SII-SWORD/CoKE huggingface dataset:
Transcription factor AP-2 alpha, N-terminal (TF_AP2_alpha_N)
Type: Domain

Activator protein-2 (AP-2) transcription factors constitute a family of closely related and evolutionarily conserved proteins that bind to the DNA
consensus sequence 5'-GCCNNNGGC-3' and stimulate target gene transcription . Five different isoforms of AP-2 have been identified in mammals, termed AP-2 alpha, beta, gamma, delta and epsilon. Each family member shares a common structure, possessing a proline/glutamine-rich domain in the N-terminal region, which is responsible for transcriptional activation , and a helix-span-helix domain in the C-terminal region, which mediates dimerisation and site-specific DNA binding .

The AP-2 family have been shown to be critical regulators of gene expression during embryogenesis. They regulate the development of facial prominence and limb buds, and are essential for cranial closure and development of the lens ; they have also been implicated in tumorigenesis. AP-2 protein expression levels have been found to affect cell transformation, tumour growth and metastasis, and may predict survival in some types of cancer . Mutations in human AP-2 have been linked with bronchio-occular-facial syndrome and Char Syndrome, congenital birth defects characterised by craniofacial deformities and patent ductus arteriosus, respectively .

AP-2 alpha was initially isolated from human HeLa cells . The protein was shown to bind to enhancer regions of the SV40 and human metallothionein IIA promoters, and to stimulate RNA synthesis . AP-2 alpha gene knockout in mice causes neural-tube defects during embryogenesis, leading to craniofacial abnormalities and anencephaly . In humans, deletion of chromosome 6 region 6p24-p25, which includes the AP-2 alpha gene, is associated with microphthalmia, corneal clouding and a number of other dysmorphic features, including hypertelorism, micrognathia, dysplastic ears, thin limbs, and congenital cardiac defects.

This entry represents the N-terminal region of these proteins, including the transcriptional activation domain.
Transcription factor AP-2 beta (TF_AP2_beta)
Type: Family

Activator protein-2 (AP-2) transcription factors constitute a family of closely related and evolutionarily conserved proteins that bind to the DNA
consensus sequence 5'-GCCNNNGGC-3' and stimulate target gene transcription . Five different isoforms of AP-2 have been identified in mammals, termed AP-2 alpha, beta, gamma, delta and epsilon. Each family member shares a common structure, possessing a proline/glutamine-rich domain in the N-terminal region, which is responsible for transcriptional activation , and a helix-span-helix domain in the C-terminal region, which mediates dimerisation and site-specific DNA binding .

The AP-2 family have been shown to be critical regulators of gene expression during embryogenesis. They regulate the development of facial prominence and limb buds, and are essential for cranial closure and development of the lens ; they have also been implicated in tumorigenesis. AP-2 protein expression levels have been found to affect cell transformation, tumour growth and metastasis, and may predict survival in some types of cancer . Mutations in human AP-2 have been linked with bronchio-occular-facial syndrome and Char Syndrome, congenital birth defects characterised by craniofacial deformities and patent ductus arteriosus, respectively .

AP-2 beta was originally isolated by cDNA screening of a human genomic library . The protein was designated AP-2 beta on the basis of its high sequence similarity to AP-2 alpha, its site-specific DNA binding, and its ability to stimulate transcription . Defects in AP-2 beta have been shown to cause Char syndrome, an autosomal dominant trait characterised by patent ductus arteriosus, facial dysmorphism and hand anomalies.
Transcription factor AP-2 gamma (TF_AP2_gamma)
Type: Family

Activator protein-2 (AP-2) transcription factors constitute a family of closely related and evolutionarily conserved proteins that bind to the DNA
consensus sequence 5'-GCCNNNGGC-3' and stimulate target gene transcription . Five different isoforms of AP-2 have been identified in mammals, termed AP-2 alpha, beta, gamma, delta and epsilon. Each family member shares a common structure, possessing a proline/glutamine-rich domain in the N-terminal region, which is responsible for transcriptional activation , and a helix-span-helix domain in the C-terminal region, which mediates dimerisation and site-specific DNA binding .

The AP-2 family have been shown to be critical regulators of gene expression during embryogenesis. They regulate the development of facial prominence and limb buds, and are essential for cranial closure and development of the lens ; they have also been implicated in tumorigenesis. AP-2 protein expression levels have been found to affect cell transformation, tumour growth and metastasis, and may predict survival in some types of cancer . Mutations in human AP-2 have been linked with bronchio-occular-facial syndrome and Char Syndrome, congenital birth defects characterised by craniofacial deformities and patent ductus arteriosus, respectively .

AP-2 gamma was originally isolated from murine carcinoma cells . The gene was found to be expressed in several embryonic areas whose development can be affected by retinoids, such as the forebrain, face and limb buds . A human homologue has also been identified which is involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer . The protein was initially termed AP-2.2, but has since been reclassified as AP-2 gamma.
Streptokinase (SK)
Type: Family

Streptokinase (SK) can be found in several species of Streptococci. It can bind not only plasminogen, but also host fibrinogen . This close interaction with the human fibrinolytic system allows the microbe to acquire unregulatable cell-surface enzymatic activity, promoting further spread from the site of infection. The complexes formed between streptococcal cells, streptokinase, plasminogen and fibrinogen can lyse fibrin clots in the host . Streptokinase has been used to treat acute myocardial infarction .
Streptothricin acetyltransferase (Streptothricin_AcTrfase)
Type: Family

A small number of bacterial pathogens are implicated in urinary tract infections (UTIs), amongst the most frequent infections in the developed world. The commonest bacterium isolated from UTI is Escherichia coli, with streptococcal and staphylococcal species coming a close second . Virulent microbes that colonise the human urinary tract usually possess sets of virulence factors specific to the host environment . The most common are adhesins, molecules that allow an infection to become established; well-characterised E. coli type I pili are a good example.

Aside from adhesins, other UTI-specific virulence moieties include: toxins, such as Cnf1 and haemolysin, and host biocides that act against other microbes competing for the same niche . Streptothricin, an antibiotic synthesised and secreted by some Gram-negative pathogens, is an example of the latter ; the antibiotic also has a toxic effect on host cells. The biocide is synthesised in a five-step process in the bacterial cytoplasm, and secreted to the cell exterior via the general secretory pathway .

The last step in the synthesis process is the acetyl co-enzyme A-dependent acetylation of the streptothricin molecule to the mature antibiotic. This is catalysed by the streptothricin acetyltransferase protein, located adjacent to the inner face of the cytoplasmic membrane . Homologues of the original gene found in Streptomyces spp. have been found in Bacillus subtilis and Staphylococcus spp., as well as E. coli . More recently, the streptothricin biosynthesis enzymes were shown to be related to those that carry out non-ribosomal peptide bond formation.
Outer membrane adhesion, Yersinia (OM_adhesion_Yersinia)
Type: Family

The genus Yersinia contains just three species: Yersinia enterocolitica, Yersinia pestis, and Yersinia pseudotuberculosis . Although the three use different routes to infect their host, each targets the lymphoid tissue for invasion, and all have developed specific systems to evade host immune cells . PYV, a major virulence plasmid common to all members of this family, harbours the genes necessary for type III secretion in the host and the exotoxins translocated by them.
Early E3 14.5kDa protein (Adeno_E3_14_5)
Type: Family

The E3B 14.5kDa was first identified in human adenovirus type 5. It is an integral membrane protein oriented with its C terminus in the cytoplasm. It functions to down-regulate the epidermal growth factor receptor and prevent tumour necrosis factor cytolysis. It achieves this through the interaction with E3 10.4kDa protein .
Competence-induced protein CinA (Competence-induced_CinA)
Type: Family

CinA is the first gene in the competence-inducible (cin) operon, and is thought to be specifically required at some stage in the process of transformation .

This family consists of putative competence-damaged proteins from the cin operon, and nicotinamide-nucleotide (NMN) amidohydrolase proteins. In the case of T. thermophilus, CinA (

) was shown to have both NMN deamidase and ADP-ribose pyrophosphatase activities .

Competence is the ability of a cell to take up exogenous DNA from its environment, resulting in transformation. It is widespread among bacteria and is probably an important mechanism for the horizontal transfer of genes. DNA usually becomes available by the death and lysis of other cells. Competent bacteria use components of extracellular filaments called type 4 pili to create pores in their membranes and pull DNA through the pores into the cytoplasm. This process, including the development of competence and the expression of the uptake machinery, is regulated in response to cell-cell signalling and/or nutritional conditions .
CinA, C-terminal (CinA_C)
Type: Domain

This entry represents a C-terminal domain found in CinA (the first gene in the competence-inducible operon) and nicotinamide-nucleotide (NMN) amidohydrolase PncC.

CinA is thought to be specifically required at some stage in the process of natural transformation, a genetic recombination process .

NMN amidohydrolase (also known as NMN deamidase) is one of the key enzymes of the bacterial pyridine nucleotide cycle. This enzyme has been shown in S. oneidensis to be encoded by the gene PncC. It is further shown in S. oneidensis PncC, that the NMN deamidase activity resides in the C-terminal "CinA" domain, also known as the PncC domain . While multiple E. coli homologs to S. oneidensis PncC have been identified, only YgaD has been shown to posses NMN deaminase activity .
Saposin B type, region 2 (SapB_2)
Type: Domain

Saposins are small lysosomal proteins that serve as activators of various lysosomal lipid-degrading enzymes . They probably act by isolating the lipid substrate from the membrane surroundings, thus making it more accessible to the soluble degradative enzymes. All mammalian saposins are synthesized as a single precursor molecule (prosaposin) which contains four Saposin-B domains, yielding the active saposins after proteolytic cleavage, and two Saposin-A domains that are removed in the activation reaction. The Saposin-B domains also occur in other proteins, many of them active in the lysis of membranes .
Saposin B type domain (SaposinB_dom)
Type: Domain

The saposin B-type domain is a ~80 amino acid domain present in saposins and
related proteins that interact with lipids. The domain is named after the
small lysosomal proteins, saposins, which serve as sphingolipid hydrolase
activator proteins in vertebrates. The mammalian saposins are synthesized as a
single precursor molecule (prosaposin) which contains two saposin A-type
domains in the extremities that are removed in the activation reaction, and four saposin B-type domains yielding the active saposins A,
B, C and D after proteolytic cleavage. Saposin-like proteins (SAPLIPs) can
have different functions, such as enzymatic activities, as cofactors of
enzymes involved in lipid metabolism, as components of lung surfactant
reducing the surface tension, as part of a complex involved in stage
regulation of Dictyostelium, as antimicrobial effector molecules, or as a
stimulator of dendritic outgrowth .

The 3D structures of different SAPLIPs have been resolved, and show that the
saposin B-type domain is formed by a four/five helical bundle. The saposin B-type domain is characterised by six conserved
cysteine residues involved in three disulfide bridges: one between helices 2
and 3, one between the first and the last helix and one from the N-terminal
part of the first helix to the C terminus. In plant aspartic proteinases the
two subdomains that are connected by the disulfide bridges occur in inverse
order, these are called "swaposin" domains . In these phytepsin proteins
the two half saposin B-type domains occur in combination with the aspartyl
protease signature .
Alanine dehydrogenase (Ala_DH)
Type: Family

The family of known L-alanine dehydrogenases includes representatives from the Proteobacteria, Firmicutes, and Cyanobacteria, all with about 50 % identity or better. An outlier to this group in both sequence and gap pattern is the homologue from Helicobacter pylori, an epsilon division Proteobacteria, which must be considered a putative alanine dehydrogenase. Related proteins include saccharopine dehydrogenase and the N-terminal half of the NAD(P) transhydrogenase alpha subunit. All of these related proteins bind NAD and/or NADP .
Alanine dehydrogenase/NAD(P) transhydrogenase, conserved site-1 (AlaDH/PNT_CS1)
Type: Conserved_site

Alanine dehydrogenases (AlaDH) and NAD(P) transhydrogenase subunit alpha (PNT) have been shown to share regions of similarity . AlaDH catalyses the NAD-dependent reversible reductive amination of pyruvate into alanine. PNT catalyses the reduction of NADP
+
to NADPH with the concomitant oxidation of NADH to NAD
+
. This enzyme is located in the plasma membrane of prokaryotes and in the inner membrane of the mitochondria of eukaryotes. The transhydrogenation between NADH and NADP is coupled with the translocation of a proton across the membrane. In prokaryotes the enzyme is composed of two different subunits, an alpha chain (gene pntA) and a beta chain (gene pntB), while in eukaryotes it is a single chain protein. The sequence of alanine dehydrogenase from several bacterial species are related with those of the alpha subunit of bacterial pyridine nucleotide transhydrogenase and of the N-terminal half of the eukaryotic enzyme. The two most conserved regions correspond respectively to the N-terminal extremity of these proteins, represented in this entry, and to a central glycine-rich region which is part of the NAD(H)-binding site.
Alanine dehydrogenase/pyridine nucleotide transhydrogenase, conserved site-2 (Ala_DH/PNT_CS2)
Type: Conserved_site

Alanine dehydrogenases (

) and pyridine nucleotide transhydrogenase (

) have been shown to share regions of similarity . Alanine dehydrogenase catalyzes the NAD-dependent reversible reductive amination of pyruvate into alanine. Pyridine nucleotide transhydrogenase catalyzes the reduction of NADP
+
to NADPH with the concomitant oxidation of NADH to NAD
+
. This enzyme is located in the plasma membrane of prokaryotes and in the inner membrane of the mitochondria of eukaryotes. The transhydrogenation between NADH and NADP is coupled with the translocation of a proton across the membrane. In prokaryotes the enzyme is composed of two different subunits, an alpha chain (gene pntA) and a beta chain (gene pntB), while in eukaryotes it is a single chain protein. The sequence of alanine dehydrogenase from several bacterial species are related with those of the alpha subunit of bacterial pyridine nucleotide transhydrogenase and of the N-terminal half of the eukaryotic enzyme. The two most conserved regions correspond respectively to the N-terminal extremity of these proteins and to a central glycine-rich region which is part of the NAD(H)-binding site.

This signature corresponds to the central glycine-rich region which is part of the NAD(H)-binding site, it is found in alanine dehydrogenases (

) and also in the lysine 2-oxoglutarate reductases.
Guanylate kinase-like domain (Guanylate_kin-like_dom)
Type: Domain

Guanylate kinase (

) (GK) catalyzes the ATP-dependent phosphorylation of GMP into GDP. It is essential for recycling GMP and indirectly, cGMP. In prokaryotes (such as Escherichia coli), lower eukaryotes (such as yeast) and in vertebrates, GK is a highly conserved monomeric protein of about 200 amino acids. GK has been shown to be structurally similar to protein A57R (or SalG2R) from various strains of Vaccinia virus.

Proteins containing one or more copies of the DHR domain, an SH3 domain as well as a C-terminal GK-like domain, are collectively termed MAGUKs (membrane-associated guanylate kinase homologues) , and include Drosophila lethal(1)discs large-1 tumor suppressor protein (gene dlg1); mammalian tight junction protein Zo-1; a family of mammalian synaptic proteins that seem to interact with the cytoplasmic tail of NMDA receptor subunits (SAP90/PSD-95, CHAPSYN-110/PSD-93, SAP97/DLG1 and SAP102); vertebrate 55kDa erythrocyte membrane protein (p55); Caenorhabditis elegans protein lin-2; rat protein CASK; and human proteins DLG2 and DLG3.

There is an ATP-binding site (P-loop) in the N-terminal section of GK, which is not conserved in the GK-like domain of the above proteins. However these proteins retain the residues known, in GK, to be involved in the binding of GMP.
Guanylate kinase/L-type calcium channel beta subunit (GK/Ca_channel_bsu)
Type: Domain

This entry represents a domain found in guanylate kinase (

) and in L-type calcium channel.

Guanylate kinase (

) (GK) catalyzes the ATP-dependent phosphorylation of GMP into GDP. It is essential for recycling GMP and indirectly, cGMP. In prokaryotes (such as Escherichia coli), lower eukaryotes
(such as yeast) and in vertebrates, GK is a highly conserved monomeric protein of about 200 amino acids. GK has been shown to be structurally similar to protein A57R (or SalG2R) from various strains of Vaccinia virus.

L-type calcium channnels are formed from different alpha-1 subunit isoforms that determine the pharmacological properties of the channel, since they form the drug binding domain. Other properties, such as gating voltage-dependence, G protein modulation and kinase susceptibility, are influenced by alpha-2, delta and beta subunits.
Glutamine synthetase, catalytic domain (Gln_synth_cat_dom)
Type: Domain

This entry represents the C-terminal catalytic domain of GS enzymes.

Glutamine synthetase (

) (GS) plays an essential role in the metabolism of nitrogen by catalysing the condensation of glutamate and ammonia to form glutamine.

There seem to be three different classes of GS :

Class I enzymes (GSI) are specific to prokaryotes, and are oligomers of 12 identical subunits. The activity of GSI-type enzyme is controlled by the adenylation of a tyrosine residue. The adenylated enzyme is inactive (see

).

Class II enzymes (GSII) are found in eukaryotes and in bacteria belonging to the Rhizobiaceae, Frankiaceae, and Streptomycetaceae families (these bacteria have also a class-I GS). GSII are octamer of identical subunits. Plants have two or more isozymes of GSII, one of the isozymes is translocated into the chloroplast.

Class III enzymes (GSIII) have been found in Bacteroides fragilis. in Butyrivibrio fibrisolvens. It is a hexamer of identical chains and in some protozoa. It is much larger (about 700 amino acids) than the GSI (450 to 470 amino acids) or GSII (350 to 420 amino acids) enzymes.

While the three classes of GS's are clearly structurally related, the sequence similarities are not so extensive.
Glutamine synthetase, N-terminal domain (Gln_synt_N)
Type: Domain

Glutamine synthetase (

) (GS) plays an essential role in the metabolism of nitrogen by catalysing the condensation of glutamate and ammonia to form glutamine. This entry represents the glutamine synthetase N-terminal domain, which adopts a β-grasp fold and contributes to the substrate binding pocket of the enzyme .
DNA photolyase class 2 (DNA_photolyase_2)
Type: Family

The cryptochrome and photolyase families consist of structurally related flavin adenine dinucleotide (FAD) proteins that use the absorption of blue light to accomplish different tasks. The photolyasess use the blue light for light-driven electron transfer to repair UV-damaged DNA, while the cryptochromes are blue-light photoreceptors involved in the circadian clock for plants and animals . On the basis of the primary structure, the cryptochrome/DNA photolyase family can be grouped into two classes . The first class contains cryptochromes and DNA photolyases from eubacteria, archaea, fungi, animals and plants. The second class contains DNA photolyases from prokaryotes, plants and animals.

Similar to the distantly related microbial class I photolyases, class 2 enzymes repair UV-induced cyclobutane pyrimidine dimer (CPD) lesions within duplex DNA using blue/near-UV light . There are a number of conserved sequence regions in all known class 2 DNA photolyases, especially in the C-terminal part. The structures of the class 2 DNA photolyase from archaea and rice have been solved .
Phytoene dehydrogenase, bacterial-type, conserved site (Phytoene_DH_bac_CS)
Type: Conserved_site

Phytoene dehydrogenase (phytoene desaturase) is an enzyme of carotenoid biosynthesis that converts phytoene into zeta-carotene via the symmetrical introduction of two double bonds at the C-11 and C-11' positions of phytoene. The sequence of phytoene dehydrogenase from bacteria (gene crtI or carC) and fungi (gene AL-1) are not related to that from cyanobacteria and plants but are evolutionary related to that of another enzyme of carotenoid biosynthesis, methoxyneurosporene dehydrogenase (gene crtD). There are two glycine-rich conserved regions, both of which probably play a role in the binding of either FAD or NAD. The first conserved region is in the N-terminal section while the second one is in the C-terminal section.
Gamma-adaptin ear (GAE) domain (GAE_dom)
Type: Domain

The adaptor proteins AP-1 and GGA (Golgi-localized, gamma ear-containing, ADP- ribosylation factor (ARF)-binding proteins) regulate membrane traffic between the trans-Golgi network (TGN) and endosome/lysosomes through ARF-regulated membrane association, recognition of sorting signals, and recruitment of clathrin and accessory proteins. The gamma-adaptin ear (GAE) domain is a C- terminal appendage or ear of about 120 residues, which is found in gamma- adaptins, the heavy subunits of the AP-1 complex, and in GGAs. The GAE domain, which is found in associated with other domains such as VHS, coiled-coils and GAT, is involved in the recruitment of accessory proteins, such as gamma-synergin, Rababptin-5, Eps15 and cyclin G-associated kinase, which modulate the functions of GAE domain containing proteins in the membrane trafficking events .

The resolution of the 3D-structure of the human gamma-adaptin GAE domain shows that it forms an immunoglobulin-like β-sandwich fold composed of eight β-strands with two short α-helices. The topology of the entire GAE domain is similar to those of the N-terminal subdomains in the alpha- and beta-adaptin ear domains of the AP-2 complex. However, the GAE domain has very low sequence identity and homology to the N-terminal immunoglobulin-like subdomains of the alpha and beta ear domains. The binding site for the accessory proteins has been located to a shallow hydrophobic trough surrounded by charged (mainly basic) residues .

This entry represents the entire GAE domain.