SII-SWORD/CoKE huggingface dataset:
FGD1, N-terminal PH domain (FGD1_PH1)
Type: Domain

This entry represents the N-terminal PH domain of FGD1.

In general, FGDs (including FGD1, FGD2, FGD3 and FGD4/Frabin) have a RhoGEF (DH) domain, followed by an N-terminal PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activates the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the N-terminal PH domain is involved in intracellular targeting of the DH domain . Mutations in the FGD1 gene are responsible for the X-linked disorder known as faciogenital dysplasia (FGDY) . Both FGD1 and FGD3 are targeted by the ubiquitin ligase SCF(FWD1/beta-TrCP) upon phosphorylation of two serine residues in its DSGIDS motif and subsequently degraded by the proteasome. However, FGD1 and FGD3 induced significantly different morphological changes in HeLa Tet-Off cells and while FGD1 induced long finger-like protrusions, FGD3 induced broad sheet-like protrusions when the level of GTP-bound Cdc42 was significantly increased by the inducible expression of FGD3. They also reciprocally regulated cell motility in inducibly expressed in HeLa Tet-Off cells, FGD1 stimulated cell migration while FGD3 inhibited it. FGD1 and FGD3 therefore play different roles to regulate cellular functions, even though their intracellular levels are tightly controlled by the same destruction pathway through SCF(FWD1/beta-TrCP) .

PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner . They share little sequence conservation, but all have a common fold, which is electrostatically polarised. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity . PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane . A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signalling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes .
CAP superfamily (CAP_sf)
Type: Homologous_superfamily

The CAP domain forms a unique 3 layer α-β-α fold with some, though not all, of the structural elements found in proteases .

The cysteine-rich secretory proteins, antigen 5, and pathogenesis-related 1 proteins (CAP) superfamily proteins are found in a wide range of organisms, including prokaryotes and non-vertebrate eukaryotes , The nine subfamilies of the mammalian CAP superfamily include: the human glioma pathogenesis-related 1 (GLIPR1), Golgi associated pathogenesis related-1 (GAPR1) proteins, peptidase inhibitor 15 (PI15), peptidase inhibitor 16 (PI16), cysteine-rich secretory proteins (CRISPs), CRISP LCCL domain containing 1 (CRISPLD1), CRISP LCCL domain containing 2 (CRISPLD2), mannose receptor like and the R3H domain containing like proteins. Members are most often secreted and have an extracellular endocrine or paracrine function and are involved in processes including the regulation of extracellular matrix and branching morphogenesis, potentially as either proteases or protease inhibitors; in ion channel regulation in fertility; as tumour suppressor or pro-oncogenic genes in tissues including the prostate; and in cell-cell adhesion during fertilisation. The overall protein structural conservation within the CAP superfamily results in fundamentally similar functions for the CAP domain in all members, yet the diversity outside of this core region dramatically alters the target specificity and, thus, the biological consequences . The Ca2-chelating function would fit with the various signalling processes (e.g. the CRISP proteins) that members of this family are involved in, and also the sequence and structural evidence of a conserved pocket containing two histidines and a glutamate. It also may explain how

blocks the Ca2 transporting ryanodine receptors.
FGD1-4, C-terminal PH domain (FGD1-4_PH2)
Type: Domain

This entry represents the C-terminal PH domain of FGD1-4.

In general, FGDs (including FGD1, FGD2, FGD3 and FGD4/Frabin) have a RhoGEF (DH) domain, followed by an N-terminal PH domain, a FYVE domain and a C-terminal PH domain. All FGDs are guanine nucleotide exchange factors that activates the Rho GTPase Cdc42, an important regulator of membrane trafficking. The RhoGEF domain is responsible for GEF catalytic activity, while the N-terminal PH domain is involved in intracellular targeting of the DH domain . Mutations in the FGD1 gene are responsible for the X-linked disorder known as faciogenital dysplasia (FGDY) . Both FGD1 and FGD3 are targeted by the ubiquitin ligase SCF(FWD1/beta-TrCP) upon phosphorylation of two serine residues in its DSGIDS motif and subsequently degraded by the proteasome. However, FGD1 and FGD3 induced significantly different morphological changes in HeLa Tet-Off cells and while FGD1 induced long finger-like protrusions, FGD3 induced broad sheet-like protrusions when the level of GTP-bound Cdc42 was significantly increased by the inducible expression of FGD3. They also reciprocally regulated cell motility in inducibly expressed in HeLa Tet-Off cells, FGD1 stimulated cell migration while FGD3 inhibited it. FGD1 and FGD3 therefore play different roles to regulate cellular functions, even though their intracellular levels are tightly controlled by the same destruction pathway through SCF(FWD1/beta-TrCP) .

PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner . They share little sequence conservation, but all have a common fold, which is electrostatically polarised. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity . PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane . A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signalling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes .
Lp2179-like superfamily (Lp2179-like_sf)
Type: Homologous_superfamily

Solution of the structure of the Lactobacillus plantarum protein from this family has indicated a potential new fold with remote similarities to TBP-like (TATA-binding protein) structures. This similarity, in combination with genomic context analysis, leads us to propose an involvement in amino-acid metabolism. The potentially novel fold is an α + β fold comprising two β sheets packed against a single helix . The enzyme is present in the cytosol.
XisI-like superfamily (XisI-like_sf)
Type: Homologous_superfamily

This family contains XisI proteins, also known as FdxN element excision controlling factors, and similar proteins. FdxN element is excised from the chromosome during heterocyst differentiation in cyanobacteria. This is accomplished by the large serine recombinase XisF (fdxN element site-specific recombinase). The xisH as well as the xisF and xisI genes are required. XisI may function as recombination directionality factor (RDF), and needs XisH which may function as an endonuclease .
YfbM-like super family (YfbM-like_sf)
Type: Homologous_superfamily

This entry represents Protein YfbM from Escherichia coli (strain K12) and similar proteins mainly found in bacteria. The structure of YfbM has been solved, showing α/β/α layers with an antiparallel β-sheet. Although this protein is been suggested to be a binding site for peptide nucleic acids (PNAs, species-selective antibacterials, ), its function is yet to be characterised.
YhaI-like superfamily (YhaI-like_sf)
Type: Homologous_superfamily

The structure of this group of uncharacterised protein is composed of five helices and presents folding similarity to the TipA-S domain.
YML108W-like superfamily (YML108W-like_sf)
Type: Homologous_superfamily

Proteins in this entry, which are synthesised by Saccharomycetes, adopt a structure consisting of a four-stranded β-sheet, with strand order beta2-beta1-beta4-beta3, and two α-helices, with an overall topology of β-β-α-β-β-α. They have no known function .
MG354-like superfamily (MG354-like_sf)
Type: Homologous_superfamily

This entry consists of Mycoplasma hypothetical proteins that adopt a multi-helical structure containing a buried central helix. Their function has not been determined yet.
YwqG-like superfamily (YwqG-like_sf)
Type: Homologous_superfamily

This entry is a set of hypothetical proteins. Their function has not been described yet.

The structure contains two similar β-x-β(4) motifs swapped with the first strands.
SopE-like, GEF domain superfamily (SopE-like_GEF_dom_sf)
Type: Homologous_superfamily

This entry represents the guanine nucleotide exchange factor domain of SopE and homologues. This domain has an α-helical structure consisting of two three-helix bundles arranged in a lamdba shape .

The type III secretion system of Gram-negative bacteria is used to transport virulence factors from the pathogen directly into the host cell and is only triggered when the bacterium comes into close contact with the host. Effector proteins secreted by the type III system do not possess a secretion signal, and are considered unique because of this. Salmonella spp. secrete an effector protein called SopE that is responsible for stimulating the reorganisation of the host cell actin cytoskeleton, and ruffling of the cellular membrane . It acts as a guanyl-nucleotide-exchange factor on Rho-GTPase proteins such as Cdc42 and Rac. As it is imperative for the bacterium to revert the cell back to its "normal" state as quickly as possible, another tyrosine phosphatase effector called SptP reverses the actions brought about by SopE .
XkdW-like superfamily (XkdW-like_sf)
Type: Homologous_superfamily

This entry includes the protein XkdW (

) from the Phage-like element PBSX in Bacillus subtilis. It also contains the phage SPbeta protein YorD, the function of which is not known.
TM1622-like superfamily (TM1622-like_sf)
Type: Homologous_superfamily

This entry includes homologues of the uncharacterised TM1622 protein from Thermotoga maritima, for which the structure has been determined. The protein is composed of seven β strands and three α-helices .
Rhomboid-like superfamily (Rhomboid-like_sf)
Type: Homologous_superfamily

This entry represents a six transmembrane helix rhomboid domain. This entry also includes derlins, inactive members of the rhomboid family of intramembrane proteases which lack an active site Ser-His dyad but retain the overall rhomboid architecture .

This domain is found in serine peptidases belonging to the MEROPS peptidase family S54 (Rhomboid, clan ST). They are integral membrane proteins related to the Drosophila melanogaster (Fruit fly) rhomboid protein

. Members of this family are found in archaea, bacteria and eukaryotes.

The rhomboid protease cleaves type-1 transmembrane domains using a catalytic dyad composed of serine and histidine. The active site is embedded within the membrane and the active site residues are on different transmembrane regions. From the tertiary structure of the Escherichia coli homologue GlpG it was shown that hydrolysis occurs in a fluid filled cavity within the membrane. Initially, a catalytic triad including a highly conserved asparagine had been proposed, but this residue has been shown not to be essential . Drosophila rhomboid cleaves the transmembrane proteins Spitz, Gurken and Keren within their transmembrane domains to release a soluble TGFalpha-like growth factor. Cleavage occurs in the Golgi, following translocation of the substrates from the endoplasmic reticulum membrane by Star, another transmembrane protein. The growth factors are then able to activate the epidermal growth factor receptor .

Few substrates of mammalian rhomboid homologues have been determined, but rhomboid-like protein 2 has been shown to cleave ephrin B3 . Parasite-encoded rhomboid enzymes are also important for invasion of host cells by Toxoplasma and the malaria parasite. Invasion of host cells first requires their recognition and this is achieved by parasite transmembrane adhesins interacting with host cell receptors. Before the parasite can enter a host cell the adhesins must be released by cleavage. In Toxoplasma rhomboid TgROM5 cleaves the adhesins, and in Plasmodium, which lacks a TgROM5 orthologue, PfROMs 1 and 4 cleave the diverse array of malaria parasite adhesins .

This entry also includes catalytically inactive rhomboid protease homologues, iRhom1/2, which are metazoan-specific and play crucial roles within the secretory pathway, including protein degradation, trafficking regulation, and inflammatory signaling . They regulate ADAM17 protease, acting as trafficking factors that escort ADAM17 from the ER to the later secretory pathway. They are required for the cleavage and release of a variety of membrane-associated proteins . iRhombs have been linked to the development and progression of several autoimmune diseases including rheumatoid arthritis, lupus nephritis, as well as hemophilic arthropathy and also in neurological disorders such as Alzheimer's and Parkinson's diseases, inflammation, cancer and skin diseases .
Dextranase, N-terminal (Dextranase_N-ter)
Type: Homologous_superfamily

Dextranase (

) and isopullulanase (

) are members of glycoside hydrolase family 49 (

). Dextranase hydrolyses alpha-1,6-glycosidic bonds in dextran polymers.

The N-terminal domain of these enzymes forms a β-sandwich structure that is similar to the immunoglobulin fold but contains two extra strands.
.
MTH677-like superfamily (MTH677-like_sf)
Type: Homologous_superfamily

Proteins in this superfamily contain a novel α+β fold, consisting of two α-helices (one N-terminal and one C-terminal) packed on the same side of a central β-hairpin . They share structural similarity to Escherichia coli MinE, a protein which controls the division that occurs at the midcell site . A hypothetical protein from Methanobacterium thermoautotrophicum (Mth), Mth677, is included in this entry.
RimP, N-terminal domain superfamily (RimP_N_sf)
Type: Homologous_superfamily

This entry represents the N-terminal domain of the ribosome maturation factor RimP (also known as yhbC), which facilitates maturation of the 30S ribosomal subunit . The N-terminal domain contains two α-helices and a three-stranded β-sheet .
Crustacean CHH/MIH/GIH neurohormone superfamily (Crust_neurohorm_sf)
Type: Homologous_superfamily

Hyperglycemic hormone, which controls blood sugar levels, is an abundant peptide in the sinus glands of isopods and decapods . The peptide is a potent secretagogue, releasing digestive enzymes from the hepatopancreas. It may act as a stress hormone. The peptide contains around 70 amino acid residues, and includes six cysteine residues involved in disulphide bond formation . The sequences show a high degree of similarity to the American lobster molt-inhibiting hormone , which also shows hyperglycemic hormone activity.

Sequence analysis reveals at least 2 discrete sequence families, characterised by distinctive N- and C-terminal signatures: broadly, the families represent separate groups of the crustacean hyperglycemic-like hormones and the molt-inhibiting-like hormones. The positions of five of the six cysteine residues are conserved between these families, the first Cys being displaced by one residue position.
SecB-like superfamily (SecB-like_sf)
Type: Homologous_superfamily

Secretion across the inner membrane in some Gram-negative bacteria occurs via the preprotein translocase pathway. Proteins are produced in the cytoplasm as precursors, and require a chaperone subunit to direct them to the translocase component . From there, the mature proteins are either targeted to the outer membrane, or remain as periplasmic proteins. The translocase protein subunits are encoded on the bacterial chromosome.

The translocase itself comprises 7 proteins, including a chaperone protein (SecB), an ATPase (SecA), an integral membrane complex (SecCY, SecE and SecG), and two additional membrane proteins that promote the release of the mature peptide into the periplasm (SecD and SecF) . The chaperone protein SecB is a highly acidic homotetrameric protein that exists as a "dimer of dimers" in the bacterial cytoplasm. SecB maintains preproteins in an unfolded state after translation, and targets these to the peripheral membrane protein ATPase SecA for secretion .

The tertiary structure of Haemophilus influenzae SecB (

) was resolved by means of X-ray crystallography to 2.5A . The chaperone comprises four chains, forming a tetramer, each chain of which has a simple α+β fold arrangement. While one binding site on the homotetramer recognises unfolded polypeptides by hydrophobic interactions, the second binds to SecA through the latter's C-terminal 22 residues.
RutC-like superfamily (RutC-like_sf)
Type: Homologous_superfamily

This entry represents the β-α-β-α-β(2) domains common both to bacterial chorismate mutase and to members of the YjgF/Yer057p/UK114 family. These proteins form trimers with a three-fold symmetry with three closely-packed β-sheets. The conserved domain is similar in structure to chorismate mutase but there is no sequence similarity and no functional connection. This domain homotrimerizes forming a distinct intersubunit cavity that may serve as a small molecule binding site .

Chorismate mutase (CM,

) is an enzyme of the aromatic amino acid biosynthetic pathway that catalyses the reaction at the branch point of the pathway leading to the three aromatic amino acids, phenylalanine, tryptophan and tyrosine (chorismic acid is the last common intermediate, and CM leads to the L-phenylalanine/L-tyrosine branch). It is part of the shikimate pathway, which is present only in bacteria, fungi and plants. The structure of chorismate mutase enzymes from Bacillus subtilis and Thermus thermophilus have been solved and were shown to have a catalytic homotrimer, with the active sites being located at the subunit interfaces, where residues from two subunits contribute to each site.

The YjgF/YER057c/UK114 family is a large, highly conserved, and widely distributed family of proteins found in bacteria, archaea and eukaryotes . YjgF (renamed RidA) deaminates reactive enamine/imine intermediates of pyridoxal 5'-phosphate (PLP)-dependent enzyme reactions. The YjgF/YER057c/UK114 family of proteins is conserved in all domains of life suggesting that reactive enamine/imine metabolites are of concern to all organisms .
Secretoglobin superfamily (Secretoglobin_sf)
Type: Homologous_superfamily

Secretoglobins are relatively small, secreted, disulphide-bridged dimeric proteins with encoding genes sharing substantial sequence similarity . Members of this family include:

Uteroglobin, a mammalian, steroid-inducible, secreted anti-inflammatory/immunomodulatory protein .

Mammaglobin, expressed in ovarian cancer cells .

Lipophilin B, which exists as a complex with mammary-specific mammaglobin A .

Clara cell 17kDa protein, which inhibits phospholipase A2 and papain, and also binds to progesterone .

Allergen Fel d 1 (Felis silvestris catus (Cat) allergen 1) chains 1 and 2, a tetrameric glycoprotein formed by two heterodimers that elicit IgE responses in people with allergy to cats .

Secretoglobin proteins have a four-helical structure, and in the case of uteroglobin, form homodimers, whereas allergen Fel d 1 forms a tetramer of two heterodimers (chains 1 and 2). The conservation of this primary and quaternary structure indicates that the genome of the eutherian common ancestor of cats, rodents, and primates contained a similar gene pair.

Uteroglobin (blastokinin or Clara cell protein CC10) is a mammalian steroid-inducible secreted protein originally isolated from the uterus of rabbits during early pregnancy . The mucosal epithelia of several organs that communicate with the external environment express uteroglobin. Its tissue-specific expression is regulated by steroid hormones, and is augmented in the uterus by non-steroidal prolactin. Uteroglobin may be a multi-functional protein with anti-inflammatory/immunomodulatory properties, acting to inhibit phospholipase A2 activity , and binding to (and possibly sequestering) several hydrophobic ligands such as progesterone, retinols, polychlorinated biphenyls, phospholipids and prostaglandins . In addition, uteroglobin has anti-chemotactic, anti-allergic, anti-tumourigenic and embryo growth-stimulatory properties. Uteroglobin may have a homeostatic role against oxidative damage, inflammation, autoimmunity and cancer . However, the true biological function of uteroglobin is poorly understood. Uteroglobin consists of a disulphide-linked homodimer with a large hydrophobic pocket located between the two dimers . Each monomer being composed of four helices that do not form a canonical four helix-bundle motif but rather a boomerang-shaped structure in which helices H1, H3, and H4 are able to bind a homodimeric partner . The hydrophobic pocket binds steroids, particularly progesterone, with high specificity. It is a member of the secretoglobin superfamily.
Rhabdovirus nucleoprotein-like (Rhabdovirus_nucleoprotein-like)
Type: Homologous_superfamily

The Nucleocapsid (N) Protein is said to have a 'tight' structure. The carboxyl end of the N-terminal domain possesses an RNA binding domain. Sequence alignments show 2 regions of reasonable conservation, approx. 64-103 and 201-329 . A whole functional protein is required for encapsidation to take place .
Rop-like superfamily (Rop-like_sf)
Type: Homologous_superfamily

The Rop protein regulates plasmid DNA replication by modulating the initiation of transcription of the primer RNA precursor. Processing of the precursor, RNAII, is inhibited by hydrogen bonding of RNAII to its complementary sequence in RNAI. Rop increases the affinity of RNAI for RNAII and thus decreases the rate of replication initiation events. The 3D structure of Rop has been determined by X-ray crystallography and refined to 1.7A resolution. The 63 amino acid protein is a homodimer, each monomer consisting almost entirely of two α-helices, the whole molecule forming a highly regular four-α-helix bundle . This can be approximated by a four-stranded rope, with radius 7.0 A, a left-handed helical twist, and pitch 172.5 A. A very compact packing of side chains in the helix interfaces of the Rop coiled-coil structure is presumed to account for its high stability . The overall details of the structure have been confirmed by proton NMR .