SII-SWORD/CoKE huggingface dataset:
Membrane insertase YidC/ALB3/OXA1/COX18 (YidC/ALB3/OXA1/COX18)
Type: Family

This entry includes membrane insertase YidC from bacteria, ALBINO3-like proteins from plants, and mitochondrial membrane insertase OXA1 and cytochrome c oxidase assembly protein COX18 from eukaryotes. They are a group of evolutionarily conserved proteins that function in membrane protein integration and protein complex stabilisation. They share a conserved region composed of five transmembrane regions .

YidC is required for the insertion of integral membrane proteins into the membrane. It may also be involved in protein secretion processes . YidC from Gram-negative bacteria contains an extra transmembrane segment (TM1) at the N-terminal and a large periplasmic domain, located between TM1 and TM2, that adopts a β-super sandwich fold that is found in sugar-binding proteins such as galactose mutarotase . The well-characterised YidC protein from Escherichia coli and its close homologues contain a large N-terminal periplasmic domain (

). This protein interacts with SecYEG protein-conducting channel and the accessory proteins SecDF-YajC to form the bacterial holo-translocon (HTL) .

COX18 is a mitochondrial membrane insertase required for the translocation of the C-terminal of cytochrome c oxidase subunit II (MT-CO2/COX2) across the mitochondrial inner membrane. It plays a role in MT-CO2/COX2 maturation following the COX20-mediated stabilisation of newly synthesised MT-CO2/COX2 protein and before the action of the metallochaperones SCO1/2 .

OXA1 is a mitochondrial inner membrane insertase that mediates the insertion of both mitochondrion-encoded precursors and nuclear-encoded proteins from the matrix into the inner membrane. It links mitoribosomes with the inner membrane .

Plant ALBINO3-like proteins are required for the insertion of some light harvesting chlorophyll-binding proteins (LHCP) into the chloroplast thylakoid membrane .
Flavoprotein pyridine nucleotide cytochrome reductase (Flavoprot_Pyr_Nucl_cyt_Rdtase)
Type: Domain

Flavoprotein pyridine nucleotide cytochrome reductases (FPNCR) catalyse the interchange of reducing equivalents between one-electron carriers and the two-electron-carrying nicotinamide dinucleotides. The enzymes include ferredoxin:NADP
+
reductases (FNR) , plant and fungal NAD(P)H:nitrate reductases , NADH:cytochrome b5 reductases , NADPH:P450 reductases , NADPH:sulphite reductases , nitric oxide synthases , phthalate dioxygenase reductase , and various other flavoproteins.

Despite functional similarities, FPNCRs show no sequence similarity to NADPH:adrenodoxin reductases , nor to bacterial ferredoxin:NAD
+
reductases and their homologues . To date, 3D-structures of 4 members of the family have been solved: Spinacia oleracea (Spinach) ferredoxin:NADP
+
reductase ; Burkholderia cepacia (Pseudomonas cepacia) phthalate dioxygenase reductase ; the flavoprotein domain of Zea mays (Maize) nitrate reductase ; and Sus scrofa (Pig) NADH:cytochrome b5 reductase . In all of them, the FAD-binding domain (N-terminal) has the topology of an anti-parallel β-barrel, while the NAD(P)-binding domain (C-terminal) has the topology of a classical pyridine dinucleotide-binding fold (i.e. a central parallel β-sheet with 2 helices on each side) . In spite of such structural similarities, the level of amino acid identity between family members is at or below the limit of significance (e.g., nitrate reductase is only 15% identical to FNR) .
Pro-adrenomedullin (Pro-ADM)
Type: Family

Pro-adrenomedullin (Pro-ADM) is a 185 amino acid long protein. It consists of a pro-ADM N-terminal 20 peptide (PAMP), a midregional pro-ADM (MR-proADM), an adrenotensin and a glycine-extended 53-amino acid peptides. The latter is subsequently converted to the mature ADM consisting of 52 amino acid by enzymatic amidation .

Adrenomedullin (ADM) is a hypotensive peptide, and was first discovered in human pheochromocytoma, it belongs to the calcitonin gene-related peptide family. The first described effects were vasodilation and blood pressure lowering effects but later, other actions were discovered in health and disease, among them stabilisation and development of the endothelial barrier and immunoregulation. ADM is widely expressed in virtually all human tissues with highest levels in adrenal medulla, cardiac atria, and lungs. Many cells are capable of producing ADM, including ECs, vascular smooth muscle cells (VSMCs), monocytes, renal parenchymal cells, and macrophages. ADM exerts its effects by interaction of its C-terminal moiety with ADM1 and ADM2 receptors which are complexes consisting of the calcitonin receptor-like receptor (CRLR) combined with a specific receptor activity-modifying protein 2 and 3 (RAMP2 and RAMP3), respectively, mostly referred to as "ADM receptors". These receptors have been detected in various tissues and organs, such as blood vessels, skeletal muscles, heart, lungs, and nerve tissue .

Recently, ADM has been characterised as pronociceptive mediator, acting as an upstream factor in the transmission of noxious information for various types of pathological pain including acute and chronic inflammatory pain, cancer pain, neuropathic pain induced by spinal nerve injury and diabetic neuropathy. It may also have a role in nerve regeneration in pathological conditions .
Phospholipase C, phosphatidylinositol-specific, Y domain (PLipase_C_Pinositol-sp_Y)
Type: Domain

Phosphatidylinositol-specific phospholipase C (

), an eukaryotic intracellular enzyme, plays an important role in signal transduction processes (see

). It catalyzes the hydrolysis of 1-phosphatidyl-D-myo-inositol-3,4,5-triphosphate into the second messenger molecules diacylglycerol and inositol-1,4,5-triphosphate. This catalytic process is tightly regulated by reversible phosphorylation and binding of regulatory proteins .

In mammals, there are at least 6 different isoforms of PI-PLC, they differ in their domain structure, their regulation, and their tissue distribution. Lower eukaryotes also possess multiple isoforms of PI-PLC.

All eukaryotic PI-PLCs contain two regions of homology, sometimes referred to as 'X-box' (see

) and 'Y-box'. The order of these two regions is always the same (NH2-X-Y-COOH), but the spacing is variable. In most isoforms, the distance between these two regions is only 50-100 residues but in the gamma isoforms one PH domain, two SH2 domains, and one SH3 domain are inserted between the two PLC-specific domains. The two conserved regions have been shown to be important for the catalytic activity. At the C-terminal of the Y-box, there is a C2 domain (see

) possibly involved in Ca-dependent membrane attachment.
Type III secretion system FHIPEP (T3SS_FHIPEP)
Type: Family

The Flagellar/Hr/Invasion Proteins Export Pore (FHIPEP) family consists of a number of proteins that constitute the type III secretion (or signal peptide-independent) pathway apparatus . This mechanism translocates proteins lacking an N-terminal signal peptide across the cell membrane in one step, as it does not require an intermediate periplasmic process to cleave the signal peptide. It is a common pathway amongst Gram-negative bacteria for secreting toxic and flagellar proteins.

The pathway apparatus comprises three components: two within the inner membrane and one within the outer . An FHIPEP protein is located within the inner membrane, although it is unknown which component it constitutes. FHIPEP proteins have all about 700 amino-acid residues. Within the sequence, the N terminus is highly conserved and hydrophobic, suggesting that this terminus is embedded within the membrane, with 6-8 transmembrane (TM) domains, while the C terminus is less conserved and appears to be devoid of TM regions. It is possible that members of the FHIPEP family serve as pores for the export of specific proteins.

Characterised proteins from the FHIPEP family include: the flagellar biosynthesis protein FlhA which is required for formation of the rod structure of the flagellar apparatus ; and the secretion system apparatus protein SsaV from
Salmonella typhimurium
which is required for the secretion of the SpvB toxin .
Proteinase inhibitor I25A, stefin (Prot_inh_stefin)
Type: Family

The cystatins are a superfamily of similar proteins present in mammals, birds, fish, insects, plants and protozoa. In general they are potent peptidase inhibitors belonging to MEROPS inhibitor family I25, clan IH.

The stefin family (MEROPS inhibitor family I25 clan IH, subfamily I25A) includes proteins that lack disulphide bonds and carbohydrates. The most abundant source of stefin A is poly-morphonuclear leucocytes from the liver, but it is also found in extracts of squamous epithelia from the mouth and oesophagus, and has been localised to the cytoplasm of the strata corneum and granulosum of the epidermis. The selective distribution of the inhibitor correlates with tissues that constitute a 'first line of defence' against pathogenic organisms. Stefin A may thus provide a protective function as an inhibitor of cysteine proteases utilised as invasive tools by many infectious agents .

The structure of stefin A contains a 5-stranded anti-parallel β-sheet, wrapped around a central helix. The loops formed between the strands are involved in inhibitor binding, one of these containing a QVVAG sequence, which is highly conserved in most members of the cystatin superfamily .
Peptidase M24, methionine aminopeptidase (Pept_M24_MAP)
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 M24 (clan MG), subfamilies M24A and M24B .

Methionine aminopeptidase (

) (MAP) is responsible for the removal of the amino-terminal (initiator) methionine from nascent eukaryotic cytosolic and cytoplasmic prokaryotic proteins if the penultimate amino acid is small and uncharged. All MAP studied to date are monomeric proteins that require cobalt ions for activity.

Two subfamilies of MAP enzymes are known to exist . While being evolutionary related, they only share a limited amount of sequence similarity mostly clustered around the residues shown to be involved in cobalt-binding. The first family consists of enzymes from prokaryotes as well as eukaryotic MAP-1, while the second group is made up of archaeal MAP and eukaryotic MAP-2. The second subfamily also includes proteins which do not seem to be MAP, but that are clearly evolutionary related such as mouse proliferation-associated protein 1 and fission yeast curved DNA-binding protein.
Calponin homology domain (CH_dom)
Type: Domain

A number of actin-binding proteins, including spectrin, alpha-actinin and fimbrin, contain a 250 amino acid stretch called the actin binding domain (ABD). The ABD has probably arisen from duplication of a domain which is also found in a single copy in a number of other proteins like calponin or the vav proto-oncogene and has been called calponin homology (CH) domain .

A detailed analysis of The CH domain-containing proteins has shown that they can be divided in three groups :

The fimbrin family of monomeric actin cross-linking molecules containing two ABDs

Dimeric cross-linking proteins (alpha-actinin, beta-spectrin, filamin, etc.) and monomeric F-actin binding proteins (dystrophin, utrophin) each containing one ABD

Proteins containing only a single amino terminal CH domain

Each single ABD, comprising two CH domains, is able to bind one actin monomer in the filament. The N-terminal CH domain has the intrinsic ability to bind actin, albeit with lower affinity than the complete ABD, whereas the C-terminal CH bind actin extremely weakly or not at all. Nevertheless both CH domains are required for a fully functional ABD; the C-terminal CH domain contributing to the overall stability of the complete ABD through inter-domain helix-helix interactions . Some of the proteins containing a single CH domain also bind to actin, although this has not been shown to be via the single CH domain alone . In addition, the CH domain occurs also in a number of proteins not known to bind actin, a notable example being the vav protooncogene.

The resolution of the 3D structure of various CH domains has shown that the conserved core consist of four major α-helices .

Proteins containing a calponin domain include:

Calponin, which is involved in the regulation of contractility and organisation of the actin cytoskeleton in smooth muscle cells .

Beta-spectrin, a major component of a submembrane cytoskeletal network connecting actin filaments to integral plasma membrane proteins .

The actin-cross-linking domain of the fimbrin/plastin family of actin filament bundling or cross-linking proteins .

Utrophin,a close homologue of dystrophin .

Dystrophin, the protein found to be defective in Duchenne muscular dystrophy; this protein contains a tandem repeat of two CH domains .

Actin-binding domain of plectin, a large and widely expressed cytolinker protein .

The N-terminal microtubule-binding domain of microtubule-associated protein eb1 (end-binding protein), a member of a conserved family of proteins that localise to the plus-ends of microtubules .

Ras GTPase-activating-like protein rng2, an IQGAP protein that is essential for the assembly of an actomyosin ring during cytokinesis .

Transgelin, which suppresses androgen receptor transactivation .
Anion exchange protein (Anion_exchange)
Type: Family

Bicarbonate (HCO
3
-
) transport mechanisms are the principal regulators of pH in animal cells. Such transport also plays a vital role in acid-base movements in the stomach, pancreas, intestine, kidney, reproductive organs and the central nervous system. Functional studies have suggested four different HCO
3
-
transport modes. Anion exchanger proteins exchange HCO
3
-
for Cl
-
in a reversible, electroneutral manner . Na
+
/HCO
3
-
co-transport proteins mediate the coupled movement of Na
+
and HCO
3
-
across plasma membranes, often in an electrogenic manner . Na
+
driven Cl
-
/HCO
3
-
exchange and K
+
/HCO
3
-
exchange activities have also been detected in certain cell types, although the molecular identities of the proteins responsible remain to be determined.

Sequence analysis of the two families of HCO
3
-
transporters that have been cloned to date (the anion exchangers and Na
+
/HCO
3
-
co-transporters) reveals that they are homologous. This is not entirely unexpected, given that they both transport HCO
3
-
and are inhibited by a class of pharmacological agents called disulphonic stilbenes . They share around ~25-30% sequence identity, which is distributed along their entire sequence length, and have similar predicted membrane topologies, suggesting they have ~10 transmembrane (TM) domains.

Anion exchange proteins participate in pH and cell volume regulation. They are glycosylated, plasma-membrane transport proteins that exchange hydrogen carbonate (HCO
3
-
) for chloride (Cl
-
) in a reversible, electroneutral manner . To date three anion exchanger isoforms have been identified (AE1-3), AE1 being the previously-characterised erythrocyte band 3 protein. They share a predicted topology of 12-14 transmembrane (TM) domains, but have differing distribution patterns and cellular localisation. The best characterised isoform, AE1, is known to be the most abundant membrane protein in mature erythrocytes. It has a molecular mass of ~95kDa and consists of two major domains. The N-terminal 390 residues form a water-soluble, highly elongated domain that serves as an attachment site for the binding of the membrane skeleton and other cytoplasmic proteins. The remainder of the protein is a 55kDa hydrophobic domain that is responsible for catalysing anion exchange. The function of the analogous domains of AE2 and AE3 remains to be determined .

Naturally-occurring mutations have been characterised in the AE1 gene, which give rise to forms of several human diseases: included are spherocytosis, affecting red blood cells, and familial distal renal tubular acidosis, a kidney disease associated with the formation of kidney stones .
CC chemokine receptor 7 (Chemokine_CCR7)
Type: Family

Chemokines (chemotactic cytokines) are a family of chemoattractant molecules. They attract leukocytes to areas of inflammation and lesions, and play a key role in leukocyte activation. Originally defined as host defense proteins, chemokines are now known to play a much broader biological role . They have a wide range of effects in many different cell types beyond the immune system, including, for example, various cells of the central nervous system , and endothelial cells, where they may act as either angiogenic or angiostatic factors .

The chemokine family is divided into four classes based on the number and spacing of their conserved cysteines: 2 Cys residues may be adjacent (the CC family); separated by an intervening residue (the CXC family); have only one of the first two Cys residues (C chemokines); or contain both cysteines, separated by three intervening residues (CX3C chemokines).

Chemokines exert their effects by binding to rhodopsin-like G protein-coupled receptors on the surface of cells. Following interaction with their specific chemokine ligands, chemokine receptors trigger a flux in intracellular calcium ions, which cause a cellular response, including the onset of chemotaxis. There are over fifty distinct chemokines and least 18 human chemokine receptors . Although the receptors bind only a single class of chemokines, they often bind several members of the same class with high affinity. Chemokine receptors are preferentially expressed on important functional subsets of dendritic cells, monocytes and lymphocytes, including Langerhans cells and T helper cells . Chemokines and their receptors can also be subclassified into homeostatic leukocyte homing molecules (CXCR4, CXCR5, CCR7, CCR9) versus inflammatory/inducible molecules (CXCR1, CXCR2, CXCR3, CCR1-6, CX3CR1).

CC chemokine receptors are a subfamily of the chemokine receptors that specifically bind and respond to cytokines of the CC chemokine family. There are currently ten members of the CC chemokine receptor subfamily, named CCR1 to 10. The receptors receptors are found in monocytes, lymphocytes, basophils and eosinophils.

This entry represents CC chemokine receptor 7 (CCR7). It is expressed in various lymphoid tissues and plays an important role in the regulation of the homing and traffic of lymphocytes into and within secondary lymphoid tissues . It has also been shown to induce antiapoptotic signaling in mature dendritic cells . CCR7 is seen as an important organiser of the primary immune response . CCR7 is also expressed by various cancer cells, such as non-small lung cancer, gastric cancer and oesophageal cancer and the expression of CCR7 by cancer cells has been linked with metastasis to lymph nodes . CCR7 binds CCL19 and CCL21 .
AP endonuclease 2 (AP_endonuc_2)
Type: Family

AP endonucleases can be classified into two families based on sequence similarity. This family contains members of AP endonuclease family 2.

Family 2 groups the enzymes listed below .

Bacterial endonuclease IV (

).

Mycobacterium leprae probable endonuclease .

Saccharomyces cerevisiae (Baker's yeast) apurinic endonuclease Apn1 (

).

Caenorhabditis elegans hypothetical protein APN-1 or T05H10.2.

Apn1 and endonuclease IV have been shown to be transition metalloproteins that bind three zinc ions . The metal-binding sites have been determined from the 3D-structure of Escherichia coli endonuclease IV , which shows an α/β-barrel fold similar to that of other divalent metal-dependent TIM barrel enzymes, such as xylose isomerase.
Threonine dehydratase, ACT-like domain (TD_ACT-like)
Type: Domain

Threonine deaminase (threonine dehydratase, TD) is the first enzyme on the pathway for the biosynthesis of isoleucine. TD is organized into two domains. The larger N-terminal domain is considered the catalytic domain as it contains the essential pyridoxal phosphate cofactor. The C-terminal regulatory domain folds as an eight-stranded antiparallel sheet. The holoenzyme is a homotetramer in which the intersubunit contacts lie between pairs of C-terminal regulatory domains and pairs of N-terminal domains .

The ACT domain is a 90 amino acid long domain, which has been named after three of the allosterically regulated enzymes in which it is found: aspartate kinase, chorismate mutase and TyrA (prephenate dehydrogenase) . The ACT domain is found in a variety of contexts and is proposed to be a structurally conserved regulatory domain involved in the binding of small ligands, such as amino acids. There is a close structural and functional relationship between the regulatory domain of TD and the ACT domain .
Glycoside hydrolase, family 7 (Glyco_hydro_7)
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 7

comprises enzymes with several known activities; endoglucanase (

) and cellobiohydrolase (

). These enzymes were formerly known as cellulase family C.

Exoglucanases and cellobiohydrolases play a role in the conversion of cellulose to glucose by cutting the dissaccharide cellobiose from the nonreducing end of the cellulose polymer chain. Structurally, cellulases and xylanases generally consist of a catalytic domain joined to a cellulose-binding domain (CBD) via a linker region that is rich in proline and/or hydroxy-amino acids. In type I exoglucanases, the CBD domain is found at the C-terminal extremity of these enzyme (this short domain forms a hairpin loop structure stabilised by 2 disulphide bridges).