SII-SWORD/CoKE huggingface dataset:
Protease inhibitor I35 (TIMP) (TIMP)
Type: Family

Tissue inhibitors of metalloproteinases (TIMPs, ) and their target matrix metalloproteinases (MMPs, MEROPS peptidase family M10A) are important in connective tissue re-modelling in diseases of the cardiovascular system and in the physiological degradation of connective tissue, as well as in pathological states such as tumour invasion and arthritis. TIMPs belong to MEROPS proteinase inhibitor family I35, clan IT.

TIMPs complex with extracellular matrix metalloproteinases (such as collagenases) and irreversibly inactivate them. Members of this family are common in extracellular regions of vertebrate species . TIMPs are proteins of about 200 amino acid residues, 12 of which are cysteines involved in disulphide bonds . The basic structure of such a type of inhibitor is shown in the following schematic representation:

+-----------------------------+ +--------------+
| | | |
CxCxCxxxxxxxxxxxxxxxxxCxxxxxxxxxCxxxxxxxCxCxCxCxCxxxxxCxxCxxx
| | | | | | | |
| +-----------------|-----------------+ +-+ +-----+
+---------------------+
'C': conserved cysteine involved in a disulphide bond.

The crystal structure of the human proMMP-2/TIMP-2 complex reveals an interaction between the hemopexin domain of proMMP-2 and the C-terminal domain of TIMP-2, leaving the catalytic site of MMP-2 and the inhibitory site of TIMP-2 distant and spatially isolated. The interfacial contact of these two proteins is characterised by two distinct binding regions composed of alternating hydrophobic and hydrophilic interactions. This unique structure provides information for how specificity for non-inhibitory MMP/TIMP complex formation is achieved .
[NiFe]-hydrogenase, small subunit (NiFe_hydrogenase_ssu)
Type: Family

Hydrogenases catalyse the reversible oxidation of molecular hydrogen and play a vital role in anaerobic metabolism. Metal-containing hydrogenases are subdivided into three classes: Fe ('iron only') hydrogenases; Ni-Fe hydrogenases; and Ni-Fe-Se hydrogenases . Hydrogen oxidation is coupled to the reduction of electron acceptors (such as oxygen, nitrate, sulphate, carbon dioxide and fumarate), whereas proton reduction (hydrogen evolution) is essential in pyruvate fermentation or in the disposal of excess electrons.

The Ni-Fe hydrogenases, when isolated, are found to catalyse both hydrogen evolution and uptake, with low-potential multihaem cytochromes, such as cytochrome c3, acting as either electron donors or acceptors, depending on their oxidation state. Both periplasmic (soluble) and membrane-bound hydrogenases are known.

The Ni-Fe hydrogenases are heterodimeric proteins consisting of small (S) and large (L) subunits. The small subunit contains three iron-sulphur clusters (two [4Fe-4S] and one [3Fe-4S]); the large subunit contains a nickel ion . Small subunits of membrane-bound Ni-Fe hydrogenases contain a C-terminal domain of about 40 residues that is absent in periplasmic forms.

The 3D structure of the Ni-Fe hydrogenase from Desulfovibrio gigas has been determined at 2.85A resolution . The small subunit consists of two domains, I(S) and II(S). The α/β twisted open sheet structure of the N-terminal I(S) domain is similar to that of flavodoxin; the C-terminal II(S) domain contains two α-helices and has no β-structure. The Fe-S clusters are distributed almost along a straight line, with the [3Fe-4S] cluster located half-way between the two [4Fe-4S] clusters. The two [4Fe-4S] clusters have been termed proximal (prox) and distal (dist), based on their distance to the Ni atom. Domain I(S) binds the [4Fe-4S]prox cluster, while domain II(S) binds the [4Fe-4S]dist and [3Fe-4S] clusters. The [4Fe-4S]prox cluster is coordinated by Cys-17, Cys-20, Cys-112 and Cys-148; [4Fe-4S]dist is coordinated by His-185, Cys-188, Cys-213 and Cys-219; and [3Fe-4S] is coordinated by Cys-228, Cys-246 and Cys-249 [4Fe-4S]dist is the first known example of a [4Fe-4S] cluster in protein structure ligated by a His side chain. A crown of acidic residues surrounds the partially-exposed His-185 and this might provide a recognition site for the redox partner (cytochrome c3) . A mechanism of electron transfer from the Ni active site through the Fe-S clusters to the cytochrome c3 has been suggested . The role of the [3Fe-4S] cluster is not clear: its high redox potential and its absence from some homologous hydrogenases put its involvement in electron transfer in doubt .
RHS protein (RHS)
Type: Family

RHS (Rearrangement hotspot) proteins are distantly related to the wall-associated protein A (WapA) and mediate intercellular competition. The protein sequences comprise highly conserved 141kDa domain containing multiple tandem 22-residue repeats, the YD-peptide repeats that define this protein family. Rhs/YD-repeat proteins are widely distributed suggesting that they play a fundamental role in biology. Rhs C-terminal regions (Rhs-CT) are highly divergent . Rhs-CT regions share sequence identity with toxic effector domains of contact-dependent growth inhibition (CDI) systems, which shows that these proteins inhibit the growth of neighboring cells in a contact-dependent manner .
Homeobox protein, antennapedia type, conserved site (Homeobox_Antennapedia_CS)
Type: Conserved_site

The homeobox is a 60-residue motif first identified in a number of Drosophila homeotic and segmentation proteins, but now known to be well-conserved in many other animals, including vertebrates . Proteins containing homeobox domains are likely to play an important role in development - most are known to be sequence-specific DNA-binding transcription factors. The domain binds DNA through a helix-turn-helix (HTH) structure.

Many homeodomain-containing proteins have now been sequenced and, while the homeodomain flanking regions vary, characteristic conserved sequences upstream of the domain allow the proteins to be grouped into 3 subfamilies: the so-called antennapedia, engrailed and 'paired box' proteins. Antennapedia, which regulates the formation of leg structures in Drosophila, was one of the first homeotic genes studied and led to the discovery of the homeobox domain. Over expression of this gene in the wrong segment of the fruit fly can lead to the formation of leg structures in these segments. For example, over expression in the head segment can lead to the formation of legs instead of antennae (hence the name antennapedia). The sequences of the antennapedia proteins contain a conserved hexapeptide 5-16 residues upstream of the homeobox, the specific function of which is unclear. The six Drosophila proteins that belong to this group are antennapedia (Antp), abdominal-A (abd-A), deformed (Dfd), proboscipedia (pb), sex combs reduced (scr) and ultrabithorax (ubx) and are collectively known as the 'antennapedia' subfamily.

In vertebrates the corresponding Hox genes are known as Hox-A2, A3, A4, A5, A6, A7, Hox-B1, B2, B3, B4, B5, B6, B7, B8, Hox-C4, C5, C6, C8, Hox-D1, D3, D4 and D8.

Caenorhabditis elegans lin-39 and mab-5 are also members of the 'antennapedia' subfamily.

Arg and Lys are most frequently found in the last position of the hexapeptide; other amino acids are found in only a few cases.
Receptor, ligand binding region (ANF_lig-bd_rcpt)
Type: Domain

This describes a ligand binding domain and includes extracellular ligand binding domains of a wide range of receptors, as well as the bacterial amino acid binding proteins of known structure .
Pili assembly chaperone, bacterial (Pili_assmbl_chaperone_bac)
Type: Family

Most Gram-negative bacteria possess a supramolecular structure - the pili - on their surface, which mediates attachment to specific receptors. Many interactive subunits are required to assemble pili, but their assembly only takes place after translocation across the cytoplasmic membrane. Periplasmic chaperones assist pili assembly by binding to the subunits, thereby preventing premature aggregation . Pili chaperones are structurally, and possibly evolutionarily, related to the immunoglobulin superfamily : they contain two globular domains, with a topology identical to an immunoglobulin fold.
Glycosyl transferase, family 20 (Glyco_trans_20)
Type: Family

The biosynthesis of disaccharides, oligosaccharides and polysaccharides involves the action of hundreds of different glycosyltransferases. These enzymes catalyse the transfer of sugar moieties from activated donor molecules to specific acceptor molecules, forming glycosidic bonds. A classification of glycosyltransferases using nucleotide diphospho-sugar, nucleotide monophospho-sugar and sugar phosphates ([ec:2.4.1.-]) and related proteins into distinct sequence based families has been described . This classification is available on the CAZy (CArbohydrate-Active EnZymes) web site. The same three-dimensional fold is expected to occur within each of the families. Because 3-D structures are better conserved than sequences, several of the families defined on the basis of sequence similarities may have similar 3-D structures and therefore form 'clans'.

Glycosyltransferase family 20

comprises enzymes with only one known activity; alpha, alpha-trehalose-phosphate synthase [UDP-forming] (

).
Immunodeficiency virus transactivating regulatory protein (Tat) (IV_Tat)
Type: Family

Like other lentiviruses, Human immunodeficiency virus 1 (HIV-1) encodes a trans-activating regulatory protein (Tat), which is essential for efficient transcription of the viral genome . Tat acts by binding to an RNA stem-loop structure, the trans-activating response element (TAR), found at the 5' ends of nascent HIV-1 transcripts. In binding to TAR, Tat alters the properties of the transcription complex, recruits a positive transcription elongation complex (P-TEFb) and hence increases the production of full-length viral RNA . Tat protein also associates with RNA polymerase II complexes during early transcription elongation after the promoter clearance and before the synthesis of full-length TAR RNA transcript. This interaction of Tat with RNA polymerase II elongation complexes is P-TEFb-independent. There are two Tat binding sites on each transcription elongation complex; one is located on TAR RNA and the other one on RNA polymerase II near the exit site for nascent mRNA transcripts which suggests that two Tat molecules are involved in performing various functions during a single round of HIV-1 mRNA synthesis .

The minimum Tat sequence that can mediate specific TAR binding
in vitro
has been mapped to a basic domain of 10 amino acids, comprising mostly Arg and Lys residues. Regulatory activity, however, also requires the 47 N-terminal residues, which interact with components of the transcription complex and function as a transcriptional activation domain .
Heat-labile enterotoxin, B chain (Enterotoxin_B)
Type: Family

Escherichia coli heat-labile enterotoxin is a bacterial protein toxin with an AB5 multimer structure, in which the B pentamer has a membrane-binding function and the A chain (

) is needed for enzymatic activity . The B subunits are arranged as a donut-shaped pentamer, each subunit participating in ~30 hydrogen bonds and 6 salt bridges with its two neighbours .

The A subunit has a less well-defined secondary structure. It predominantly interacts with the pentamer via the C-terminal A2 fragment, which runs through the charged central pore of the B subunits. A putative catalytic residue in the A1 fragment (Glu112) lies close to a hydrophobic region, which packs two loops together. It is thought that this region might be important for catalysis and membrane translocation .
Adenylate cyclase-associated CAP (Adenylate_cyclase-assoc_CAP)
Type: Family

Cyclase-associated proteins (CAPs) are highly conserved actin-binding proteins present in a wide range of organisms including yeast, fly, plants, and mammals. CAPs are multifunctional proteins that contain several structural domains. CAP is involved in species-specific signalling pathways . In Drosophila, CAP functions in Hedgehog-mediated eye development and in establishing oocyte polarity. In Dictyostelium (slim mold), CAP is involved in microfilament reorganisation near the plasma membrane in a PIP2-regulated manner and is required to perpetuate the cAMP relay signal to organise fruitbody formation. In plants, CAP is involved in plant signalling pathways required for co-ordinated organ expansion. In yeast, CAP is involved in adenylate cyclase activation, as well as in vesicle trafficking and endocytosis. In both yeast and mammals, CAPs appear to be involved in recycling G-actin monomers from ADF/cofilins for subsequent rounds of filament assembly . In mammals, there are two different CAPs (CAP1 and CAP2) that share 64% amino acid identity.

This entry represents CAP proteins from various organisms.
Transforming growth factor-beta, C-terminal (TGF-b_C)
Type: Domain

Transforming growth factor-beta (TGF-beta) is a multifunctional peptide that controls proliferation, differentiation and other functions in many cell types. TGF-beta-1 is a peptide of 112 amino acid residues derived by proteolytic cleavage from the C-terminal of a precursor protein .

A number of proteins are known to be related to TGF-beta-1 . Proteins from the TGF-beta family are only active as homo- or heterodimer; the two chains being linked by a single disulphide bond. From X-ray studies of TGF-beta-2 , it is known that all the other cysteines are involved in intrachain disulphide bonds. There are four disulphide bonds in the TGF-beta and in inhibin beta chains, while the other members of this family lack the first bond.

The regulatory cytokine TGFbeta exerts tumour-suppressive effects, but also modulates cell invasion and immune regulation . Misregulation of the TGF-beta signalling pathway can result in tumour development.
Anaphylatoxin, complement system domain (Anaphylatoxn_comp_syst_dom)
Type: Domain

Complement components C3, C4 and C5 are large glycoproteins that have important functions in the immune response and host defence . They have a wide variety of biological activities and are proteolytically activated by cleavage at a specific site, forming a-and b-fragments . A-fragments form distinct structural domains of approximately 76 amino acids, coded for by a single exon within the complement protein gene. The C3a, C4a and C5a components are referred to as anaphylatoxins : they cause smooth muscle contraction, histamine release from mast cells, and enhanced vascular permeability ; they also mediate chemotaxis, inflammation, and generation of cytotoxic oxygen radicals . The proteins are highly hydrophilic, with a mainly α-helical structure held together by 3 disulphide bridges .

Some of the proteins in this group are responsible for the molecular basis of the blood group antigens, surface markers on the outside of the red blood cell membrane. Most of these markers are proteins, but some are carbohydrates attached to lipids or proteins [Reid M.E., Lomas-Francis C. The Blood Group Antigen FactsBook Academic Press, London / San Diego, (1997)]. Complement C4 belongs to the Chido/Rodgers blood group system and is associated with Ch1 to Ch6, WH, Rg1 and Rg2 antigens.
Zinc finger, RING-type (Znf_RING)
Type: Domain

This entry represents RING-type zinc finger domains. The RING-finger is a specialised type of Zn-finger of 40 to 60 residues that binds two atoms of zinc, and is probably involved in mediating protein-protein interactions . There are two different variants, the C3HC4-type and a C3H2C3-type, which are clearly related despite the different cysteine/histidine pattern. The latter type is sometimes referred to as 'RING-H2 finger'. The RING domain is a protein interaction domain that has been implicated in a range of diverse biological processes. E3 ubiquitin-protein ligase, in Homo sapiens

, activity is intrinsic to the RING domain of c-Cbl and is likely to be a general function of this domain. E3 ubiquitin-protein ligases determine the substrate specificity for ubiquitylation and have been classified into HECT and RING-finger families. Various RING fingers also exhibit binding to E2 ubiquitin-conjugating enzymes (Ubc's) .

Several 3D-structures for RING-fingers are known . The 3D structure of the zinc ligation system is unique to the RING domain and is referred to as the 'cross-brace' motif. The spacing of the cysteines in such a domain is C-x(2)-C-x(9 to 39)-C-x(1 to 3)-H-x(2 to 3)-C-x(2)-C-x(4 to 48)-C-x(2)-C. Metal ligand pairs one and three co-ordinate to bind one zinc ion, whilst pairs two and four bind the second.

Note that in the older literature, some RING-fingers are denoted as LIM-domains. The LIM-domain Zn-finger is a fundamentally different family, albeit with similar Cys-spacing (see

).

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.
Peptidase M36, fungalysin (Peptidase_M36)
Type: Family

Over 70 metallopeptidase families have been identified to date. In these enzymes a divalent cation, which is usually zinc but may be cobalt, manganese or copper, activates the water molecule. The metal ion is held in place by amino acid ligands, usually three in number. In some families of co-catalytic metallopeptidases, two metal ions are observed in crystal structures ligated by five amino acids, with one amino acid ligating both metal ions. The known metal ligands are His, Glu, Asp or Lys. At least one other residue is required for catalysis, which may play an electrophilic role.

Many metalloproteases contain an HEXXH motif, which has been shown in crystallographic studies to form part of the metal-binding site . The HEXXH motif is relatively common but can be more stringently defined for metalloproteases as 'abXHEbbHbc', where 'a' is most often valine or threonine and forms part of the S1' subsite in thermolysin and neprilysin, 'b' is an uncharged residue, and 'c' a hydrophobic residue. Proline is never found in this site, possibly because it would break the helical structure adopted by this motif in metalloproteases .

This group of metallopeptidases belong to MEROPS peptidase family M36 (fungalysin family, clan MA(E)). The predicted active site residues for members of this family and thermolysin, the type example for clan MA, occur in the motif HEXXH.

Fungalysin is produced by fungi, Aspergillus and other species, to aid degradation of host lung cell walls on infection. The enzyme is a 42kDa single chain protein, with a pH optimum of 7.5-8.0 and optimal temperature of 60 celcius .
Fragilysin (Fragilysin)
Type: Family

Fragilysin is a metalloprotease toxin which is cytopathic to intestinal epithelial cells and induces fluid secretion and tissue damage in ligated intestinal loops .
Chaperonin Cpn60/GroEL (Cpn60/GroEL)
Type: Family

The assembly of proteins has been thought to be the sole result of properties inherent in the primary sequence of polypeptides themselves. In some cases, however, structural information from other protein molecules is required for correct folding and subsequent assembly into oligomers . These `helper' molecules are referred to as molecular chaperones, a subfamily of which are the chaperonins . They are required for normal cell growth (as demonstrated by the fact that no temperature sensitive mutants for the chaperonin genes can be found in the temperature range 20 to 43 degrees centigrade ), and are stress-induced, acting to stabilise or protect disassembled polypeptides under heat-shock conditions . This entry represents the 60kDa chaperonin (Cpn60), its bacterial homologue groEL and RuBisCO subunit-binding protein ), which are mainly present in bacteria and eukaryots.

The 60kDa form of chaperonin is the immunodominant antigen of patients with Legionnaire's disease , and is thought to play a role in the protection of the Legionella spp. bacteria from oxygen radicals within macrophages. This hypothesis is based on the finding that the cpn60 gene is upregulated in response to hydrogen peroxide, a source of oxygen radicals. Cpn60 has also been found to display strong antigenicity in many bacterial species , and has the potential for inducing immune protection against unrelated bacterial infections. The RuBisCO subunit binding protein (which has been implicated in the assembly of RuBisCO) and cpn60 have been found to be evolutionary homologues, the RuBisCO subunit binding protein having the C-terminal Gly-Gly-Met repeat found in all bacterial cpn60 sequences. Although the precise function of this repeat is unknown, it is thought to be important as it is also found in 70kDa heat-shock proteins . The crystal structure of Escherichia coli GroEL has been resolved to 2.8A .