SII-SWORD/CoKE huggingface dataset:
ABC transporter, TroCD-like (ABC_TroCD)
Type: Family

Periplasmic Binding Protein (PBP)-dependent ATP-Binding Cassette (ABC) transporters are involved in the uptake of siderophores, heme, vitamin B12, or the divalent cations Mg2+ and Zn2+. PBP-dependent ABC transporters consist of a PBP, two transmembrane regions (TMs), and two cytoplasmic ABCs, and are mainly involved in importing solutes from the environment . The solute is captured by the PBP which delivers it to a gated translocation pathway formed by the two TMs. The TMs are bundles of α helices that transverse the cytoplasmic membrane multiple times. The two ABCs bind and hydrolyze ATP and drive the transport reaction. Each TM has a prominent cytoplasmic loop which contacts an ABC and represents a conserved motif. The two TMs form either a homodimer (e.g. in the case of the BtuC subunits of the Escherichia coli BtuCD vitamin B12 transporter) , a heterodimer (e.g. the TroC and TroD subunits of the Treponema pallidum general transition metal transporter, TroBCD) , or a pseudo-heterodimer (e.g. the FhuB protein of the E. coli ferrichrome transporter, FhuBC) .

This subfamily consists of integral membrane components from a number of bacterial transport systems that have similar sequences , and include TroC and TroD, and ScaB (required for Mn2+ import in Streptococcus ).
Sema domain (Semap_dom)
Type: Domain

The Sema domain occurs in semaphorins, which are a large family of secreted and transmembrane proteins, some of which function as repellent signals during axon guidance. Sema domains also occur in plexins , receptors for multiple classes of semaphorins, in hepatocyte growth factor receptor, and in viral proteins .

The Sema domain is characterised by a conserved set of cysteine residues, which form four disulphide bonds to stabilise the structure. The Sema domain fold is a variation of the β propeller topology, with seven blades radially arranged around a central axis. Each blade contains a four-stranded (strands A to D) antiparallel β sheet. The inner strand of each blade (A) lines the channel at the centre of the propeller, with strands B and C of the same repeat radiating outward, and strand D of the next repeat forming the outer edge of the blade. The large size of the Sema domain is not due to a single inserted domain but results from the presence of additional secondary structure elements inserted in most of the blades. The Sema domain uses a 'loop and hook' system to close the circle between the first and the last blades. The blades are constructed sequentially with an N-terminal β-strand closing the circle by providing the outermost strand (D) of the seventh (C-terminal) blade. The β-propeller is further stabilised by an extension of the N terminus, providing an additional, fifth β-strand on the outer edge of blade 6 .
Zinc finger, nuclear hormone receptor-type (Znf_hrmn_rcpt)
Type: Domain

This entry represents the two C4-type zinc finger modules involved in DNA-binding.

Steroid or nuclear hormone receptors constitute an important superfamily of transcription regulators that are involved in widely diverse physiological functions, including control of embryonic development, cell differentiation and homeostasis. The receptors function as dimeric molecules in nuclei to regulate the transcription of target genes in a ligand-responsive manner. Nuclear hormone receptors consist of a highly conserved DNA-binding domain that recognises specific sequences, connected via a linker region to a C-terminal ligand-binding domain (

). In addition, certain nuclear hormone receptors have an N-terminal modulatory domain (

). The DNA-binding domain can elicit either an activating or repressing effect by binding to specific regions of the DNA known as hormone-response elements . These response elements position the receptors, and the complexes recruited by them, close to the genes of which transcription is affected. The DNA-binding domains of nuclear receptors consist of two zinc-nucleated modules and a C-terminal extension, where residues in the first zinc module determine the specificity of the DNA recognition and residues in the second zinc module are involved in dimerisation. The DNA-binding domain is furthermore involved in several other functions including nuclear localisation, and interaction with transcription factors and co-activators .

Zinc finger (Znf) domains are relatively small protein motifs which contain multiple finger-like protrusions that make tandem contacts with their target molecule. Some of these domains bind zinc, but many do not; instead binding other metals such as iron, or no metal at all. For example, some family members form salt bridges to stabilise the finger-like folds. They were first identified as a DNA-binding motif in transcription factor TFIIIA from Xenopus laevis (African clawed frog), however they are now recognised to bind DNA, RNA, protein and/or lipid substrates . Their binding properties depend on the amino acid sequence of the finger domains and of the linker between fingers, as well as on the higher-order structures and the number of fingers. Znf domains are often found in clusters, where fingers can have different binding specificities. There are many superfamilies of Znf motifs, varying in both sequence and structure. They display considerable versatility in binding modes, even between members of the same class (e.g. some bind DNA, others protein), suggesting that Znf motifs are stable scaffolds that have evolved specialised functions. For example, Znf-containing proteins function in gene transcription, translation, mRNA trafficking, cytoskeleton organisation, epithelial development, cell adhesion, protein folding, chromatin remodelling and zinc sensing, to name but a few . Zinc-binding motifs are stable structures, and they rarely undergo conformational changes upon binding their target.
cAMP response element binding (CREB) protein (Leuzip_CREB)
Type: Family

Transcription initiation is dictated by the presence and activity of specific nuclear factors that bind to DNA regulatory sequences and interact with the transcriptional machinery. The functions of some of these factors can be altered by phosphorylation, which affects both DNA binding and transcriptional activation . Phosphorylation is effected by specific protein kinases that have been activated by the stimulus of signal transduction pathways, resulting in the regulation of gene transcription by modulating the phosphorylation sites of transcription factors.

Cyclic AMP (cAMP) regulates the expression of many genes via a conserved gene promoter element CRE (cAMP response element) , which has the sequence 5'-TGACGTCA-3' . The cAMP response element binding protein (CREB) is a nuclear factor that is regulated by protein kinase A phosphorylation. Transcription is stimulated on binding to the CRE of a phosphorylated CREB dimer, which is held together by leucine zippers. Dimerisation and transcriptional efficacy have been found to be stimulated by phosphorylation at several distinct sites, and it has thus been suggested that CREB may be regulated by multiple kinases. Sequence analysis of the gene has revealed a cluster of protein kinase A, protein kinase C, and casein kinase II consensus recognition sites near the N terminus of the protein sequence, and the proximity of these sites to one another indicates the possibility of interaction in a positive or negative fashion to regulate CREB bioactivity.

The 'leucine zipper' is a structure that is believed to mediate the function of several eukaryotic gene regulatory proteins. The zipper consists of a periodic repetition of leucine residues at every seventh position, and regions containing them appear to span 8 turns of α-helix. The leucine side chains that extend from one helix interact with those from a similar helix, hence facilitating dimerisation in the form of a coiled-coil. Leucine zippers are present in many gene regulatory proteins, including the CREB proteins, Jun/AP1 transcription factors, fos oncogene and fos-related proteins, C-myc, L-myc and N-myc oncogenes, and so on.
G-protein beta subunit, WD40 repeats (WD40_G-protein_beta)
Type: Domain

This entry consists of the G protein beta subunit, which assumes a barrel-shaped β-propeller structure containing WD-40 repeats preceded by an N-terminal α helix. The beta subunit forms a stable dimer with the gamma subunit. The alpha subunit only contacts the beta subunit in the dimer, lying on the opposite face from the gamma subunit. RGS proteins that contain GGL (G protein gamma-like) domains can interact with beta subunits to form novel dimers that prevent gamma subunit binding, and may prevent heterotrimer formation by inhibiting alpha subunit binding.

Guanine nucleotide binding proteins (G-proteins) are membrane-associated, heterotrimeric proteins composed of three subunits: alpha (

), beta (

) and gamma (

) . G proteins and their receptors (GPCRs) form one of the most prevalent signalling systems in mammalian cells, regulating systems as diverse as sensory perception, cell growth and hormonal regulation . At the cell surface, the binding of ligands such as hormones and neurotransmitters to a GPCR activates the receptor by causing a conformational change, which in turn activates the bound G protein on the intracellular-side of the membrane. The activated receptor promotes the exchange of bound GDP for GTP on the G protein alpha subunit. GTP binding changes the conformation of switch regions within the alpha subunit, which allows the bound trimeric G protein (inactive) to be released from the receptor, and to dissociate into active alpha subunit (GTP-bound) and beta/gamma dimer. The alpha subunit and the beta/gamma dimer go on to activate distinct downstream effectors, such as adenylyl cyclase, phosphodiesterases, phospholipase C, and ion channels. These effectors in turn regulate the intracellular concentrations of secondary messengers, such as cAMP, diacylglycerol, sodium or calcium cations, which ultimately lead to a physiological response, usually via the downstream regulation of gene transcription. The cycle is completed by the hydrolysis of alpha subunit-bound GTP to GDP, resulting in the re-association of the alpha and beta/gamma subunits and their binding to the receptor, which terminates the signal . The length of the G protein signal is controlled by the duration of the GTP-bound alpha subunit, which can be regulated by RGS (regulator of G protein signalling) proteins or by covalent modifications .

G protein alpha subunits are 350-400 amino acids in length and have molecular weights in the range 40-45kDa. Seventeen distinct types of alpha subunit have been identified in mammals. These fall into 4 main groups on the basis of both sequence similarity and function: alpha-S (

), alpha-Q (

), alpha-I (

)and alpha-12(

) .

The specific combination of subunits in heterotrimeric G proteins affects not only which receptor it can bind to, but also which downstream target is affected, providing the means to target specific physiological processes in response to specific external stimuli . G proteins carry lipid modifications on one or more of their subunits to target them to the plasma membrane and to contribute to protein interactions.
EAL domain (EAL_dom)
Type: Domain

This domain is found in diverse bacterial signalling proteins. It is called EAL after its conserved residues. The EAL domain has been shown to stimulate degradation of a second messenger, cyclic di-GMP , and is a good candidate for a diguanylate phosphodiesterase function. Together with the GGDEF domain, EAL might be involved in regulating cell surface adhesiveness in bacteria . The domain contains many conserved acidic residues that could participate in metal binding and might form the phosphodiesterase active site. It often but not always occurs along with

and

domains that are also found in many signalling proteins
.
Adenosine receptor (Adenosn_rcpt)
Type: Family

G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups . The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence . The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) . GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice . Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs .

The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices .

In addition to their role in energy metabolism, purines (especially adenosine and adenine nucleotides) produce a wide range of pharmacological effects mediated by activation of cell surface receptors. Distinct receptors exist for adenosine. In the periphery, the main effects of adenosine include vasodilation, bronchoconstriction, immunosuppresion, inhibition of platelet aggregation, cardiac depression, stimulation of nociceptive afferents, inhibition of neurotransmitter release and inhibition of the release of other factors, e.g. hormones. In the CNS, adenosine exerts a pre- and post-synaptic depressant action, reducing motor activity, depressing respiration, inducing sleep and relieving anxiety. The physiological role of adenosine is thought to be to adjust energy demands in line with oxygen supply. Many of the clinical actions of methylxanthines are thought to be mediated through antagonism of adenosine receptors. Four subtypes of receptor have been identified, designated A1, A2A, A2B and A3.
Flagellar hook-length control protein FliK (Flag_hook_Flik)
Type: Family

FliK controls the length of the flagellar hook. It detects when the flagellar hook substructure has reached its optimal length. Then, it terminates hook export and assembly and transmits a signal to begin filament export, the final stage in flagellar biosynthesis. The exact mechanism of how FliK achieves this is not known . FliK is a two-domain protein with the central portion of the sequence acting as a hinge or connector between the two .
Phosphoribosylaminoimidazole-succinocarboxamide synthase (SAICAR_synth)
Type: Family

Phosphoribosylaminoimidazole-succinocarboxamide synthase (

) (SAICAR synthetase) catalyses the seventh step in the
de novo
purine biosynthetic pathway; the ATP-dependent conversion of 5'-phosphoribosyl-5-aminoimidazole-4-carboxylic acid and aspartic acid to SAICAR .

In bacteria (purC), fungi (ADE1) and plants (Pur7), SAICAR synthetase is a monofunctional protein; in animals it is the N-terminal domain of a bifunctional enzyme that also catalyse phosphoribosylaminoimidazole carboxylase (AIRC) activity (see

).

This entry represents a protein family including SAICAR synthetases from bacteria, fungi and archaea.
Glutamine synthetase class-I, adenylation site (Gln_synth_I_adenylation_site)
Type: Conserved_site

Glutamine synthetase (

) (GS) plays an essential role in the metabolism of nitrogen by catalyzing 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.

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) has, currently, only been found in Bacteroides fragilis and in butyrivibrio fibrisolvens. It is a hexamer of identical chains. 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.
Solute-binding protein family 3/N-terminal domain of MltF (Solute-binding_3/MltF_N)
Type: Domain

Bacterial high affinity transport systems are involved in active transport of solutes across the cytoplasmic membrane. Most of the bacterial ABC (ATP-binding cassette) importers are composed of one or two transmembrane permease proteins, one or two nucleotide-binding proteins and a highly specific periplasmic solute-binding protein. In Gram-negative bacteria the solute-binding proteins are dissolved in the periplasm, while in archaea and Gram-positive bacteria, their solute-binding proteins are membrane-anchored lipoproteins .

On the basis of sequence similarities, the vast majority of these solute-binding proteins can be grouped into eight families or clusters, which generally correlate with the nature of the solute bound.

This entry represents a domain found in the solute-binding protein family 3 members from Gram-positive bacteria, Gram-negative bacteria and archaea. This domain can also be found in the N-terminal of the membrane-bound lytic murein transglycosylase F (MltF) protein. MltF is a murein-degrading enzyme that degrades murein glycan strands and insoluble, high-molecular weight murein sacculi, with the concomitant formation of a 1,6-anhydromuramoyl product .

Familiy 3 members include:

Histidine-binding protein (gene hisJ) of Escherichia coli and related bacteria. An homologous lipoprotein exists in Neisseria gonorrhoeae.

Lysine/arginine/ornithine-binding proteins (LAO) (gene argT) of Escherichia coli and related bacteria are involved in the same transport system than hisJ. Both solute-binding proteins interact with a common membrane-bound receptor hisP of the binding protein dependent transport system HisQMP.

Glutamine-binding proteins (gene glnH) of Escherichia coli and Bacillus stearothermophilus.

Glutamate-binding protein (gene gluB) of Corynebacterium glutamicum.

Arginine-binding proteins artI and artJ of Escherichia coli.

Nopaline-binding protein (gene nocT) from Agrobacterium tumefaciens.

Octopine-binding protein (gene occT) from Agrobacterium tumefaciens.

Major cell-binding factor (CBF1) (gene: peb1A) from Campylobacter jejuni.

Bacteroides nodosus protein aabA.

Cyclohexadienyl/arogenate dehydratase of Pseudomonas aeruginosa, a periplasmic enzyme which forms an alternative pathway for phenylalanine biosynthesis.

Escherichia coli L-cystine-binding protein TcyJ, previously known as protein fliY.

Vibrio harveyi protein patH.

Bacillus subtilis Probable ABC transporter extracellular-binding protein yckB.

Bacillus subtilis L-cystine-binding protein TcyA, also known as yckK.

This entry also includes domains found in a number of eukaryotic proteins including Glutamate receptors, Lysine/arginine/ornithine as well as Glutamate/glutamine/aspartate/asparagine-binding periplasmic proteins.
Type II secretion system protein GspC (T2SS_protein-GspC)
Type: Family

GspC is part of the type 2 secretion systems (T2SSs). GspC interacts with GspD. It is an inner membrane protein consisting of a short N-terminal cytoplasmic sequence and an α-helical transmembrane segment, followed by two periplasmic domains: a so-called homology region (HR) and a C-terminal PDZ domain .

The type II secretion system (T2SS) is one of several extracellular secretion systems in gram-negative bacteria. It delivers toxins and a range of hydrolytic enzymes including proteases, lipases and carbohydrate-active enzymes to the cell surface or extracellular space . T2SS systems are composed of 11 to 15 different proteins, which are generally called GspA to GspO and GspS. The T2SS spans the two bacterial membranes and ensures secretion of folded proteins across the outer membrane pore formed by GspD. The inner membrane complex contains GspC, GspL, GspM, and GspF. The cytoplasmic domains of GspL and GspF interact with an ATPase, GspE. GspE is thought to energize the formation of a short pseudopilus by several pilin-like proteins, GspG to GspK . GspD has been shown to interact with the inner membrane component GspC .
Phosphatidylglycerol--prolipoprotein diacylglyceryl transferase Lgt (Lgt)
Type: Family

Phosphatidylglycerol--prolipoprotein diacylglyceryl transferase lgt is an integral membrane enzyme that catalyses the first reaction of the three-step post-translational lipid modification . It transfers the n-acyl diglyceride group onto what will become the N-terminal cysteine of membrane lipoproteins. This enzyme is an integral membrane protein.