SII-SWORD/CoKE huggingface dataset:
Acetylglutamate kinase ArgB (ArgB)
Type: Family

N -Acetylglutamate (NAG) fulfils distinct biological roles in lower and higher organisms. In prokaryotes, lower eukaryotes and plants it is the first intermediate in the biosynthesis of arginine, whereas in ureotelic (excreting nitrogen mostly in the form of urea) vertebrates, it is an essential allosteric cofactor for carbamyl phosphate synthetase I (CPSI), the first enzyme of the urea cycle. The pathway that leads from glutamate to arginine in lower organisms employs eight steps, starting with the acetylation of glutamate to form NAG. In these species, NAG can be produced by two enzymatic reactions: one catalysed by NAG synthase (NAGS) and the other by ornithine acetyltransferase (OAT). In ureotelic species, NAG is produced exclusively by NAGS. In lower organisms, NAGS is feedback-inhibited by L-arginine, whereas mammalian NAGS activity is significantly enhanced by this amino acid. The NAGS genes of bacteria, fungi and mammals are more diverse than other arginine-biosynthesis and urea-cycle genes. The evolutionary relationship between the distinctly different roles of NAG and its metabolism in lower and higher organisms remains to be determined .

The pathway from glutamate to arginine is:

NAGS; N-acetylglutamate synthase (

) (glutamate to N-acetylglutamate)

NAGK; N-acetylglutamate kinase (

) (N-acetylglutamate to N-acetylglutamate-5P)

N-acetyl-gamma-glutamyl-phosphate reductase (

) (N-acetylglutamate-5P to N-acetylglumate semialdehyde)

Acetylornithine aminotransferase (

) (N-acetylglumate semialdehyde to N-acetylornithine)

Acetylornithine deacetylase (

) (N-acetylornithine to ornithine)

Arginase (

) (ornithine to arginine)

This family represents acetylglutamate kinase ArgB (

).
[LysW]-aminoadipate/[LysW]-glutamate kinase (LysZ)
Type: Family

LysZ has substantial amino acid sequence identity to E. coli N-acetylglutamate kinase ArgB, an enzyme in the biosynthetic pathway from glutamate to arginine. LysZ from Sulfolobus catalyzes both the phosphorylation of LysW-bound precursors AAA (alpha-aminoadipate) and glutamate, indicating that it functions in the biosynthesis of both lysine and arginine . On the other hand, Thermus thermophilus LysZ catalyzes the phosphorylation of LysW-gamma-alpha-aminoadipate exclusively, and does not phosphorylate N-acetyl-glutamate .
Protein P (HBV_DPOL)
Type: Family

This entry represents protein P from hepatitis B virus. Protein P is a multifunctional enzyme that converts the viral RNA genome into dsDNA in viral cytoplasmic capsids .
Peptidoglycan D,D-transpeptidase FtsI (FtsI_transpept)
Type: Family

In addition to the cytoplasmic proteins FtsZ and FtsA, a number of integral membrane proteins are required for cell division. Among these, FtsI, also called penicillin-binding protein 3 (PBP3), is involved in septum formation . FtsI is responsible for the synthesis of septal peptidoglycan and is also required for FtsN localization to the septum .
Matrix protein 1 (INFV_M1)
Type: Family

Matrix protein (M1) of influenza virus is a bifunctional membrane/RNA-binding protein that mediates the encapsidation of RNA-nucleoprotein cores into the membrane envelope. It is therefore required that M1 binds both membrane and RNA simultaneously . M1 is comprised of two domains connected by a linker sequence. The N-terminal domain has a multi-helical structure that can be divided into two subdomains . The C-terminal domain also contains an α-helical structure.
Polymerase acidic protein (INFV_PA)
Type: Family

This entry represents the polymerase acidic (PA) protein from influenza virus. PA plays an essential role in viral RNA transcription and replication by forming the heterotrimeric polymerase complex together with PB1 and PB2 subunits .
[LysW]-L-2-aminoadipate/[LysW]-L-glutamate phosphate reductase (LysY)
Type: Family

Several bacteria and archaea utilize the amino group-carrier protein LysW for lysine biosynthesis, whereas the hyperthermophilic archaeon Sulfolobus utilizes LysW for the biosynthesis of both lysine and arginine .

LysY is the third enzyme involved in LysW-mediated lysine biosynthesis from alpha-aminoadipat(AAA). During lysine biosynthesis, an isopeptide bond is formed between LysW and alpha-aminoadipate (AAA). The resulting LysW-gamma-AAA is phosphorylated by LysZ to form LysW-gamma-AAA phosphate, and is subsequently reduced to LysW-gamma-aminoadipic semialdehyde (LysW-gamma-AASA) by LysY . In Sulfolobus, LysY functions both as a [LysW]-L-2-aminoadipate phosphate reductase and a [LysW]-L-glutamate phosphate reductase .
Packaging protein 3 (ADV_PKG3)
Type: Family

This entry represents packaging protein 3 (also known as L1) from adenovirus. It is involved in viral genome packaging through its interaction with packaging protein 1 and 2 .
[LysW]-aminoadipate semialdehyde/glutamate semialdehyde transaminase (LysJ)
Type: Family

Several bacteria and archaea utilize the amino group-carrier protein LysW for lysine biosynthesis, whereas the hyperthermophilic archaeon Sulfolobus utilizes LysW for the biosynthesis of both lysine and arginine .

LysJ from Sulfolobus acts both as a [LysW]-aminoadipate semialdehyde transaminase and a [LysW]-glutamate semialdehyde transaminase, and is involved in the lysine and arginine biosynthetic pathways respectively . LysJ from Thermus thermophilus is thought to function only as a [LysW]-aminoadipate semialdehyde transaminase .
UTP--glucose-1-phosphate uridylyltransferase, cyanobacteria (CugP_cyano)
Type: Family

UDP-glucose pyrophosphorylases catalyze the formation of UDP-glucose from UTP and glucose 1-phosphate. CugP is a UDP-glucose pyrophosphorylase found in cyanobacteria. It has a central role as the substrate supplier for galactolipid synthesis. Galactolipids are major constituents of the photosynthetic thylakoid membrane and important for photosynthetic activity .
4-hydroxythreonine-4-phosphate dehydrogenase, epsilonproteobacteria (PdxA_epsilonprot)
Type: Family

PdxA is an NAD+-dependent 4-hydroxythreonine 4-phosphate dehydrogenase (

) active in pyridoxal phosphate biosynthesis .

This family consists of putative 4-hydroxy-L-threonine phosphate dehydrogenases from Epsilonproteobacteria. PdxA from Campylobacter jejuni has been shown to play an important role in the PLP (vitamin B6, pyridoxal-5'-phosphate) dependent regulation of flagellar motility, thereby altering host colonization .
DNA-binding protein, Adenovirus (ADV_DNB2)
Type: Family

This entry represents the DNA-binding protein (DBP) from adenovirus. It plays a role in the elongation phase of viral strand displacement replication by unwinding the template in an ATP-independent fashion, employing its capacity to form multimers . DBP is also involved in other essential functions important in the adenovirus life cycle, including viral RNA stability, virus assembly, determination of virus host range and transformation .
Uncharacterized MFS-type transporter YfcJ (MFS_YfcJ)
Type: Family

This is a family of uncharacterised MFS-type transporters. YfcJ is a sugar efflux transporter candidate. Deletion of yfcJ was found to increase intracellular arabinose concentrations .
Adenovirus hexon protein (ADV_hexon)
Type: Family

Hexon (also known as protein II) is a major capsid protein that self-associates to form 240 hexon trimers, each in the shape of a hexagon, building most of the pseudo T=25 capsid .
Prokaryotic ubiquitin-like protein UBact (UBact)
Type: Family

UBact is a ubiquitin-like protein found in Gram-negative bacteria. It differs from ubiquitin and most ubiquitin-like proteins (including the mycobacterial Pup) in that it lacks the characteristic C-terminal di-glycine motif. UBact conjugation-degradation system appears to be homologous to the pupylation system for proteasomal degradation in bacteria .
Cyanide hydratase (CN_hydrolase)
Type: Family

Fungal cyanide hydratases (CHTs) belong to the nitrilase family and catalyze the hydration of cyanide to formamide . They differ from bacterial cyanide dihydratases in their reaction products (formamide vs. formic acid and ammonia, respectively). Some CHTs can also transform nitriles, but less efficiently. These enzymes hold promise for applications in the bioremediation of cyanide wastes .
Tripartite DENN domain, FNIP1/2-type (DENN_FNIP1/2)
Type: Domain

This entry represents the FNIP1/FNIP2-type divergent tripartite DENN domain.

The tripartite DENN (after differentially expressed in neoplastic versus normal cells) domain is found in several proteins that share common structural features and have been shown to be guanine nucleotide exchange factors (GEFs) for Rab GTPases, which are regulators of practically all membrane trafficking events in eukaryotes. The tripartite DENN domain is composed of three distinct modules which are always associated due to functional and/or structural constraints: upstream DENN or uDENN, the better conserved central or core or cDENN, and downstream or dDENN regions. The tripartite DENN domain is found associated with other domains, such as RUN, PLAT, PH, PPR, WD-40, GRAM or C1. The function of DENN domain remains to date unclear, although it appears to represent a good candidate for a GTP/GDP exchange activity .

Some proteins known to contain a tripartite DENN domain are listed below:

Rat Rab3 GDP/GTP exchange protein (Rab3GEP).

Human mitogen-activated protein kinase activating protein containing death domain (MADD). It is orthologous to Rab3GEP.

Caenorhabditis elegans regulator of presynaptic activity aex-3, the ortholog of Rab3GEP.

Mouse Rab6 interacting protein 1 (Rab6IP1).

Human SET domain-binding factor 1(SBF1).

Human suppressor of tumoreginicity 5 (ST5).

Human C-MYC promoter-binding protein IRLB.

The DENN domain forms a heart-shaped structure, with the N-terminal residues forming one and the C-terminal residues forming the second one. The N-terminal half forms the uDENN domain and consists of a central antiparallel β-sheet layered between one helix and two helices. A long random-coil region links the two lobes. The C-terminal lobe is composed of the cDENN and dDENN domains. The cDENN domain is an α/β three layered sandwich domain with a central sheet of 5-strands. The dDENN domain is an all-α helical domain, whose core contains two α-hairpins which diverge rapidly in sequence .

Divergent types of the tripartite DENN domain have also been detected in other protein families :

Folliculin (FLCN), a tumor suppressor protein disrupted in various cancers and the Birt-Hogg-Dube syndrome, and Smith-Magenis syndrome chromosomal region candidate eight protein (SMCR8), which has been implicated in autophagy .

FLCN-interacting proteins (FNIP1 and FNIP2), interact with FLCN and function in conjunction with it to regulate cellular energy metabolism both in the kidney tissue and B-cells.

C9ORF72 protein, expansions of the hexanucleotide GGGGCC in the first intron of its gene have been implicated in amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD).
Transcription factor SAC51-like (SAC51-like)
Type: Family

This is a family of transcription factors from plants. They play a central role in thermospermine responses in Arabidopsis .
Protein SAMBA (SAMBA)
Type: Family

SAMBA is a plant-specific negative regulator of the APC/C complex that plays a key role in organ size control. It regulates cell proliferation during early development by targeting CYCLIN A2 for APC/C-mediated proteolysis .
Bouquet formation protein 4 (Bqt4)
Type: Family

Bqt4 is a Schizosaccharomyces pombe protein that anchors telomeres to the inner nuclear membrane during both vegetative growth and meiosis. This is required for telomere clustering to the spindle pole body to form the bouquet arrangement of chromosomes during the meiotic prophase .
Uncharacterized protein C19orf18 (C19orf18)
Type: Family

This family of uncharacterised proteins is specific to mammals.
Sec23, C-terminal (Sec23_C)
Type: Domain

Vesicular carriers mediate a continuous flux of proteins and lipids between endoplasmic reticulum (ER) and the Golgi. Anterograde and retrograde transport is mediated by distinct sets of cytosolic coat proteins, the COPI and COPII coats, respectively, which act on the membrane to capture cargo proteins into nascent vesicles .

Sec23 is a component of the coat protein complex II (COPII). Polymerization of the coat requires the recruitment of the Sec13/Sec31 complex (coat outer shell) by the Sec23/Sec24 complex. The Sec23/Sec24 coat complex then sorts the fusion machinery (SNAREs) into vesicles as they bud from the ER. Sec23 has been shown to interact in a sequential manner with other proteins (Sar1, TRAPPI and Hrr25) to control the direction of anterograde membrane flow .

This entry represents the C-terminal domain of Sec23. This domain is distantly related to gelsolin-like repeats and the actin depolymerizing domains found in cofilin and similar proteins. The function of the Sec23 C-terminal domain is unclear.
DAZ, RNA recognition motif, vertebrates (DAZ_RRM_vert)
Type: Domain

This entry represents the RRM of DAZ proteins from vertebrates.

DAZ family members include BOULE, DAZ-Like (DAZL) and DAZ. They are found almost exclusively in germ cells and are key players for germ cell development . They contain a highly conserved RNA-binding motif (RNA recognition motif; RRM) and a unique DAZ repeat . Their RRM has been shown to bind 3'-UTR sequences of target mRNAs. They may be involved in regulation of mRNA translation .
Outer dense fibre protein 1, alpha crystallin domain (ODF1_ACD)
Type: Domain

ODF1 is a component of the outer dense fibres (ODF), which are cytoskeletal structures specifically found in the sperm tails of vertebrates. ODF1 has been assigned to the heat shock protein family based on its overall structural features and especially on its conserved alpha-crystallin domain, and it is also known as HSPB10 . ODF1 is essential for tight linkage of sperm head to tail and is essential for male fertility .

This entry represents the alpha crystallin domain (ACD) of ODF1.
Von Willebrand factor (Von_Willebrand_factor)
Type: Family

Von Willebrand factor (VWF) is a multimeric adhesive protein involved in the initiation and progression of thrombus formation at sites of vascular injury . VWF allows platelets to adhere to sites of vascular injury, forming a bridge between the sub-endothelial collagen matrix and the platelet-surface receptor complex GPIb-IX-V . VWF is also a chaperone for coagulation factor VIII, delivering it to the injury site and protecting it from clearance from the plasma . The protein is multidomain with four VWFD domains, four TIL domains, three VWFA domains, three VWFC domains and a C-terminal CTCK domain . VWF is cleaved to release von Willebrand antigen 2 by a furin-like endopeptidase . Von Willebrand diseases 1, 2 and 3 are deficiencies of VWF, resulting in impaired platelet aggregation and prolonged bleeding after trauma . Von Willebrand disease 3 results in haemophilia.
Fibrinogen/angiopoietin-like (FIB_ANG-like)
Type: Family

This entry includes the alpha, beta and gamma chains of fibrinogen (FGA/B/G), Angiopoietin-1/2 (ANGPT1/2) and similar animal proteins.

This entry also includes Fibrinogen-like Protein 1 that is a major immune inhibitory ligand of Lymphocyte-activation gene 3 (LAG-3). Blockade of the FGL1-LAG-3 interaction by monoclonal antibodies was shown to stimulate tumor immunity and is therapeutic against established mouse tumors .

Fibrinogens are cleaved by thrombin to yield fibrins, which polymerize to form the insoluble fibrin clot which blocks sites of vascular injury, preventing further blood loss. The clot is subsequently degraded by plasmin (fibrinolysis). There are three fibrinogens, alpha, beta and gamma . Thrombin activates fibrinogen to release a fibrinopeptide . The newly exposed N terminus forms an Glu-Lys isopeptide bond, which is stabilized by factor XIIIA . Fibrinogen is also required for successful pregnancy, and in knockout mice fatal uterine bleeding occurs around the tenth day of gestation .

Several diseases are a result of mutations in the FGA gene, including congenital afibrinogenemia, resulting in a hemophilia which can be mild to severe ; amyloidosis 8, which causes extensive visceral amyloid deposits, renal amyloidosis and hypertension and congenital dysfibrinogenemia .

ANGPT1 binds and activates the tyrosine kinase receptor TEK/TIE2 by inducing its dimerisation and tyrosine phosphorylation. It plays an important role in the regulation of angiogenesis, endothelial cell survival, proliferation, migration, adhesion and cell spreading, reorganization of the actin cytoskeleton, but also maintenance of vascular quiescence . ANGPT2 binds to TEK/TIE2, competing for the ANGPT1 binding site, and modulating ANGPT1 signalling .
Ragulator complex protein LAMTOR2-like (LAMTOR2-like)
Type: Family

This entry represents the Ragulator complex protein LAMTOR2. The Ragulator complex consists of LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5 . The Ragulator complex is involved in amino acid sensing and activation of the mTORC1 signalling pathway. The complex is activated by amino acids through a mechanism involving the lysosomal V-ATPase, and functions as a guanine nucleotide exchange factor activating the small GTPases Rag , . This entry also includes uncharacterised proteins from bacteria and archaea.
Target of rapamycin complex subunit LST8 (MLST8)
Type: Family

This entry represents target of rapamycin complex subunit LST8 (MLST8 or GbetaL), a component of both mTORC1 and mTORC2, complexes that regulate cell growth in response to nutrients. The mTORC1 complex consists of MTOR, MLST8, RPTOR, AKT1S1/PRAS40 and DEPTOR. The mTORC2 complex contains MTOR, MLST8, PRR5, RICTOR, MAPKAP1 and DEPTOR . In mTORC1, MLST8 interacts directly with MTOR and enhances its kinase activity .

This entry also includes the target of rapamycin complex subunit wat1 (pop3 or wat1) from Schizosaccharomyces pombe, which is also a component of yeast TORC1 and TORC2 complexes. The subunits of TORC1 in fission yeasts are known as mip1, pop3/wat1, tco89, toc1 and tor2; and the subunits of the TORC2 complex are bit61, pop3/wat1, sin1, ste20 and tor1 .
GATOR2 complex protein WDR24 (WDR24)
Type: Family

This entry represents GATOR complex protein WDR24, a component of the GATOR subcomplex GATOR2. GATOR2 is part of the amino acid-sensing branch of the TORC1 signalling pathway, activating mTORC1 by inhibition of the GATOR1 subcomplex. The GATOR2 complex consists of MIOS, SEC13, SEH1L, WDR24 and WDR59 . WDR24 has a secondary role in the GATOR-independent promotion of lysosome acidity and regulation of autophagic flux .

This entry also includes the restriction of telomere capping protein 1 (Rtc1 or Sea2) from the budding yeast Saccharomyces cerevisiae. It is a component of the SEA complex, termed as GATOR in mammals, which coats the vacuolar membrane and is involved in intracellular trafficking, autophagy, response to nitrogen starvation, and amino acid biogenesis .
MIOS/Sea4 (MIOS/Sea4)
Type: Family

This entry includes the GATOR complex protein MIOS, a component of the GATOR subcomplex GATOR2. The GATOR2 complex consists of MIOS, SEC13, SEH1L, WDR24 and WDR59, and it activates mTORC1 and the TORC1 signalling pathway through the inhibition of the GATOR1 subcomplex .

This entry also includes Sea4 from budding yeasts. Sea4 is a subunit of SEACAT, a subcomplex of the SEA complex. It inhibits the TORC1 inhibitory role of the Iml1p/SEACIT (Iml1-Npr2-Npr3) subcomplex .
Reversibly glycosylated polypeptide family (RGP_fam)
Type: Family

This family includes UDP-arabinopyranose mutases and putative alpha-1,4-glucan-protein synthase [UDP-forming]. The former catalyses the interconversion of UDP-L-arabinopyranose (UDP-Arap) and UDP-L-arabinofuranose (UDP-Araf), while the latter catalyses the reaction between UDP-glucose and a protein to produce UDP and alpha-D-glucosyl-protein. UDP-arabinopyranose mutases are essential for cell wall establishment and plant development . This entry also includes uncharacterised prokaryotic proteins.
TFCP2L1, SAM domain (TFCP2L1_SAM)
Type: Domain

TFCP2L1 (also known as LBP9) is involved in transcriptional regulation from early development to terminal differentiation. In mice, it is required for proper maturation of the duct of the salivary gland and the kidney . In humans, it is involved in the regulation of P450scc (the cholesterol side-chain cleavage enzyme, cytochrome) in placental JEG-3 cells . TFCP2L1 is also involved in establishment and maintenance of pluripotency in embryonic stem cells through formation of complex transcriptional networks with the other transcription factors, OCT4, SOX2, and NANOG .
Transcription factor CP2, SAM domain (TFCP2_SAM)
Type: Domain

TFCP2 (CP2 transcription factor) is a critical regulator of erythroid gene expression . It also regulates the expressison of the male-dominant sex-determining gene SRY . TFCP2 can interact with NF-E4 proteins forming heteromeric stage selector protein complex (SSP); this complex is able to bind stage selector element (SSE) and regulate embryonic globin expression in fetal-erythroid cells .

TFCP2 has an N-terminal DNA-binding CP2 domain, a central predicted SAM domain and a C-terminal dimerization domain. This entry represents the SAM domain.
Upstream-binding protein 1, SAM domain (Ubp1_SAM)
Type: Domain

Ubp1 (also known as LBP-1) is involved in transcriptional regulation from early development to terminal differentiation. It regulates alpha-globin in erythroid cells and P450scc (the cholesterol side-chain cleavage enzyme, cytochrome) in human placenta . Human Ubp1 is known to be induced by HIV type I infection in lymphocytes; it represses HIV transcription by preventing the binding of TFIID to the virus promoter . Ubp1 might also be part of a network controlling blood pressure .
ANKS4B, SAM domain (ANKS4B_SAM)
Type: Domain

ANKS4B (also known as Harp) is part of the intermicrovillar adhesion complex (IMAC) and plays a role in epithelial brush border differentiation, controlling microvilli organization and length. It interacts with USH1C and MYO7B, which link protocadherins to the actin cytoskeleton . In mouse epithelial tissues, HARP interacts with the PDZ domain of harmonin. This scaffolding complex facilitates signal transduction in epithelia .
USH1G, SAM domain (USH1G_SAM)
Type: Domain

pre-mRNA splicing regulator USH1G (also known as SANS) is a multifunctional scaffold protein. It regulates Magi2-mediated endocytosis and interacts with MYO7A and USH1C . Mice lacking USH1G exhibit a loss of tip-links, defects in stereocilia morphology and organization, loss of mechanotransduction currents, and perturbations to hearing and balance . Mutations in human USH1G gene cause Usher syndrome 1G (USH1G), a genetically heterogeneous condition characterised by the association of retinitis pigmentosa with sensorineural deafness .
SEC23-interacting protein, SAM domain (SEC23IP_SAM)
Type: Domain

SEC23IP contains an N-terminal proline-rich region, a central region containing a SAM domain and a C-terminal region with a predicted metal-binding domain. It interacts with Sec23p/Sec24p, which is a component of the COPII-coated vesicles complex involved in protein export from the endoplasmic reticulum. The proline-rich region plays an essential role in this interaction . This entry represents the SAM domain, which is a potential protein-protein interaction domain.
Scm-like with four MBT domains protein 1/2, SAM domain (Scm-like-4MBT1/2_SAM)
Type: Domain

Scm-like-4MBT1 and Scm-like-4MBT2 are structurally related to the transcriptional repressor Polycomb group (PcG) proteins. They contain a SAM domain, a SLED domain , and four MBT repeats . The MBT repeats of the human SFMBT1 protein are responsible for association with the nuclear matrix and for selective binding of H3 histone N-terminal tails . SFMBT1 also forms a stable complex with LSD1 and CoREST that causes chromatin compaction and transcriptional repression of target genes, including those encoding replication-dependent histones .

This entry represents the SAM domain of Scm-like-4MBT1/2.