that apparently carries out acyltransferase and decarboxylase reactions at the same active site . LnmK belongs to a polyketide biosynthetic gene cluster for leinamycin biosynthesis. This domain may occur in free-standing proteins such as LnmK, or in large, multidomain polyketide synthases or other contexts.
Uncharacterised protein family MTH865 (Uncharacterised_MTH865)
Type: Family

This entry represents a group of uncharacterised hypothetical proteins from archaea and bacteria, including the 8.4kDa protein MTH865 from Methanobacterium thermoautotrophicum. The NMR structure of MTH865 reveals an EF-Hand-like fold consisting of four helices in two hairpins .
Cytochrome f large domain (Cyt_f_lg_dom)
Type: Domain

The cytochrome b6f integral membrane protein complex transfers electrons between the two reaction centre complexes of oxygenic photosynthetic membranes, and participates in formation of the transmembrane electrochemical proton gradient by also transferring protons from the stromal to the internal lumen compartment. The cytochrome b6f complex contains four polypeptides: cytochrome f (285 aa); cytochrome b6 (215 aa); Rieske iron-sulphur protein (179 aa); and subunit IV (160 aa) . In its structure and functions, the cytochrome b6f complex bears extensive analogy to the cytochrome bc1 complex of mitochondria and photosynthetic purple bacteria; cytochrome f (cyt f) plays a role analogous to that of cytochrome c1, in spite of their different structures .

The 3D structure of Brassica rapa (Turnip) cyt f has been determined . The lumen-side segment of cyt f includes two structural domains: a small one above a larger one that, in turn, is on top of the attachment to the membrane domain. The large domain consists of an anti-parallel β-sandwich and a short haem-binding peptide, which form a three-layer structure. The small domain is inserted between β-strands F and G of the large domain and is an all-beta domain. The haem nestles between two short helices at the N terminus of cyt f. Within the second helix is the sequence motif for the c-type cytochromes, CxxCH (residues 21-25), which is covalently attached to the haem through thioether bonds to Cys-21 and Cys-24. His-25 is the fifth haem iron ligand. The sixth haem iron ligand is the alpha-amino group of Tyr-1 in the first helix . Cyt f has an internal network of water molecules that may function as a proton wire . The water chain appears to be a conserved feature of cyt f.

This entry represents the large domain of cytochrome f.
Vesicle tethering protein p115 (Vesicle_P115)
Type: Family

General vesicular transport factor P115, also known as USO1, is required for inter-cisternal transport in the Golgi stack and for transcytotic fusion and/or subsequent binding of the vesicles to the target membrane . It is required for both the formation of the Golgi stacks and the maintenance of the individual cisternae .
NO signalling/Golgi transport ligand-binding domain superfamily (NO_sig/Golgi_transp_ligand-bd)
Type: Homologous_superfamily

This superfamily represents a domain is found in different trafficking protein particle complex (TRAPP) subunits involved in vesicular transport from the endoplasmic reticulum to Golgi . It is also found in soluble guanylate cyclases, where it binds heme via a covalent linkage to histidine . Soluble guanylate cyclases are nitric oxide-responsive signaling proteins.
Basic helix-loop-helix leucine zipper transcription factor (bHLH_ZIP_TF)
Type: Family

This family consists of different transcription factors that have a basic helix-loop-helix and a leucine zipper motif. Many different functions have been identified for these proteins in animals, including the control of cell proliferation and development of specific cell lineages .
Transcription factor EB, bHLHzip domain (bHLHzip_TFEB)
Type: Domain

The MiT/TFE family of basic helix-loop-helix leucine zipper transcription factors includes MITF (microphthalmia-associated transcription factor) and related family members TFE3, TFEB and TFEC . The transcription factors heterodimerize with each other and recognise the same DNA sequences . They recognise and bind E-box sequences (3'-CANNTG-5').

TFEB is a transcription factor that acts as a master regulator of lysosomal biogenesis, autophagy, lysosomal exocytosis, lipid catabolism, energy metabolism and immune response . In association with TFE3, TFEB activates the expression of CD40L in T-cells, thereby playing a role in T-cell-dependent antibody responses in activated CD4+ T-cells and thymus-dependent humoral immunity . It also plays a role in the signal transduction processes required for normal vascularisation of the placenta . It is involved in the cellular response to amino acid availability by acting downstream of mTOR: in the presence of nutrients, TFEB phosphorylation by MTOR promotes its cytosolic retention and subsequent inactivation, while upon starvation or lysosomal stress, inhibition of mTOR induces TFEB dephosphorylation, resulting in nuclear localization and transcription factor activity .

This entry represents the basic Helix-Loop-Helix-zipper (bHLHzip) domain of TFEB.