SII-SWORD/CoKE huggingface dataset:
Hexapeptide transferase, conserved site (Hexapep_transf_CS)
Type: Conserved_site

A variety of bacterial transferases contain a repeat structure composed of tandem repeats of a [LIV]-G-X(4) hexapeptide, which, in the tertiary structure of LpxA (UDP N-acetylglucosamine acyltransferase) , has been shown to form a left-handed parallel β helix. A number of different transferase protein families contain this repeat, such as galactoside acetyltransferase-like proteins , the gamma-class of carbonic anhydrases , and tetrahydrodipicolinate-N-succinlytransferases (DapD), the latter containing an extra N-terminal 3-helical domain .

The signature pattern of this entry represents a fourfold repeat of the a [LIV]-G-x(4) hexapeptide.
Disintegrin, conserved site (Disintegrin_CS)
Type: Conserved_site

This entry represents a conserved central region that contains five of the cysteines involved in disulfide bonds.

Disintegrins are a family of small proteins from viper venoms that function as potent inhibitors of both platelet aggregation and integrin-dependent cell adhesion . Integrin receptors are involved in cell-cell and cell-extracellular matrix interactions, serving as the final common pathway leading to aggregation via formation of platelet-platelet bridges, which are essential in thrombosis and haemostasis. Disintegrins contain an RGD (Arg-Gly-Asp) or KGD (Lys-Gly-Asp) sequence motif that binds specifically to integrin IIb-IIIa receptors on the platelet surface, thereby blocking the binding of fibrinogen to the receptor-glycoprotein complex of activated platelets. Disintegrins act as receptor antagonists, inhibiting aggregation induced by ADP, thrombin, platelet-activating factor and collagen . The role of disintegrin in preventing blood coagulation renders it of medical interest, particularly with regard to its use as an anti-coagulant .

Disintegrins from different snake species have been characterised: albolabrin, applagin, barbourin, batroxostatin, bitistatin, obtustatin , schistatin , echistatin , elegantin, eristicophin, flavoridin , halysin, kistrin, tergeminin, salmosin and triflavin.

Disintegrin-like proteins are found in various species ranging from slime mold to humans. Some other proteins known to contain a disintegrin domain are:

Some snake venom zinc metalloproteinases consist of an N-terminal catalytic domain fused to a disintegrin domain. Such is the case for trimerelysin I (HR1B), atrolysin-e (Ht-e) and trigramin. It has been suggested that these proteinases are able to cleave themselves from the disintegrin domains and that the latter may arise from such a post-translational processing.

The beta-subunit of guinea pig sperm surface protein PH30 . PH30 is a protein involved in sperm-egg fusion. The beta subunit contains a disintegrin at the N-terminal extremity.

Mammalian epididymial apical protein 1 (EAP I) . EAP I is associated with the sperm membrane and may play a role in sperm maturation. Structurally, EAP I consists of an N-terminal domain, followed by a zinc metalloproteinase domain, a disintegrin domain, and a large C-terminal domain that contains a transmembrane region.
Bromodomain, conserved site (Bromodomain_CS)
Type: Conserved_site

Bromodomains are found in a variety of mammalian, invertebrate and yeast DNA-binding proteins . Bromodomains are highly conserved α-helical motifs that can specifically interact with acetylated lysine residues on histone tails . In some proteins, the classical bromodomain has diverged to such an extent that parts of the region are either missing or contain an insertion (e.g., mammalian protein HRX, Caenorhabditis elegans hypothetical protein ZK783.4, yeast protein YTA7). The bromodomain may occur as a single copy, or in duplicate.

This domain is present in proteins involved in a wide range of functions such as acetylating histones, remodelling chromatin, and recruiting other factors necessary for transcription, thus playing a critical role in the regulation of transcription .
Calcitonin, conserved site (Calcitonin_CS)
Type: Conserved_site

Calcitonin is a 32 amino acid polypeptide hormone that causes a rapid but short-lived drop in the level of calcium and phosphate in the blood, by promoting the incorporation of these ions in the bones. This is the alpha type. Alternative splicing of the gene coding for calcitonin produces a distantly related peptide of 37 amino acids, called calcitonin gene-related peptide (CGRP), beta type. CGRP induces vasodilatation in a variety of vessels, including the coronary, cerebral and systemic vasculature. Its abundance in the CNS also points toward a neurotransmitter or neuromodulator role.

Islet amyloid polypeptide (IAPP) (also known as diabetes-associated peptide (DAP), or amylin) is a peptide of 37 amino acids that selectively inhibits insulin-stimulated glucose utilisation and glycogen deposition in muscle, while not affecting adipocyte glucose metabolism. Structurally, IAPP is closely related to CGRP.

Calcitonin receptor-stimulating peptide 1 stimulates cAMP production via the calcitonin receptor.

Two conserved cysteines in the N-terminal of these peptides are known to be involved in a disulphide bond. The C-terminal residue of all three peptides is amidated.

xCxxxxxCxxxxxxxxxxxxxxxxxxxxxxxxxxxx-NH(2)
| | Amide group
+-----+

'C': conserved cysteine involved in a disulphide bond.
Caveolin, conserved site (Caveolin_CS)
Type: Conserved_site

Caveolae are 50-100 nm invaginations located at the plasma membrane of many cell types and are known to transport molecules across endothelial cells . Caveolae require the caveolin protein for formation. Caveolins may act as scaffolding proteins within caveolar membranes by compartmentalizing and concentrating signalling molecules. Mammals have three caveolin proteins:caveolin-1 (Cav-1, or VIP21), caveolin-2 and caveolin-3 (or M-caveolin). Various classes of signalling molecules, including G-protein subunits, receptor and non-receptor tyrosine kinases, endothelial nitric oxide synthase (eNOS), and small GTPases, bind Cav-1 through its 'caveolin-scaffolding domain' .

Caveolins are proteins of about 20 Kd, they form high molecular mass homo-oligomers. Structurally they seem to have N-terminal and C-terminal hydrophilic segments and a long central transmembrane domain that probably forms a hairpin in the membrane. Both extremities are known to face the cytoplasm. Caveolae are enriched with cholesterol and Cav-1 is one of the few proteins that binds cholesterol tightly and specifically.
CCAAT-binding factor, conserved site (CCAAT-binding_factor_CS)
Type: Conserved_site

The CCAAT-binding factor (CBFB/NF-YA) is a mammalian transcription factor that binds to a CCAAT motif in the promoters of a wide variety of genes, including type I collagen and albumin . The factor is a heteromeric complex of A and B subunits, both of which are required for DNA-binding . The subunits can interact in the absence of DNA-binding, conserved regions in each being important in mediating this interaction.

The B subunit contains a region of similarity with the yeast protein HAP2 . For the B subunit it has been suggested that the N-terminal portion of the conserved region is involved in subunit interaction and the C-terminal region involved in DNA-binding .
CD59 antigen, conserved site (CD59_antigen_CS)
Type: Conserved_site

CD59 (also called 1F-5Ag, H19, HRF20, MACIF, MIRL, P-18 or protectin) inhibits formation of membrane attack complex (MAC), thus protecting cells from complement mediated lysis. It has a signalling role, as a GPI-anchored molecule, in T cell activation and appears to have some role in cell adhesion through CD2 (controversial). CD59 associates with C9, inhibiting incorporation into C5b-8 preventing terminal steps in polymerisation of the (MAC) in plasma membranes. Genetic defects in GPI-anchor attachment that cause a reduction or loss of both CD59 and CD55 on erythrocytes produce the symptoms of the disease paroxysmal nocturnal haemoglobinuria (PNH).
Cell cycle, FtsW / RodA / SpoVE, conserved site (Cell_cycle_FtsW-rel_CS)
Type: Conserved_site

A number of prokaryotic integral membrane proteins involved in cell cycle processes have been found to be structurally related . These proteins include, the Escherichia coli and related bacteria cell division protein ftsW and the rod shape-determining protein rodA (or mrdB), the Bacillus subtilis stage V sporulation protein E (spoVE), the B. subtilis hypothetical proteins ywcF and ylaO and the Cyanophora paradoxa cyanelle ftsW homologue.

FtsW is an integral membrane protein with ten transmembrane segments . In general, it is one of two paralogues involved in peptidoglycan biosynthesis, the other being RodA, and is essential for cell division . In endospore-forming bacteria (e.g. Bacillus subtilis) three or more RodA/FtsW/SpoVE family paralogues are present . SpoVE acts in spore cortex formation and is dispensable for growth .

FtsW belongs to the so called SEDS (shape, elongation, division and sporulation) family, which are thought to be peptidoglycan polymerases .

Treponema pallidum RodA and Escherichia coli MrdB are probable peptidoglycan polymerases that are essential for cell wall elongation . RodA is a member of the FtsW/RodA/SpoVE family. It is found only in species with rod (or spiral) shapes. RodA is required for the maintenance of the rod cell shape and is essential for the elongation of the lateral wall of the cell . In Escherichai coli, the rodA and pbpA genes occur in the same operon, and RodA is required for the expression of the enzymatic activity of the penicillin-binding protein 2 (PbpA) .
Carbohydrate-binding type-2, conserved site (CBM2_CS)
Type: Conserved_site

The microbial degradation of cellulose and xylans requires several types of enzyme such as endoglucanases (

), cellobiohydrolases (

) (exoglucanases), or xylanases (

) . Structurally, cellulases and xylanases generally consist of a catalytic domain joined to a cellulose-binding domain (CBD) by a short linker sequence rich in proline and/or hydroxy-amino acids.

The CBD domain is found either at the N-terminal or at the C-terminal extremity of these enzymes. As it is shown in the following schematic representation, there are two conserved cysteines in this CBD domain - one at each extremity of the domain - which have been shown to be involved in a disulphide bond. There are also four conserved tryptophan, two are involved in cellulose binding. The CBD of a number of bacterial cellulases has been shown to consist of about 105 amino acid residues .

+-------------------------------------------------+
| |
xCxxxxWxxxxxNxxxWxxxxxxxWxxxxxxxxWNxxxxxGxxxxxxxxxxCx

'C': conserved cysteine involved in a disulphide bond.
ClpA/B, conserved site 1 (ClpA/B_CS1)
Type: Conserved_site

The ClpA/B family of ATP-binding proteins includes the regulatory subunit of the ATP-dependent protease Clp, ClpA; heat shock proteins ClpB, 104 and 78; and chloroplast proteins CD4a (ClpC) and CD4b . The proteins are thought to protect cells from stress by controlling the aggregation and denaturation of vital cellular structures. They vary in size, but share two conserved regions of about 200 amino acids that each contains an ATP-binding site .

This entry represents a conserved site found in the first conserved region.
Chaperonin GroES, conserved site (Chaprnonin_Cpn10_CS)
Type: Conserved_site

The chaperonins are 'helper' molecules required for correct folding and subsequent assembly of some proteins . These are required for normal cell growth , and are stress-induced, acting to stabilise or protect disassembled polypeptides under heat-shock conditions. Type I chaperonins present in eubacteria, mitochondria and chloroplasts require the concerted action of 2 proteins, chaperonin 60 (cpn60) and chaperonin 10 (cpn10) .
Chaperonin Cpn60, conserved site (Chaperonin_Cpn60_CS)
Type: Conserved_site

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 . Type I chaperonins present in eubacteria, mitochondria and chloroplasts require the concerted action of 2 proteins, chaperonin 60 (cpn60) and chaperonin 10 (cpn10). Type II chaperonins, found in eukaryotic cytosol and in Archaebacteria, comprise only a cpn60 member.

The 10kDa chaperonin (cpn10 - or groES in bacteria) exists as a ring-shaped oligomer of between 6 to 8 identical subunits, whereas the 60kDa chaperonin (cpn60 - or groEL in bacteria) forms a structure comprising 2 stacked rings, each ring containing 7 identical subunits . These ring structures assemble by self-stimulation in the presence of Mg2+-ATP. The central cavity of the cylindrical cpn60 tetradecamer provides as isolated environment for protein folding whilst cpn-10 binds to cpn-60 and synchronizes the release of the folded protein in an Mg
2+
-ATP dependent manner . The binding of cpn10 to cpn60 inhibits the weak ATPase activity of cpn60.

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 .
Chitin-binding, type 1, conserved site (Chitin-binding_1_CS)
Type: Conserved_site

A number of plant and fungal proteins that bind N-acetylglucosamine (e.g. solanaceous lectins of tomato and potato, plant endochitinases, the wound-induced proteins: hevein, win1 and win2, and the Kluyveromyces lactis killer toxin alpha subunit) contain this domain . The domain may occur in one or more copies and is thought to be involved in recognition or binding of chitin subunits . In chitinases, as well as in the potato wound-induced proteins, the 43-residue domain directly follows the signal sequence and is therefore at the N terminus of the mature protein; in the killer toxin alpha subunit it is located in the central section of the protein.
Chloramphenicol acetyltransferase, active site (Chloramphenicol_AcTrfase_AS)
Type: Active_site

Chloramphenicol acetyltransferase (CAT) (

) catalyzes the acetyl-CoA dependent acetylation of chloramphenicol (Cm), an antibiotic which inhibits prokaryotic peptidyltransferase activity. Acetylation of Cm by CAT inactivates the antibiotic. The pattern signature for this entry contains the histidine residue, located in the C-terminal section of the enzyme, that plays a central role in its catalytic mechanism.

There is a second family of CAT , evolutionary unrelated to the main family described above. These CAT belong to the bacterial hexapeptide-repeat containing-transferases family (see

).

The crystal structure of the type III enzyme from Escherichia coli with chloramphenicol bound has been determined. CAT is a trimer of identical subunits (monomer Mr 25,000) and the trimeric structure is stabilised by a number of hydrogen bonds, some of which result in the extension of a β-sheet across the subunit interface. Chloramphenicol binds in a deep pocket located at the boundary between adjacent subunits of the trimer, such that the majority of residues forming the binding pocket belong to one subunit while the catalytically essential histidine belongs to the adjacent subunit. His195 is appropriately positioned to act as a general base catalyst in the reaction, and the required tautomeric stabilisation is provided by an unusual interaction with a main-chain carbonyl oxygen .

This signature pattern covers the region surrounding an active site histidine residue located in the C-terminal section of the enzyme; this residue plays a central role in its catalytic mechanism.
Coproporphyrinogen III oxidase, conserved site (Coprogen_oxidase_CS)
Type: Conserved_site

Coprogen oxidase (i.e. coproporphyrin III oxidase or coproporphyrinogenase) catalyses the oxidative decarboxylation of coproporphyrinogen III to proto-porhyrinogen IX in the haem and chlorophyll biosynthetic pathways . The protein is a homodimer containing two internally bound iron atoms per molecule of native protein . The enzyme is active in the presence of molecular oxygen that acts as an electron acceptor. The enzyme is widely distributed having been found in a variety of eukaryotic and prokaryotic sources.
Enoyl-CoA hydratase/isomerase, conserved site (Enoyl-CoA_hyd/isom_CS)
Type: Conserved_site

The crotonase superfamily is comprised of mechanistically diverse proteins that share a conserved trimeric quaternary structure (sometimes a hexamer consisting of a dimer of trimers), the core of which consists of 4 turns of a (β/β/α)n superhelix. Some enzymes in the superfamily have been shown to display dehalogenase, hydratase, and isomerase activities, while others have been implicated in carbon-carbon bond formation and cleavage as well as the hydrolysis of thioesters . However, these different enzymes share the need to stabilise an enolate anion intermediate derived from an acyl-CoA substrate. This is accomplished by two structurally conserved peptidic NH groups that provide hydrogen bonds to the carbonyl moieties of the acyl-CoA substrates and form an "oxyanion hole". The CoA thioester derivatives bind in a characteristic hooked shape and a conserved tunnel binds the pantetheine group of CoA, which links the 3'-phosphate ADP binding site to the site of reaction . Enzymes in the crotonase superfamily include:

Enoyl-CoA hydratase (crotonase;

), which catalyses the hydration of 2-trans-enoyl-CoA into 3-hydroxyacyl-CoA .

3-2 trans-enoyl-CoA isomerase (or dodecenoyl-CoA isomerise;

), which shifts the 3-double bond of the intermediates of unsaturated fatty acid oxidation to the 2-trans position .

3-hydroxybutyryl-CoA dehydratase (crotonase;

), a bacterial enzyme involved in the butyrate/butanol-producing pathway.

4-Chlorobenzoyl-CoA dehalogenase (

), a Pseudomonas enzyme which catalyses the conversion of 4-chlorobenzoate-CoA to 4-hydroxybenzoate-CoA .

Dienoyl-CoA isomerase, which catalyses the isomerisation of 3-trans,5-cis-dienoyl-CoA to 2-trans,4-trans-dienoyl-CoA .

Naphthoate synthase (MenB, or DHNA synthetase;

), a bacterial enzyme involved in the biosynthesis of menaquinone (vitamin K2) .

Carnitine racemase (gene caiD), which catalyses the reversible conversion of crotonobetaine to L-carnitine in Escherichia coli .

Methylmalonyl CoA decarboxylase (MMCD;

), which has a hexameric structure (dimer of trimers) .

Carboxymethyl Proline synthase (CarB), which is involved in carbapenem biosynthesis .

6-oxo camphor hydrolase, which catalyses the desymmetrization of bicyclic beta-diketones to optically active keto acids .

The alpha subunit of fatty oxidation complex, a multi-enzyme complex that catalyses the last three reactions in the fatty acid beta-oxidation cycle .

AUH protein, a bifunctional RNA-binding homologue of enoyl-CoA hydratase .
C-type lectin, conserved site (C-type_lectin_CS)
Type: Conserved_site

Lectins occur in plants, animals, bacteria and viruses. Initially described for their carbohydrate-binding activity , they are now recognised as a more diverse group of proteins, some of which are involved in protein-protein, protein-lipid or protein-nucleic acid interactions . There are at least twelve structural families of lectins:

C-type lectins, which are Ca+-dependent.

S-type (galectins), a widespread family of glycan-binding proteins .

I-type, which have an immunoglobulin-like fold and can recognise sialic acids, other sugars and glycosaminoglycans .

P-type, which bind phosphomannosyl receptors .

Pentraxins .

(Trout) egg lectins.

Calreticulin and calnexin, which act as molecular chaperones of the endoplasmic reticulum .

ERGIC-53 and VIP-36 .

Discoidins .

Eel aggutinins (fucolectins) .

Annexin lectins .

Fibrinogen-type lectins, which includes ficolins, tachylectins 5A and 5B, and Limax flavus (Spotted garden slug) agglutinin (these proteins have clear distinctions from one another, but they share a homologous fibrinogen-like domain used for carbohydrate binding).

Also unclassified orphan lectins, including amphoterin, Cel-II, complement factor H, thrombospondin, sailic acid-binding lectins, adherence lectin, and cytokins (such as tumour necrosis factor and several interleukins).

C-type lectins can be further divided into seven subgroups based on additional non-lectin domains and gene structure: (I) hyalectans, (II) asialoglycoprotein receptors, (III) collectins, (IV) selectins, (V) NK group transmembrane receptors, (VI) macrophage mannose receptors, and (VII) simple (single domain) lectins .

Therefore, lectins are a diverse group of proteins, both in terms of structure and activity. Carbohydrate binding ability may have evolved independently and sporadically in numerous unrelated families, where each evolved a structure that was conserved to fulfil some other activity and function. In general, animal lectins act as recognition molecules within the immune system, their functions involving defence against pathogens, cell trafficking, immune regulation and the prevention of autoimmunity .
BEN domain (BEN_domain)
Type: Domain

The BEN domain is found in diverse proteins including:

SMAR1 (Scaffold/Matrix attachment region-binding protein 1; also known as BANP), a tumour-suppressor MAR-binding protein that down-regulates Cyclin D1 expression by recruiting HDAC1-mSin3A co-repressor complex at Cyclin D1 promoter locus; SMAR1 is the target of prostaglandin A2 (PGA2) induced growth arrest .

NAC1, a novel member of the POZ/BTB (Pox virus and Zinc finger/Bric-a-bracTramtrack Broad complex), but which varies from other proteins of this class in that it lacks the characteristic DNA-binding motif .

Mod(mdg4) isoform C, the modifier of the mdg4 locus in Drosophila melanogaster (Fruit fly), where mdg4 encodes chromatin proteins which are involved in position effect variegation, establishment of chromatin boundaries, nerve path finding, meiotic chromosome pairing and apoptosis . Trans-splicing of Mod(mdg4) produces at least 26 transcripts.

E5R protein from Chordopoxvirus virosomes, which is found in cytoplasmic sites of viral DNA replication .

Several proteins of polydnaviruses.

BEN-containing proteins were characterised to have chromatin-related functions as an adaptor for the higher-order structuring of chromatin, and recruitment of chromatin modifying factors in transcriptional regulation. BEN domain is an intrinsic sequence-specific DNA-binding domain . The presence of BEN domains in a poxviral early virosomal protein and in polydnavirus proteins also suggests a possible role in the organisation of viral DNA during replication or transcription. They are generally linked to other globular domains with functions related to transcriptional regulation and chromatin structure, such as BTB, C4DM, and C2H2 fingers .

This domain forms an all-α fold with four conserved helices. Its conservation pattern reveals several conserved residues, most of which have hydrophobic side-chains and are likely to stabilise the fold through helix-helix packing .