SII-SWORD/CoKE huggingface dataset:
Insulin/IGF/relaxin (Ins/IGF/rlx)
Type: Family

The insulin/IGF/relaxin superfamily is an ancient family of functionally diverse proteins . The 3D structures of a number of family members have been determined . The fold comprises two polypeptide chains (A and B) linked by two disulphide bonds: all share a conserved arrangement of four cysteines in their A chain, the first of which is linked by a disulfide bond to the third, while the second and fourth are linked by interchain disulfide bonds to cysteines in the B chain.

This family includes:

Insulin and insulin-like proteins

Relaxin and prorelaxin

Insect prothoracicotropic hormone (bombyxin)

Insulin-like growth factors (IGF1 and IGF2)

Mammalian Leydig cell-specific insulin-like peptide (gene INSL3)

Invertebrates insulin-related peptides (IRPs)
Insulin, conserved site (Insulin_CS)
Type: Conserved_site

This entry describes the insulin and insulin related family signature pattern The pattern is represented by the following sequence: C-C-{P}-{P}-x-C-[STDNEKPI]-x(3)-[LIVMFS]-x(3)-C.

Insulin is found in many animals, and is involved in the regulation of normal glucose homeostasis. It also has other specific physiological effects, such as increasing the permeability of cells to monosaccharides, amino acids and fatty acids, and accelerating glycolysis and glycogen synthesis in the liver . Insulin exerts its effects by interaction with a cell-surface receptor, which may also result in the promotion of cell growth .

The insulin/IGF/relaxin superfamily is an ancient family of functionally diverse proteins . The 3D structures of a number of family members have been determined . The fold comprises two polypeptide chains (A and B) linked by two disulphide bonds: all share a conserved arrangement of four cysteines in their A chain, the first of which is linked by a disulfide bond to the third, while the second and fourth are linked by interchain disulfide bonds to cysteines in the B chain.

This family includes:

Insulin and insulin-like proteins

Relaxin and prorelaxin

Insect prothoracicotropic hormone (bombyxin)

Insulin-like growth factors (IGF1 and IGF2)

Mammalian Leydig cell-specific insulin-like peptide (gene INSL3)

Invertebrates insulin-related peptides (IRPs)
Pheromone-binding protein Gp-9 (Pheromone-bd_protein_Gp-9)
Type: Family

The fire ant, Solenopsis invicta, exists in either monogyne or polygyne social forms: the former contains a single reproductive queen, the latter multiple queens. These social behavioural differences are associated with variation at gene Gp-9, colonies bearing only the B allelic variant being monogyne, those bearing both B and b-like variants being polygyne .
Neurogenic locus Notch 4 (Notch_4)
Type: Family

Notch cell surface receptors are large, single-pass type-1 transmembrane proteins found in a diverse range of metazoan species, from human to Caenorhabditis species. The fruit fly, Drosophila melanogaster, possesses only one Notch protein, whereas in C.elegans, two receptors have been found; by contrast, four Notch paralogues (designated N1-4) have been identified in mammals, playing both unique and redundant roles.

The hetero-oligomer Notch comprises a large extracellular domain (ECD), containing 10-36 tandem Epidermal Growth Factor (EFG)-like repeats, which are involved in ligand interactions; a negative regulatory region, including three cysteine-rich Lin12-Notch Repeats (LNR); a single trans-membrane domain (TM); a small intracellular domain (ICD), which includes a RAM (RBPjk-association module) domain; six ankyrin repeats (ANK), which are involved in protein-protein interactions; and a PEST domain. Drosophila Notch also contains an OPA domain .

Notch signalling is an evolutionarily conserved pathway involved in a wide variety of developmental processes, including adult homeostasis and stem cell maintenance, cell proliferation and apoptosis . Notch is activated by a range of ligands -the so-called DSL ligands (Delta/Seratte/LAG-2). Activation is also mediated by a sequence of proteolytic events: ligand binding leads to cleavage of Notch by ADAM proteases at site 2 (S2) and presenilin-1/g-secretase at sites 3 (S3)and 4 (S4) .The last cleavage releases the Notch intracellular part of the protein (NICD) from the membrane and, upon release, the NICD translocates to the nucleus where it associates with a CBF1/RBJk/Su(H)/Lag1 (CSL) family of DNA-binding proteins. The subsequent recruitment of a co-activator mastermind like (MAML1) protein promotes transcriptional activation of Notch target genes: well established Notch targets are the Hes and Hey gene families.

Notch 4 is selectively expressed in vascular endothelium, and regulates vascular remodelling .
Interleukin-11, fish (IL-11_fish)
Type: Family

Interleukins (IL) are a group of cytokines that play an important role in the immune system. They modulate inflammation and immunity by regulating growth, mobility and differentiation of lymphoid and other cells.

Interleukin-11 (IL-11) is a pleiotropic cytokine that stimulates megakaryocytopoiesis, resulting in increased production of platelets, as well as activating osteoclasts, inhibiting epithelial cell proliferation and apoptosis, and inhibiting macrophage mediator production. These functions may be particularly important in mediating the hematopoietic, osseous and mucosal protective effects of IL-11 . The cytokine also possesses anti-inflammatory activity, and has been proposed as a therapeutic agent in the treatment of chronic inflammatory diseases, such as Crohn's disease and rheumatoid arthritis .

Although IL-11 was initially believed to be restricted to mammals, subsequent studies demonstrated it to be expressed in ray-finned fish . Two fish paralogues have now been identified, designated IL-11A and IL-11B .

This entry represents interleukin-11 found in fish, and covers both fish paralogues IL-11A and IL-11B.
Major intrinsic protein, conserved site (MIP_CS)
Type: Conserved_site

This entry represents a conserved region which is located in the cytoplasmic loop between the second and third transmembrane regions of MIP family members.

The major intrinsic protein (MIP) family is large and diverse, possessing over 100 members that form transmembrane channels. These channel proteins function in water, small carbohydrate (e.g., glycerol), urea, NH3, CO2 and possibly ion transport, by an energy independent mechanism. They are found ubiquitously in bacteria, archaea and eukaryotes.

The MIP family contains two major groups of channels: aquaporins and glycerol facilitators. The known aquaporins cluster loosely together as do the known glycerol facilitators. MIP family proteins are believed to form aqueous pores that selectively allow passive transport of their solute(s) across the membrane with minimal apparent recognition. Aquaporins selectively transport water (but not glycerol) while glycerol facilitators selectively transport glycerol but not water. Some aquaporins can transport NH3 and CO2. Glycerol facilitators function as solute nonspecific channels, and may transport glycerol, dihydroxyacetone, propanediol, urea and other small neutral molecules in physiologically important processes. Some members of the family, including the yeast FPS protein and tobacco NtTIPA may transport both water and small solutes.
Aminoglycoside phosphotransferase, bacteria (Aminoglycoside_PTrfase_bact)
Type: Domain

This entry includes enzymes found in the rumen bacterium Fibrobacter succinogenes subsp succinogenes S85. They are homologous to the aminoglycoside phosphotransferase enzyme family associated with resistance to aminoglycoside antibiotics.
Tumour necrosis factor receptor 11A (TNFR_11A)
Type: Family

The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins. Family members are defined based on similarity in their extracellular domain - a region that contains many cysteine residues arranged in a specific repetitive pattern . The cysteines allow formation of an extended rod-like structure, responsible for ligand binding .

Upon receptor activation, different intracellular signalling complexes are assembled for different members of the TNFR superfamily, depending on their intracellular domains and sequences . Activation of TNFRs can therefore induce a range of disparate effects, including cell proliferation, differentiation, survival, or apoptotic cell death, depending upon the receptor involved .

TNFRs are widely distributed and play important roles in many crucial biological processes, such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis . Drugs that manipulate their signalling have potential roles in the prevention and treatment of many diseases, such as viral infections, coronary heart disease, transplant rejection, and immune disease .

TNF receptors 11A and 11B mediate the effects of receptor activator for NF-kappa-B ligand (RANKL), an essential osteoclast regulatory factor. The receptors have opposing effects - activation of TNF receptor 11A by RANKL promotes osteoclast differentiation , while TNF receptor 11B acts as a soluble decoy receptor for the ligand, thus inhibiting differentiation .
Neurogenic locus notch homolog protein 1 (Notch_1)
Type: Family

Notch cell surface receptors are large, single-pass type-1 transmembrane proteins found in a diverse range of metazoan species, from human to Caenorhabditis species. The fruit fly, Drosophila melanogaster, possesses only one Notch protein, whereas in C.elegans, two receptors have been found; by contrast, four Notch paralogues (designated N1-4) have been identified in mammals, playing both unique and redundant roles.

The hetero-oligomer Notch comprises a large extracellular domain (ECD), containing 10-36 tandem Epidermal Growth Factor (EFG)-like repeats, which are involved in ligand interactions; a negative regulatory region, including three cysteine-rich Lin12-Notch Repeats (LNR); a single trans-membrane domain (TM); a small intracellular domain (ICD), which includes a RAM (RBPjk-association module) domain; six ankyrin repeats (ANK), which are involved in protein-protein interactions; and a PEST domain. Drosophila Notch also contains an OPA domain .

Notch signalling is an evolutionarily conserved pathway involved in a wide variety of developmental processes, including adult homeostasis and stem cell maintenance, cell proliferation and apoptosis . Notch is activated by a range of ligands -the so-called DSL ligands (Delta/Seratte/LAG-2). Activation is also mediated by a sequence of proteolytic events: ligand binding leads to cleavage of Notch by ADAM proteases at site 2 (S2) and presenilin-1/g-secretase at sites 3 (S3)and 4 (S4) .The last cleavage releases the Notch intracellular part of the protein (NICD) from the membrane and, upon release, the NICD translocates to the nucleus where it associates with a CBF1/RBJk/Su(H)/Lag1 (CSL) family of DNA-binding proteins. The subsequent recruitment of a co-activator mastermind like (MAML1) protein promotes transcriptional activation of Notch target genes: well established Notch targets are the Hes and Hey gene families.

Notch 1 has a widespread pattern of expression and has been demonstrated to be involved in several processes such as mesenchymal cell differentiation, spermatogenesis, and osteoblastic cell differentiation. The pattern of expression of Notch 1 in adult human tissues reveals that this receptor may play multiple roles in several cell types, including neurons, lymphoid cells and skeletal muscle cells, as well as suprabasal cells in stratified epithelia .
Bacteriophage TP901-1, major tail protein (Phage_TP901-1_major-tail)
Type: Family

Two major structural proteins from the lactococcal temperate bacteriophage TP901-1 have been sequenced: the Major Head Protein (MHP) and the Major Tail Protein (MTP) . Homologues of the major tail protein have since been found in Staphylococcus, Streptococcus and Lactobacillus phages. The sequences are fairly short, typically ~150-200 amino acid residues in length, and are well conserved. This family of proteins (designated here phage MTP 2) has its own distinct sequence signature that distinguishes it from the MTP 1 family (see MTP1FAMILY

).

This entry represents the lactococcal proteins from the MTP2 family.
Clathrin, heavy chain, propeller repeat (Clathrin_H-chain_propeller_rpt)
Type: Repeat

This entry represents the propeller repeat found in clathrin heavy chains. The N terminus of the heavy chain is known as the globular domain, and is composed of seven repeats which form a β propeller .

Proteins synthesized on the ribosome and processed in the endoplasmic reticulum are transported from the Golgi apparatus to the trans-Golgi network (TGN), and from there via small carrier vesicles to their final destination compartment. These vesicles have specific coat proteins (such as clathrin or coatomer) that are important for cargo selection and direction of transport . Clathrin coats contain both clathrin (acts as a scaffold) and adaptor complexes that link clathrin to receptors in coated vesicles. Clathrin-associated protein complexes are believed to interact with the cytoplasmic tails of membrane proteins, leading to their selection and concentration. The two major types of clathrin adaptor complexes are the heterotetrameric adaptor protein (AP) complexes, and the monomeric GGA (Golgi-localising, Gamma-adaptin ear domain homology, ARF-binding proteins) adaptors .

Clathrin is a trimer composed of three heavy chains and three light chains, each monomer projecting outwards like a leg; this three-legged structure is known as a triskelion . The heavy chains form the legs, their N-terminal β-propeller regions extending outwards, while their C-terminal α-α-superhelical regions form the central hub of the triskelion. Peptide motifs can bind between the β-propeller blades. The light chains appear to have a regulatory role, and may help orient the assembly and disassembly of clathrin coats as they interact with hsc70 uncoating ATPase . Clathrin triskelia self-polymerise into a curved lattice by twisting individual legs together. The clathrin lattice forms around a vesicle as it buds from the TGN, plasma membrane or endosomes, acting to stabilise the vesicle and facilitate the budding process . The multiple blades created when the triskelia polymerise are involved in multiple protein interactions, enabling the recruitment of different cargo adaptors and membrane attachment proteins .
Pup deamidase (Pup_deamidase)
Type: Family

This protein family includes a group of bacterial proteins such as Pup deamidase/depupylase from Mycolicibacterium smegmatisis (Dop), which specifically catalyses the deamidation of the C-terminal glutamine of the prokaryotic ubiquitin-like protein Pup to glutamate, thereby rendering Pup competent for conjugation . This group is related to

, which represents proteins associated with targeting to the proteasome, and with proteasome subunits themselves.
2-oxoacid:acceptor oxidoreductase, alpha subunit (2-oxoacid/accept_OxRdtase_asu)
Type: Family

This entry represents the alpha subunit of 2-oxoacid:acceptor oxidoreductases, which catalyse CoA-dependent oxidative decarboxylation of 2-oxoacids. Proteins in this family contain a thiamine diphosphate (TPP) binding domain typical of flavodoxin/ferredoxin oxidoreductases (

), and an N-terminal domain similar to the gamma subunit of the same group of oxidoreductases (

). The genes encoding the proteins are always found in association with a neighbouring gene for a beta subunit (

) which also occurs in a four-subunit (alpha/beta/gamma/ferredoxin) version of the system. This pair of genes is not consistently observed in proximity to any electron acceptor genes, but is found next to putative ferredoxins or ferredoxin-domain proteins in Aromatoleum aromaticum EbN1, Bradyrhizobium japonicum USDA 110, Frankia sp CcI3, Rhodoferax ferrireducens T118, Rhodopseudomonas palustris BisB5, Os, Sphingomonas wittichii RW1 and Streptomyces clavuligerus. Other potential acceptors are also sporadically observed in close proximity including ferritin-like proteins, reberythrin, peroxiredoxin and a variety of other flavin and iron-sulfur cluster-containing proteins.

The phylogenetic distribution of this family encompasses archaea, a number of deeply-branching bacterial clades and only a small number of firmicutes and proteobacteria. The enzyme from Sulfolobus has been characterised with respect to its substrate specificity which is described as wide, encompassing various 2-oxoacids such as 2-oxoglutarate, 2-oxobutyrate and pyruvate. Halobacterium salinarum (and most halophilic archaea) contains two 2-oxoacid:ferredoxin oxidoreductases. One (Kor) functions as an oxoglutarate-ferredoxin oxidoreductase , whereas the other (Por) has been characterised as a pyruvate-ferredoxin oxidoreductase .

The enzyme from Hydrogenobacter thermophilus has been shown to have a high specificity towards 2-oxoglutarate and is one of the key enzymes in the reverse TCA cycle in this organism. Furthermore, considering its binding of coenzyme A (CoA), it can be reasonably inferred that the product of the reaction is succinyl-CoA. The genes for this enzyme in Prevotella intermedia 17, Persephonella marina EX-H1 and Picrophilus torridus DSM 9790 are in close proximity to a variety of TCA cycle genes. Persephonella marina and P. torridus are believed to encode complete TCA cycles, and none of these contains the lipoate-based 2-oxoglutarate dehydrogenase (E1/E2/E3) system. That system is presumed to be replaced by this one. In fact, the lipoate system is absent in most organisms possessing a member of this family, providing additional circumstantial evidence that many of these enzymes are capable of acting as 2-oxoglutarate dehydrogenases and supporting flux through TCA cycles in either the forward or reverse directions.
Putative thiazole-containing bacteriocin maturation protein (Thiazole_bacteriocin_mat_put)
Type: Family

Members of this protein family are found in a three-gene operon in Bacillus anthracis and related Bacillus species, where the other two genes are clearly identified with maturation of a putative thiazole-containing bacteriocin precursor. While there is no detectable pairwise sequence similarity between members of this family and the proposed cyclodehydratases such as SagC of Streptococcus pyogenes (see family

), both families show similarity through PSI-BLAST to ThiF, a protein involved in biosynthesis of the thiazole moiety for thiamine biosynthesis. This family, therefore, may contribute to cyclodehydratase function in heterocycle-containing bacteriocin biosyntheses. In Bacillus licheniformis ATCC 14580, the bacteriocin precursor gene is adjacent to the gene for this protein.
Integral membrane protein TerC, riboswitch-linked (Integral_membrane_TerC_rswitch)
Type: Family

This entry represents a subset of TerC proteins which are mostly encoded on genes preceded by a structured RNA element known as the yybP-ykoY leader. The yybP-ykoY leader (also known as SraF) may function in the regulation of these genes as riboswitch . This entry also includes the putative membrane-bound redox modulator Alx .

A family containing a number of integral membrane proteins is named after TerC protein. TerC has been implicated in resistance to tellurium, and may be involved in efflux of tellurium ions. The tellurite-resistant Escherichia coli strain KL53 was found during testing of a group of clinical isolates for antibiotic and heavy metal ion resistance . The determinant of the strain's tellurite resistance was located on a large conjugative plasmid, and analyses showed the genes terB, terC, terD and terE were essential for conservation of this resistance. Members of this family contain a number of conserved aspartates which may be involved in metal ion binding.

A TerC homologue is known from the chloroplast thylakoid membrane from
Arabidopsis
which is important for thylakoid membrane biogenesis in the developing chloroplast ; it is required for insertion of proteins into the thylakoid membrane .
Phosphosulpholactate synthase (Arch_ComA)
Type: Family

This entry represents the ComA (Coenzyme M biosynthesis A) protein and phosphosulpholactate synthase in methanogenic archaea. The ComABC pathway is one of at least two pathways to the intermediate sulphopyruvate. Coenzyme M occurs rarely and sporadically outside of the archaea.
Exopolyphosphatase (Exopolyphosphatase)
Type: Domain

Exopolyphosphatases (Ppx) is involved in the degradation of inorganic polyphosphates and belongs to the same family as the guanosine pentaphosphate phosphatase .
Accessory secretory system protein Asp1 (Accessory_SS_Asp1)
Type: Family

This entry represents Asp1 which, along with SecY2 and SecA2, is part of the accessory secretory protein system . This system is involved in the export of serine-rich glycoproteins important for virulence in a number of Gram-positive species, including Streptococcus gordonii and Staphylococcus aureus. This protein family is assigned to a transport function rather than glycosylation, but its specific molecular role is unknown.
KaiC domain-containing protein (KaiC_containing)
Type: Family

This entry represents KaiC domain-containing proteins that occur across a broad taxonomic range (Euryarchaeota, Aquificae, Dictyoglomi, Epsilonproteobacteria, and Firmicutes), but exclusively in thermophiles.
Energy-dependent translational throttle protein EttA (EttA)
Type: Family

ABC-F proteins compose one of the most widely distributed branches of the ATP-binding cassette (ABC) superfamily. EttA/YjjK is the most prevalent eubacterial ABC-F protein. Its role consists in gating ribosome entry into the translation elongation cycle through a nucleotide-dependent interaction sensitive to ATP/ADP ratio . The ATP-bound form of EttA binds to the ribosomal tRNA-exit site, and forms a bridge between the ribosomal L1 stalk and the tRNA bound in the peptidyl-tRNA-binding site . EttA may regulate protein synthesis in energy-depleted cells, which have a low ATP/ADP ratio.
PQQ-dependent catabolism-associated CXXCW motif (PQQ_CXXCW)
Type: Family

This entry represents proteins with a CXXXCW motif, consistent with a possible role in redox cofactor binding. These proteins show strong relationships by phylogenetic profiling and conserved gene neighbourhoods with a transport system for alcohols metabolised by PQQ-dependent enzymes. Members of this protein family are mostly found in Proteobacteria.
Small hydrophilic plant seed protein, conserved site (Sm_Hydphi_plant_seed_CS)
Type: Conserved_site

This entry represents a conserved site in hydrophilic plant seed proteins that are structurally related:

Arabidopsis thaliana proteins GEA1 and GEA6

Cotton late embryogenesis abundant (LEA) protein D-19

Carrot EMB-1 protein

Barley LEA proteins B19.1A, B19.1B, B19.3 and B19.4

Maize late embryogenesis abundant protein Emb564

Radish late seed maturation protein p8B6

Rice embryonic abundant protein Emp1

Sunflower 10 Kd late embryogenesis abundant protein (DS10)

Wheat Em proteins

These proteins may play a role in equipping the seed for survival, maintaining a minimal level of hydration in the dry organism and preventing the denaturation of cytoplasmic components . They may also play a role during imbibition by controlling water uptake.
F420-dependent oxidoreductase-predicted, MSMEG2249 (F420_OxRdatse_MSMEG2249_pred)
Type: Family

Coenzyme F420 has a limited phylogenetic distribution, including methanogenic archaea, Mycobacterium tuberculosis and related species, Colwellia psychrerythraea 34H and Rhodopseudomonas palustris HaA2. Partial phylogenetic profiling identifies protein subfamilies, within the larger family called luciferase-like monooxygenanases (

), that appear only in F420-positive genomes and are likely to be F420-dependent. This entry describes a distinctive subfamily, found only in F420-biosynthesising members of the Actinobacteria of the bacterial luciferase-like monooxygenase (LLM) superfamily.