SII-SWORD/CoKE huggingface dataset:
Radiation-inducible immediate-early gene IEX-1 (IEX-1)
Type: Family

Radiation-inducible immediate-early gene IEX-1 is a protein that in humans is encoded by the IER3 gene. The protein is involved in cell proliferation and survival, including the protection of cells from TNF-induced apoptosis . It is rapidly induced by growth factors, viral infections or chemical carcinogens .

IEX-1 has a dual role in extracellular signal-regulated kinase (ERK) signalling. Upon phosphorylation by ERK, IEX-1 acquires the ability to inhibit cell death induced by various stimuli. In turn, by binding to active ERK, IEX-1 potentiates ERK activation in response to various growth factors .
Uroplakin-3 (Uroplakin-3)
Type: Family

This entry represents uroplakin-3 and related proteins.

Uroplakins (UPs) are a family of proteins that associate with each other to form plaques on the apical surface of the urothelium, the pseudo-stratified epithelium lining the urinary tract from renal pelvis to the bladder outlet . UPs are classified into 3 types: UPIa and UPIb, UPII, and UPIIIa and IIIb. UPIs are tetraspanins that have four transmembrane domains separating one large and one small extracellular domain while UPII and UPIIIs are single-pass transmembrane proteins. UPIa and UPIb form specific heterodimers with UPII and UPIII, respectively, which allows them to exit the endoplasmatic rediculum. UPII/UPIa and UPIIIs/UPIb form heterotetramers and six of these tetramers form the 16nm particle, seen in the hexagonal array of the asymmetric unit membrane, which is believed to form a urinary tract barrier . Uroplakins are also believed to play a role during urinary tract morphogenesis .
Regulated endocrine-specific protein 18 (RESP18)
Type: Family

Regulated endocrine-specific protein 18 (RESP18) is a major glucocorticoid-responsive protein that is mainly distributed in the peripheral endocrine and neuroendocrine tissues . The protein shares sequence homology with the luminal region of IA-2, a dense core vesicle (DCV) transmembrane protein involved in insulin secretion .

The function of RESP18 is unknown, but it may may play an important regulatory role in corticotrophs and peptidergic neurons .
Synaptonemal complex protein 2-like (SYCP2-like)
Type: Family

This entry includes synaptonemal complex protein 2 (SYCP2) and synaptonemal complex protein 2-like (SYCP2L).

SYCP2 is one of the major components of the transverse filaments of the synaptonemal complex. Synaptonemal complexes are structures that are formed between homologous chromosomes during meiotic prophase .

SYCP2L has partial sequence homology to a SYCP2 and is the major component of nucleolar cortical skeleton in Xenopus oocytes . In humans, SYCP2L promotes primordial oocytes survival, thus being associated with age at natural menopause (ANM) .
Janus kinase and microtubule-interacting protein (JAKMIP)
Type: Family

Janus kinase and microtubule interacting proteins (JAKMIPs) are predominantly expressed in neural tissues and lymphoid organs. Three family members have been identified, termed JAKMIP1-3. They contain an N-terminal region that targets the protein to microtubule polymers and a C-terminal region that is able to associate with Janus kinase (Jak) family members, such as Tyk2 or Jak1 . The proteins may have a role in Jak signalling and regulation of microtubule cytoskeleton rearrangements.

JAKMIP1 has also been shown to interact with GABA(B) receptor R1 subunits , and may be involved in microtubule-dependent transport of the GABA-B receptor .
Triple repetitive-sequence of QXXK/R protein (TRIQK)
Type: Family

TRIQK is a small protein family that is conserved across vertebrates. It is named after the characteristic triple repeat of the sequence QXXK/R that is shared by all family members . The proteins are localised to the endoplasmic reticulum membrane. They may play a role in cell growth and the maintenance of cell morphology .
Dapper (Dapper)
Type: Family

Dact (dapper) proteins were identified through binding to dishevelled, a cytoplasmic protein central to Wnt signaling. The different dact proteins seem to have distinct signaling and developmental roles. In Zebrafish, dact1 but not dact2 is required to enhance Wnt/beta-catenin activity, while functional interaction with Wnt/Ca2+-PCP signaling has been described for dact2, but not dact1 . Data from other vertebrates seems to be consistent with a distinct signaling and developmental role for dact1, dact2 and dact3 .
Actin remodeling regulator NHS-like (NHS-like)
Type: Family

Nance-Horan syndrome is an X-linked disorder characterised by congenital cataracts, dental anomalies, dysmorphic features, and, in some cases, mental disabilities . The syndrome is caused by defects in the NHS gene , which appears to play a key role in the regulation of eye, tooth, brain, and craniofacial development . It may function in cell morphology by maintaining the integrity of the circumferential actin ring and controlling lamellipodia formation . However, the protein's exact function is unknown.

This entry represents the NHS protein family, which includes Actin remodeling regulator NHS, as well as NHS-like proteins 1, 2 and 3. NHSL3, also known as KIAA1522, has been proposed as a novel prognostic biomarker in patients with non-small cell lung cancer .
Shootin-1 (Shootin-1)
Type: Family

Shootin-1 is involved in the generation of internal asymmetric signals required for neuronal polarisation . The protein has been shown to interact with phosphatidylinositol 3-kinase (PI 3-kinase), which is a key regulator in the initial events of neuronal polarisation .
Kinectin (Kinectin)
Type: Family

Kinectin is a protein that binds kinesin and has a role in organelle motility . Different isoforms exist that may be involved in intracellular motility in different cellular processes. As an integral transmembrane protein on the endoplasmic reticulum it is involved in endoplasmic reticulum extension. A smaller isoform was found to be associated with mitochondria, and its interaction with kinesin shown to influence mitochondrial dynamics .
UNC79 (UNC79)
Type: Family

The NALCN cation channel, which controls neuronal excitability, can be activated by a reduction in extracellular calcium ions. Its activation in neurons requires the proteins UNC79 and UNC80, where UNC79 indirectly associates with NALCN through its interaction with UNC80 .
Cappuccino (Cappuccino)
Type: Family

This entry represents the cappuccino family. In mouse, the cappuccino protein is part of the biogenesis of lysosome-related organelles complex 1 (BLOC-1). The BLOC-1 complex is required for normal biogenesis of lysosome-related organelles, such as platelet dense granules and melanosomes. It plays a role in intracellular vesicle trafficking . Mutations in cappuchino are characterised by a severe oculocutaneous albinism due to abnormal melanosome formation, and prolonged bleeding due to deficiency of platelet dense body contents .
Golgin subfamily A (GOLGA)
Type: Family

Members of the Golgin subfamily A were identified as Golgi auto-antigens . They might be involved in maintaining cis-Golgi structure . One of the members of this family, member 2 or GM130, is a specific interacting partner of the small GTPase Rab1b and plays a key role in the disassembly and reassembly of the Golgi apparatus during mitosis. GM130 is also involved in vesicle tethering and fusion at the cis-cisternae to facilitate transit between transport vesicles and the stacked cisternae. It interacts with GRASPs proteins, which mediate the stacking of Golgi cisternae . Additionally, GM130 was localised to the spindle poles and regulates microtubule organisation . Structurally, GM130 is comprised of six coiled-coil regions in the middle, a Golgi-targeting domain at the C-terminal, and a p115-interacting motif at the N-terminal .
Donson (Donson)
Type: Family

The downstream neighbour of Son (DONSON) protein, also known as protein humpty dumpy (Hd) in Drosophila, is essential for DNA amplification in the ovary, and is required for cell proliferation during development (the humpty dumpty name arises from the thin-eggshell phenotype of hd mutants) . Depletion of the Hd protein has been shown to cause severe defects in genome replication and to result in DNA damage. Hd is largely found in nuclear foci; some may traverse the nuclear envelope. Its expression peaks during late G1 and S phase, and it responds to transcription factor E2F1/Dp . The Hd protein sequence is conserved from plants to humans, and may constitute a new gene family required for cell proliferation in multicellular eukaryotes .
Transient receptor potential cation channel subfamily V (TRPV)
Type: Family

Transient receptor potential (TRP) channels can be described as tetramers formed by subunits with six transmembrane domains and containing cation-selective pores, which in several cases show high calcium permeability. The molecular architecture of TRP channels is reminiscent of voltage-gated channels and comprises six putative transmembrane segments (S1-S6), intracellular N-and C-termini, and a pore-forming reentrant loop between S5 and S6 .

TRP channels represent a superfamily conserved from worms to humans that comprise seven subfamilies : TRPC (canonical), TRPV (vanilloid), TRPM (melastatin or long TRPs), TRPA (ankyrin, whose only member is Transient receptor potential cation channel subfamily A member 1, TrpA1), TRPP (polycystin), TRPML (mucolipin) and TRPN (Nomp-C homologues), which has a single member that can be found in worms, flies, and zebrafish. TRPs are classified essentially according to their primary amino acid sequence rather than selectivity or ligand affinity, due to their heterogeneous properties and complex regulation.

TRP channels are involved in many physiological functions, ranging from pure sensory functions, such as pheromone signalling, taste transduction, nociception, and temperature sensation, over homeostatic functions, such as Ca2+ and Mg2+ reabsorption and osmoregulation, to many other motile functions, such as muscle contraction and vaso-motor control .

The TRPV (vanilloid) subfamily can be divided into two distinct groups. The first, which comprises TrpV1, TrpV2, TrpV3, and TrpV4, with nonselective cation conducting pores, has members which can be activated by temperature as well as chemical stimuli. They are involved in a range of functions including nociception, thermosensing and osmolarity sensing. The second group, which consists of TrpV5 and TrpV6, (also known as epithelial calcium channels 1 and 2), highly calcium selective, are involved in renal Ca2+ absorption/reabsorption .
Nucleoporin Nup54/Nup57/Nup44 (Nup54/Nup57/Nup44)
Type: Family

Nucleoporins are components of the nuclear pore complex, which is required for trafficking across the nuclear membrane . Nucleoporins are named for their molecular weight.

This entry represents Nup54 from metazoa , and related nucleoporins from yeast and plants.
Nuclear factor related to kappa-B-binding protein (NFRKB)
Type: Family

NFRKB is a putative regulatory component of the chromatin remodelling INO80 complex which is involved in transcriptional regulation, DNA replication and probably DNA repair .
Four-jointed box protein 1/four-jointed protein (FJX1/FJ)
Type: Family

The mouse four-jointed box protein 1 (fjx1) gene and Drosophila four-jointed (fj) gene are homologues . Fj encodes a partially secreted transmembrane (TM) type II glyco- protein. In Drosophila, the gene is a downstream target of the Notch signalling pathway in leg-segmentation and planar-cell polarity processes during eye development. Conserved in vertebrates, the murine homologue, fjx1, is also a direct target of Notch signalling . The gene is expressed in mouse brain, in the peripheral nervous system, in epithelial cells of multiple organs, and during limb development .

The protein product is processed and secreted as a presumptive ligand . fjx1 binding sites have been identified at complementary locations, suggesting that fjx1 may function as a novel signalling molecule .
FAM20 (FAM20)
Type: Family

FAM20 is a family of secreted proteins with a potential role in regulating differentiation and function of hematopoietic and other tissues. Proteins in this family include FAM20A , FAM20B or glycosaminoglycan xylosylkinase , and FAM20C or dentin matrix protein 4 .
HEXIM (HEXIM)
Type: Family

Hexamethylene bisacetamide-inducible proteins (HEXIMs) are transcriptional regulators that function as general RNA polymerase II transcription inhibitors. HEXIMs, aided by the 7SK snRNA, sequester positive transcriptional elongation factor b (P-TEFb) into a large inactive 7SK snRNP complex . This prevents P-TEFb from phosphorylating RNA polymerase II and blocks subsequent transcriptional elongation.

Two HEXIM family members have been identified in mammals, termed HEXIM1 and HEXIM2, which exhibit distinct expression patterns .
Transcription factor Maf family (Transcription_factor_Maf_fam)
Type: Family

Maf transcription factors form a distinct subfamily of the basic leucine zipper (bZip) transcription factors . Maf genes have been identified in a wide range of higher eukaryotes, including both vertebrate and invertebrate species. These proteins are unique among the bZip factors in that they contain a highly conserved extended homology region (EHR), or ancillary DNA binding region, in addition to a typical basic region, and both regions are involved in target DNA sequence recognition. Maf transcription factors regulate tissue-specific gene expression and cell-differentiation in a wide variety of tissues and are also involved in human diseases and oncogenic transformation. Tissue-specific expression invloves Maf binding to Maf-recognition elements (MAREs) in the regulatory regions of target genes, and interacting with other transcription factors.
Protein Lines (Protein_Lines)
Type: Family

In Drosophila, Lines is a segment polarity protein and a modulator of the Abd-B HOX protein. Lines is needed for Abd-B to activate its downstream targets cut,
spalt and ems, which are involved in posterior spiracle morphogenesis .
T-cell immunomodulatory protein (Tip)
Type: Family

T-cell immunomodulatory protein (Tip) is a modulator of T-cell function. It has a protective effect in graft versus host disease model and may protect the parasite against attack by the host immune system by immunomodulation .

This entry also includes LINKIN from C. elegans. LINKIN is a transmembrane protein required for maintaining tissue integrity through cell adhesion and apical polarization. It is suggested to be an adhesion molecule that uses its extracellular domain to bind molecules on the surface of neighbouring cells and its intracellular domain to regulate microtubule dynamics .
Nucleoporin p58/p45/NUP49 (NUP58/p45/49)
Type: Family

Nucleoporin proteins p58 and p45 are components of the p62 complex, an assembly of four O-linked glycoproteins localised near the central gated channel of the nuclear pore complex, a complex required for the trafficking across the nuclear membrane . The p45 and p58 isoforms are generated by mRNA alternative splicing . This entry also includes Nup58 protein from Drosophila melanogaster, Nup45 from Schizosaccharomyces pombe and NUP49, the fungal counterpart of Nup58 .
Neurensin (Neurensin)
Type: Family

Neurensin-1 is a vesicular membrane protein expressed exclusively in brain that may play an important role in vesicular organelles transport and nerve signals . Neurensin-2 is also expressed in neural cells, but with a different intracellular localisation: neurensin-1 was found mainly in neuritic processes, while neurensin-2 is found in cell bodies .
N-acyl-phosphatidylethanolamine-hydrolysing phospholipase D (NAPE-PLD)
Type: Family

N-acyl-phosphatidylethanolamine-hydrolysing phospholipase D (NAPE-PLD) hydrolyzes N-acyl-phosphatidylethanolamines (NAPEs) to produce N-acylethanolamines (NAEs) . It is responsible for the generation of the NAE anandamide, the ligand of cannabinoid and vanilloid receptors . Although predominantly bacterial, a mitochondrial form exists . NAPE-PLD belongs to the metallo-beta-lactamase family .
Neuronatin (Neuronatin)
Type: Family

Neuronatin is involved in brain development and may participate in the maintenance of segment identity in the hindbrain and pituitary development, and maturation or maintenance of the overall structure of the nervous system .
Bone marrow stromal antigen 2 (BST2)
Type: Family

Bone marrow stromal antigen 2, also known as tetherin, is an antiretroviral defence protein, that blocks release of enveloped virus from the cell surface . Bst2/tetherin contains two membrane anchors which are employed to retain some enveloped viruses, including HIV-1, tethered to the plasma membrane in the absence of virus encoded antagonists . Its expression is induced by interferon-alpha and was originally linked to B cell development .
Ashwin (Ashwin)
Type: Family

Ashwin is a developmental protein that is expressed in the neural plate, and later in the embryonic brain, eyes, and spinal cord . It may be involved in the regulation cell survival and anteroposterior patterning. Ashwin has been shown to form a complex with HSPC117, which is a catalytic subunit of the tRNA-splicing ligase complex .
(R)-citramalate synthase CimA (Citramalate_synthase_CimA)
Type: Family

Citramalate (also known as 2-methylate) is an intermediate in a large number of biochemical pathways. This entry represents the archaeal citramalate synthase enzyme CimA, which is thought to be involved in isoleucine biosynthesis .
Antiholin-like protein LrgB (Antiholin-like_LrgB)
Type: Family

Staphylococcus aureus lrgAB operon negatively regulates murein hydrolase activity and promotes tolerance to penicillin . LgrB inhibits the expression or activity of extracellular murein hydrolases by interacting, possibly with LrgA, with the holin-like proteins CidA and/or CidB.
Aromatic amino acid aminotransferase (ArAT)
Type: Family

Proteins in this family belong to the class-II pyridoxal-phosphate-dependent aminotransferase family. They catalyse the conversion of aromatic amino acids and 2-oxoglutarate into corresponding aromatic oxo acids and L-glutamate . ArAT from Mycobacterium tuberculosis has a high activity with phenylalanine, and lower activity with tyrosine and tryptophan .
ATP phosphoribosyltransferase HisG, short form (ATP_PRibTrfase_HisG_short)
Type: Family

ATP phosphoribosyltransferase (ATP-PRT,

) is the enzyme that catalyses the first step in the biosynthesis of histidine in bacteria, fungi and plants as shown below. It is a member of the larger phosphoribosyltransferase superfamily of enzymes which catalyse the condensation of 5-phospho-alpha-D-ribose 1-diphosphate with nitrogenous bases in the presence of divalent metal ions .

ATP + 5-phospho-alpha-D-ribose 1-diphosphate = 1-(5-phospho-D-ribosyl)-ATP + diphosphate

Histidine biosynthesis is an energetically expensive process and ATP-PRT activity is subject to control at several levels. Transcriptional regulation is based primarily on nutrient conditions and determines the amount of enzyme present in the cell, while feedback inhibition rapidly modulates activity in response to cellular conditions. The enzyme has been shown to be inhibited by 1-(5-phospho-D-ribosyl)-ATP, histidine, ppGpp (a signal associated with adverse environmental conditions) and ADP and AMP (which reflect the overall energy status of the cell). As this pathway of histidine biosynthesis is present only in prokaryotes, plants and fungi, this enzyme is a promising target for the development of novel antimicrobial compounds and herbicides.

ATP-PRT come in two forms: a long form containing two catalytic domains and a C-terminal regulatory domain, and a short form in which the regulatory domain is missing. The long form is catalytically competent, but in organisms with the short form, a histidyl-tRNA synthetase paralogue, HisZ, is required for enzyme activity .

The enzyme was initially thought to exist in equilibrium between an active dimeric form, an inactive hexameric form and higher aggregates . However, it has been shown later that this protein is a hexamer in equilibrium between an open and probably active state and a more compact closed and presumably inhibited form. These conformational changes are related to the allosteric inhibition by histidine. The ATP-PRT from Campylobacter jejuni is organised into three domains. The first two domains form a bilobal core unit that harbours the catalytic site in the cleft between them, where the binding of ATP and AMP is observed, and the C-terminal is a regulatory ACT domain, which binds histidine .

This entry represents the short form ATP phosphoribosyltransferases.
Bifunctional pantoate ligase/cytidylate kinase (Pantoate_ligase/cytidylate_kin)
Type: Family

This entry represents a bifunctional pantoate ligase/cytidylate kinase resulting from a fusion of the individual enzymes. This fusion has so far only been found in cyanobacteria.

Cytidylate kinase (

) catalyses the phosphorylation of cytidine 5-monophosphate (dCMP) to cytidine 5 -diphosphate (dCDP) in the presence of ATP or GTP. UMP and dCMP can also act as acceptors .

D-Pantothenate is synthesized via four enzymes from ketoisovalerate, which is an intermediate of branched-chain amino acid synthesis . Pantoate-beta-alanine ligase, also know as pantothenate synthase, (PanC;

) catalyzes the formation of pantothenate from pantoate and alanine in the pantothenate biosynthesis pathway .

PanC belongs to a large superfamily of nucleotidyltransferases that includes ATP sulfurylase (ATPS), phosphopantetheine adenylyltransferase (PPAT), and the amino-acyl tRNA synthetases. The enzymes of this family are structurally similar and share a dinucleotide-binding domain .
Propionate kinase PduW (Propionate_kinase_PduW)
Type: Family

PduW is a propionate kinase that is involved in the catabolism of both propionate and 1,2-propanediol during growth on these substrates . This protein restores growth to an eutQ deletion on ethanolamine and tetrathionate under anoxic conditions .
Octanoyltransferase LipL (LipL)
Type: Family

Lipoic acid is an organosulphur compound that is an essential coenzyme in several multienzyme complexes, including pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase and the glycine cleavage system. Many Gram-positive bacteria, such as Bacillus subtilis, require three proteins for lipoic acid cofactor biosynthesis: LipJ, LipL and LipM . LipM is a lipoate:protein ligase that transfers an octanoyl moiety from acyl-carrier protein to the GcvH protein of the glycine cleavage system. LipL, an octanoyltransferase, then transfers this moiety from GcvH to other enzyme complexes. LipA inserts the sulphur group to form the active lipoate cofactor.

This entry represents the LipL component of this system. It includes Lipoyl-[GcvH]:protein N-lipoyltransferase from Listeria monocytogenes serovar 1/2a (

) and Octanoyl-[GcvH]:protein N-octanoyltransferase (

) from Bacillus subtilis .
Octanoyltransferase LipM (LipM)
Type: Family

Lipoic acid is an organosulphur compound that is an essential coenzyme in several multienzyme complexes, including pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase and the glycine cleavage system. Many Gram-positive bacteria, such as Bacillus subtilis, require three proteins for lipoic acid cofactor biosynthesis: LipJ, LipL and LipM . LipM is a lipoate:protein ligase that transfers an octanoyl moiety from acyl-carrier protein to the GcvH protein of the glycine cleavage system. LipL, an octanoyltransferase, then transfers this moiety from GcvH to other enzyme complexes. LipA inserts the sulphur group to form the active lipoate cofactor.

This entry represents the LipM component of this system.
Nitrogen fixation-sustaining protein CowN (CowN)
Type: Family

Nitrogen fixation is catalysed by the nitrogenase complex and can be inhibited by carbon monoxide. The CowN protein protects against this inhibition, allowing nitrogen fixation-dependent growth to occur in the presence of carbon monoxide . Disruption of CowN specifically impaires Mo-nitrogenase-dependent growth at carbon monoxide concentrations still tolerated by the wild type . The mechanism by which CowN confers this protection is not known.