SII-SWORD/CoKE huggingface dataset:
AGC-kinase, C-terminal (AGC-kinase_C)
Type: Domain

The AGC (cAMP-dependent, cGMP-dependent and protein kinase C) protein kinase family embraces a collection of protein kinases that display a high degree of sequence similarity within their respective kinase domains. AGC kinase proteins are characterised by three conserved phosphorylation sites that critically regulate their function. The first one is located in an activation loop in the centre of the kinase domain. The two other phosphorylation sites are located outside the kinase domain in a conserved region on its C-terminal side, the AGC-kinase C-terminal domain. These sites serves as phosphorylation-regulated switches to control both intra- and inter-molecular interactions. Without these priming phosphorylations, the kinases are catalytically inactive .

Several structures of the AGC-kinase C-terminal domain have been solved. The first phosphorylation site is located in a turn motif, the second one at the end of the domain in an hydrophobic pocket. In PKB the phosphorylated hydrophobic motif engages a hydrophobic groove within the N-lobe of the kinase domain which orders α helices close to the active site .

Protein phosphorylation, which plays a key role in most cellular activities, is a reversible process mediated by protein kinases and phosphoprotein phosphatases. Protein kinases catalyse the transfer of the gamma phosphate from nucleotide triphosphates (often ATP) to one or more amino acid residues in a protein substrate side chain, resulting in a conformational change affecting protein function. Phosphoprotein phosphatases catalyse the reverse process.
Protein kinases fall into three broad classes, characterised with respect to substrate specificity :

Serine/threonine-protein kinases

Tyrosine-protein kinases

Dual specificity protein kinases (e.g. MEK -phosphorylates both Thr and Tyr on target proteins)

Protein kinase function is evolutionarily conserved from Escherichia coli to human . Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins. The catalytic subunits of protein kinases are highly conserved, and several structures have been solved , leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases .
Zinc finger, DksA/TraR C4-type (Znf_DskA_TraR)
Type: Domain

This entry represents domains identified in zinc finger-containing members of the DksA/TraR family. DksA is a critical component of the rRNA transcription initiation machinery that potentiates the regulation of rRNA promoters by ppGpp and the initiating NTP. In delta-dksA mutants, rRNA promoters are unresponsive to changes in amino acid availability, growth rate, or growth phase. In vitro, DksA binds to RNAP, reduces open complex lifetime, inhibits rRNA promoter activity, and amplifies effects of ppGpp and the initiating NTP on rRNA transcription . The dksA gene product suppresses the temperature-sensitive growth and filamentation of a dnaK deletion mutant of Escherichia coli. Gene knockout and deletion experiments have shown the gene to be non-essential, mutations causing a mild sensitivity to UV light, but not affecting DNA recombination . In
Pseudomonas aeruginosa, dksA is a novel regulator involved in the post-transcriptional control of extracellular virulence factor production .

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.
GPR domain (GPR_dom)
Type: Domain

Gamma-glutamyl phosphate reductase (

) (GPR) is the enzyme that catalyses the second step in the biosynthesis of proline from glutamate, the NADP-dependent reduction of L-glutamate 5-phosphate into
L-glutamate 5-semialdehyde and phosphate. In bacteria (gene proA) and yeast (gene PRO2), GPR is a monofunctional protein, while in plants and mammals, it is a bifunctional enzyme (P5CS) that consists of two domains, an N-terminal glutamate 5-kinase domain (

) and a C-terminal GPR domain. In humans, the P5CS (ALDH18A1), an inner mitochondrial membrane enzyme, is essential to the de novo synthesis of the amino acids proline and arginine . Tomato (Lycopersicon esculentum) has both the prokaryotic-like polycistronic operons encoding GK and GPR (PRO1, ALDH19) and the full-length, bifunctional P5CS (PRO2, ALDH18B1) .

This entry represents the C-terminal GPR domain of the gamma-glutamyl phosphate reductase.
Metallothionein, family 5, Diptera (Metalthion_5)
Type: Family

Metallothioneins (MT) are small proteins that bind heavy metals, such as zinc, copper, cadmium, and nickel. They have a high content of cysteine residues that bind the metal ions through clusters of thiolate bonds species, including sea urchins, fungi, insects and cyanobacteria. Class III MTs are atypical polypeptides composed of gamma-glutamylcysteinyl units. This original classification system has been found to be limited, in the sense that it does not allow clear differentiation of patterns of structural similarities, either between or within classes. Consequently, all class I and class I MTs (the proteinaceous sequences) have now been grouped into families of phylogenetically-related and thus alignable sequences.

Diptera (Drosophila, family 5) MTs are 40-43 residue proteins that contain 10 conserved cysteines arranged in five Cys-X-Cys groups. In particular, the consensus pattern C-G-x(2)-C-x-C-x(2)-Q-x(5)-C-x-C-x(2)-D-C-x-C has been found to be diagnostic of family 5 MTs. The protein is found primarily in the alimentary canal, and its induction is stimulated by ingestion of cadmium or copper . Mercury, silver and zinc induce the protein to a lesser extent. Family 5 includes subfamilies: d1, d2. Only one d2 is known until now. Subfamilies hit the same entry.
Zinc finger, NF-X1-type (Znf_NFX1)
Type: Domain

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.

This entry represents a domain presumed to be a zinc binding domain. The following pattern describes the zinc finger:

C-X(1-6)-H-X-C-X3-C(H/C)-X(3-4)-(H/C)-X(1-10)-C

where X can be any amino acid, and numbers in brackets indicate the number of residues. The two position can be either His or Cys. This central cysteine-rich portion encodes the DNA-binding domain which is highly conserved in eukaryotes . The NFX1 family of proteins may have additional roles mediated by protein-protein interactions regarding the reiterated RING finger motifs in this central domain which strongly suggest that NFX1 is a probable E3 ubiquitin protein ligase . This domain is found in the human transcriptional repressor NK-X1, a repressor of HLA-DRA transcription ; the Drosophila shuttle craft protein, which plays an essential role during the late stages of embryonic neurogenesis and has been shown to be a DNA- or RNA-binding protein ; and the yeast FKBP12-associated protein 1 (FAP1) .
Influenza nuclear export protein NS2 (Flu_NS2)
Type: Family

The Influenza A virus belongs to the class of ssRNA negative-strand viruses. Influenza virus NS2 protein (also known as NEP) has an important role in the nucleocytoplasmic transport of the viral ribonucleoprotein. The NS2 proteins perform this function in virus-infected cells by interacting with nuclear pore complex components of the host cell . It is also involved in important functions during influenza virus replication. Regulation of viral RNA transcription and replication by NS2 was shown to be an important factor in the adaptation of highly pathogenic avian H5N1 influenza viruses to the mammalian host .
FACT complex subunit SSRP1/POB3 (SSRP1/POB3)
Type: Family

FACT (facilitates chromatin transactions) is a general chromatin factor that acts to reorganise nucleosomes. It is a complex that consists of several subunits . This entry represents the FACT complex subunits POB3, which is present in yeast, and the related SSRP1, found in higher eukaryotes.

SSRP1 binds specifically to DNA modified with the anti-cancer drug cisplatin. It contains a high mobility group (HMG) box domain (

) that probably constitutes the structure recognition element for cisplatin-modified DNA, the probable recognition motif being the local duplex unwinding and bending that occurs on formation of intra-strand cross-links .
Globin (Globin)
Type: Domain

This entry covers most of the globin family of proteins, but it omits some bacterial globins and the protoglobins.

Globins are haem-containing proteins involved in binding and/or transporting oxygen. They belong to a very large and well studied family that is widely distributed in many organisms . Globins have evolved from a common ancestor and can be divided into three groups: single-domain globins, and two types of chimeric globins, flavohaemoglobins and globin-coupled sensors. Bacteria have all three types of globins, while archaea lack flavohaemoglobins, and eukaryotes lack globin-coupled sensors . Several functionally different haemoglobins can coexist in the same species. The major types of globins include:

Haemoglobin (Hb): tetramer of two alpha and two beta chains, although embryonic and foetal forms can substitute the alpha or beta chain for ones with higher oxygen affinity, such as gamma, delta, epsilon or zeta chains. Hb transports oxygen from lungs to other tissues in vertebrates . Hb proteins are also present in unicellular organisms where they act as enzymes or sensors .

Myoglobin (Mb): monomeric protein responsible for oxygen storage in vertebrate muscle .

Neuroglobin: a myoglobin-like haemprotein expressed in vertebrate brain and retina, where it is involved in neuroprotection from damage due to hypoxia or ischemia . Neuroglobin belongs to a branch of the globin family that diverged early in evolution.

Cytoglobin: an oxygen sensor expressed in multiple tissues. Related to neuroglobin .

Erythrocruorin: highly cooperative extracellular respiratory proteins found in annelids and arthropods that are assembled from as many as 180 subunit into hexagonal bilayers .

Leghaemoglobin (legHb or symbiotic Hb): occurs in the root nodules of leguminous plants, where it facilitates the diffusion of oxygen to symbiotic bacteriods in order to promote nitrogen fixation.

Non-symbiotic haemoglobin (NsHb): occurs in non-leguminous plants, and can be over-expressed in stressed plants .

Flavohaemoglobins (FHb): chimeric, with an N-terminal globin domain and a C-terminal ferredoxin reductase-like NAD/FAD-binding domain. FHb provides protection against nitric oxide via its C-terminal domain, which transfers electrons to haem in the globin .

Globin-coupled sensors: chimeric, with an N-terminal myoglobin-like domain and a C-terminal domain that resembles the cytoplasmic signalling domain of bacterial chemoreceptors. They bind oxygen, and act to initiate an aerotactic response or regulate gene expression .

Protoglobin: a single domain globin found in archaea that is related to the N-terminal domain of globin-coupled sensors .

Truncated 2/2 globin: lack the first helix, giving them a 2-over-2 instead of the canonical 3-over-3 α-helical sandwich fold. Can be divided into three main groups (I, II and II) based on structural features .

Anaerobic nitrite reductase: phytoglobin that reduces nitrite to nitric oxide (NO) under anoxic conditions .
Octamer-binding transcription factor (TF_octamer)
Type: Family

The octamer-binding protein is a transcription factor that binds specifically to the octamer motif (ATTTGCAT) of immunoglobulin promoters and activates these genes. There are two Ig octamer-binding proteins, designated NF-A1 and NF-A2. NF-A1 is found in all cell types, while NF-A2 is found only in lymphoid cells. The sequences of these proteins contain a region that corresponds closely to the DNA-binding homeobox domains and POU transcription factors.
T-cell surface antigen CD4 (CD4)
Type: Family

CD4 is a glycoprotein found on the surface of T cells. It is a co-receptor that assists the T cell receptor (TCR) in communicating with an antigen-presenting cell (APC). The structure of a soluble fragment of CD4 has been determined to 2.3 A and reveals that the molecule has two intimately-associated immunoglobulin-like domains connected by a continuous β strand. Residues implicated in HIV recognition reside in domain D1. Domain D2 is distinguished by a variation in the β-strand topologies of antibody domains that results in a truncated β-barrel with a non-standard intra-sheet disulphide bond . The binding sites for monoclonal antibodies, class II major histocompatibility complex molecules, and HIV gp120 can be mapped on the molecular surface. Ligation of CD4 by MHC-II on blood monocytes mediates macrophage differentiation and it also increases the susceptibility of blood-derived monocytes to HIV binding and subsequent infection .
Glycoside hydrolase, family 22, lysozyme (Glyco_hydro_22_lys)
Type: Family

O-Glycosyl hydrolases (

) are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycosyl hydrolases, based on sequence similarity, has led to the definition of 85 different families . This classification is available on the CAZy (CArbohydrate-Active EnZymes) website.

Glycoside hydrolase family 22

comprises enzymes with two known activities; lysozyme type C (

) and alpha-lactalbumins. Asp and/or the carbonyl oxygen of the C-2 acetamido group of the substrate acts as the catalytic nucleophile/base.

Lysozyme is a muramidase that hydrolyses beta-1,4-links between N-acetyl-
muramic acid and N-acetyl-D-glucosamine in the peptidoglycan of bacterial cell walls , thus helping to fight invading bacteria. In this capacity, the enzyme is found in tears and saliva, but it has also been recruited for a digestive role in the true stomach (abomasum) of ruminants and colobine monkeys: here it probably degrades the cell walls of bacteria passing from the foregut, allowing the breakdown products to be digested by other stomach enzymes . The stomach form of lysozyme is endowed with special physiochemical properties that allow it to function in an acidic and protease-rich environment.

Lysozyme C is similar to alpha-lactalbumin in terms of primary sequence and structure , and both have probably evolved from a common ancestral protein. There is, however, no similarity in function, lactalbumin being involved in the formation of lactose and is essential for milk production. Another significant difference between the two enzymes is that while all lactalbumins have the ability to bind calcium, this property is restricted to only a few lysozymes .

From human testis cDNA libraries, a group of lysozyme c-like sequences is identified . The function of this group of lysozyme c-like proteins is not clear. Some of them (LYZL2, SLLP1/SPACA3/LYXL3, LYZL4 and LYZL6) are expressed in the male reproductive tract and may be involved in fertilisation.
Interleukin-1 family (IL-1_fam)
Type: Family

Interleukin-1 alpha and interleukin-1 beta (IL-1 alpha and IL-1 beta) are cytokines that participate in the regulation of immune responses, inflammatory reactions, and hematopoiesis . Two types of IL-1 receptor, each with three extracellular immunoglobulin (Ig)-like domains, limited sequence similarity (28%) and different pharmacological characteristics have been cloned from mouse and human cell lines: these have been termed type I and type II receptors . The receptors both exist in transmembrane (TM) and soluble forms: the soluble IL-1 receptor is thought to be post-translationally derived from cleavage of the extracellular portion of the membrane receptors. The receptors can both bind all three forms of IL-1: IL-1 alpha, IL-1 beta and the receptor antagonist IL-1RA .

This entry represents the Interleukin-1 family, which includes seven ligands with agonist activity (IL1-alpha and IL1-beta, IL-18, IL-33, IL36-alpha, IL36-beta, IL36-gamma), three receptor antagonists (IL-1Ra, IL-36Ra, IL-38), and an anti-inflammatory cytokine (IL-37) .
Wilm's tumour protein, N-terminal (Wilms_tumour_N)
Type: Domain

Wilm's tumour (WT) is an embryonal malignancy of the kidney, affecting around 1 in 10,000 infants. It occurs in both sporadic and hereditary forms. Inactivation of WT1 is one of the causes of Wilm's tumour. Defects in the WT1 gene are also associated with Denys-Drash Syndrome (DDS), which is characterised by typical nephropathy and genital abnormalities. The WT1 gene product shows similarity to the zinc fingers of the mammalian growth regulated EGR1 and EGR2 proteins .
DNA ligase, ATP-dependent (DNA_ligase_ATP-dep)
Type: Family

This entry represents DNA ligases from the three domains of life.

DNA ligase (polydeoxyribonucleotide synthase) is the enzyme that joins two DNA fragments by catalysing the formation of an internucleotide ester bond between phosphate and deoxyribose. It is active during DNA replication, DNA repair and DNA recombination. There are two forms of DNA ligase, one requires ATP (

), the other NAD (

), the latter being restricted to eubacteria. Eukaryotic, archaebacterial, viral and some eubacterial DNA ligases are ATP-dependent. The first step in the ligation reaction is the formation of a covalent enzyme-AMP complex. The co-factor ATP is cleaved to pyrophosphate and AMP, with the AMP being covalently joined to a highly conserved lysine residue in the active site of the ligase. The activated AMP residue is then transferred to the 5'phosphate of the nick, before the nick is sealed by phosphodiester-bond formation and AMP elimination .

Vertebrate cells encode three well-characterised DNA ligases (DNA ligases I, III and IV), all of which are related in structure and sequence. With the exception of the atypically small PBCV-1 viral enzyme, two regions of primary sequence are common to all members of the family. The catalytic region comprises six conserved sequence motifs (I, III, IIIa, IV, V-VI), motif I includes the lysine residue that is adenylated in the first step of the ligation reaction. The function of the second, less well-conserved region is unknown. When folded, each protein comprises of two distinct sub-domains: a large amino-terminal sub-domain ('domain 1') and a smaller carboxy-terminal sub-domain ('domain 2'). The ATP-binding site of the enzyme lies in the cleft between the two sub-domains. Domain 1 consists of two antiparallelβ-sheets flanked by α-helices, whereas domain 2 consists of a five-stranded β-barrel and a single α-helix, which form the oligonucleotide-binding fold .
Adenoviral fibre protein, knob (Adeno_fibre_knob)
Type: Domain

Adenoviruses are responsible for diseases such as pneumonia, cystitis, conjunctivitis and diarrhoea, all of which can be fatal to patients who are immunocompromised . Viral infection commences with recognition of host cell receptors by means of specialised proteins on viral surfaces. Specific attachment of adenovirus is achieved through interactions between host-cell receptors and the adenovirus fibre protein and is mediated by the globular carboxy-terminal domain of the adenovirus fibre protein, termed the carboxy-terminal knob domain. Fibre protein forms spikes that protrude from each vertex of the icosahedral capsid. Fibre proteins are shed during virus entry, when virus is still at the cell surface .
Phosphodiesterase MJ0936/Vps29 (Phosphodiesterase_MJ0936/Vps29)
Type: Family

Members of this largely uncharacterised family share a motif approximating DXH(X25)GDXXD(X25)GNHD as found in several phosphoesterases, including the nucleases SbcD and Mre11, and a family of uncharacterised archaeal putative phosphoesterases. In this family, the His residue in GNHD portion of the motif is not conserved. The member MJ0936, one of two from Methanocaldococcus jannaschii (Methanococcus jannaschii), was shown to act on model phosphodiesterase substrates; a divalent cation was required. This entry also represents Vps29 which is part of the retromer complex in yeast .

This entry also includes vacuolar protein sorting-associated protein 29 (vps29), which is an essential component of the retromer complex, a conserved complex required in endosome-to-Golgi retrograde transport .