SII-SWORD/CoKE huggingface dataset:
Small GTPase Tem1/Spg1 (Small_GTPase_Tem1/Spg1)
Type: Family

Small GTPases form an independent superfamily within the larger class of regulatory GTP hydrolases. This superfamily contains proteins that control a vast number of important processes and possess a common, structurally preserved GTP-binding domain . Sequence comparisons of small G proteins from various species have revealed that they are conserved in primary structures at the level of 30-55% similarity .

Crystallographic analysis of various small G proteins revealed the presence of a 20kDa catalytic domain that is unique for the whole superfamily . The domain is built of five α helices (A1-A5), six β-strands (B1-B6) and five polypeptide loops (G1-G5). A structural comparison of the GTP- and GDP-bound forms allows one to distinguish two functional loop regions: switch I and switch II that surround the gamma-phosphate group of the nucleotide. The G1 loop (also called the P-loop) that connects the B1 strand and the A1 helix is responsible for the binding of the phosphate groups. The G3 loop provides residues for Mg2 and phosphate binding and is located at the N terminus of the A2 helix. The G1 and G3 loops are sequentially similar to Walker A and Walker B boxes that are found in other nucleotide binding motifs. The G2 loop connects the A1 helix and the B2 strand and contains a conserved Thr residue responsible for Mg2 binding. The guanine base is recognised by the G4 and G5 loops. The consensus sequence NKXD of the G4 loop contains Lys and Asp residues directly interacting with the nucleotide. Part of the G5 loop located between B6 and A5 acts as a recognition site for the guanine base .

The small GTPase superfamily can be divided into at least 8 different families, including:

Arf small GTPases. GTP-binding proteins involved in protein trafficking by modulating vesicle budding and uncoating within the Golgi apparatus.

Ran small GTPases. GTP-binding proteins involved in nucleocytoplasmic transport. Required for the import of proteins into the nucleus and also for RNA export.

Rab small GTPases. GTP-binding proteins involved in vesicular traffic.

Rho small GTPases. GTP-binding proteins that control cytoskeleton reorganisation.

Ras small GTPases. GTP-binding proteins involved in signalling pathways.

Sar1 small GTPases. Small GTPase component of the coat protein complex II (COPII) which promotes the formation of transport vesicles from the endoplasmic reticulum (ER).

Mitochondrial Rho (Miro). Small GTPase domain found in mitochondrial proteins involved in mitochondrial trafficking.

Roc small GTPases domain. Small GTPase domain always found associated with the COR domain.

This entry includes Tem1 from budding yeasts and Spg1 from fission yeasts. They are GTPases involved in the regulation of the cell cycle.

In Schizosaccharomyces pombe, Spg1 is required for the localisation of Cdc7 (part of the septation initiation network) to the spindle pole body (SPB) . It is regulated negatively by a GTPase-activating protein (GAP) comprising two subunits - Byr4 and Cdc16. In anaphase B, Spg1 is localised on the new SPB .
Nitrogen regulation protein NtrY (NtrY)
Type: Family

Two-component signal transduction systems enable bacteria to sense, respond, and adapt to a wide range of environments, stressors, and growth conditions . Some bacteria can contain up to as many as 200 two-component systems that need tight regulation to prevent unwanted cross-talk . These pathways have been adapted to response to a wide variety of stimuli, including nutrients, cellular redox state, changes in osmolarity, quorum signals, antibiotics, and more . Two-component systems are comprised of a sensor histidine kinase (HK) and its cognate response regulator (RR) . The HK catalyses its own auto-phosphorylation followed by the transfer of the phosphoryl group to the receiver domain on RR; phosphorylation of the RR usually activates an attached output domain, which can then effect changes in cellular physiology, often by regulating gene expression. Some HK are bifunctional, catalysing both the phosphorylation and dephosphorylation of their cognate RR. The input stimuli can regulate either the kinase or phosphatase activity of the bifunctional HK.

A variant of the two-component system is the phospho-relay system. Here a hybrid HK auto-phosphorylates and then transfers the phosphoryl group to an internal receiver domain, rather than to a separate RR protein. The phosphoryl group is then shuttled to histidine phosphotransferase (HPT) and subsequently to a terminal RR, which can evoke the desired response .

Signal transducing histidine kinases are the key elements in two-component signal transduction systems, which control complex processes such as the initiation of development in microorganisms . Examples of histidine kinases are EnvZ, which plays a central role in osmoregulation , and CheA, which plays a central role in the chemotaxis system . Histidine kinases usually have an N-terminal ligand-binding domain and a C-terminal kinase domain, but other domains may also be present. The kinase domain is responsible for the autophosphorylation of the histidine with ATP, the phosphotransfer from the kinase to an aspartate of the response regulator, and (with bifunctional enzymes) the phosphotransfer from aspartyl phosphate back to ADP or to water . The kinase core has a unique fold, distinct from that of the Ser/Thr/Tyr kinase superfamily.

This entry represents signal transduction histidine kinases involved in nitrogen fixation and metabolism regulation, such as NtrY .
WD repeat protein 35 (WDR35)
Type: Family

WD repeat protein 35 (WDR35) is a component of the IFT complex A (IFT-A), a complex required for retrograde ciliary transport . Mutations in the WDR35 gene cause diseases such as cranioectodermal dysplasia 2 and short-rib thoracic dysplasia 7 with or without polydactyly .
RNA-directed RNA polymerase, rhabdovirus (RNA-dir_pol_rhabdovirus)
Type: Family

RNA-directed RNA polymerase (RdRp) (

) is an essential protein encoded in the genomes of all RNA containing viruses with no DNA stage . It catalyses synthesis of the RNA strand complementary to a given RNA template, but the precise molecular mechanism remains unclear.
The postulated RNA replication process is a two-step mechanism. First, the initiation step of RNA synthesis begins at or near the 3' end of the RNA template by means of a primer-independent (de novo) mechanism. The de novo initiation consists in the addition of a nucleotide tri-phosphate (NTP) to the 3'-OH of the first initiating NTP. During the following so-called elongation phase, this nucleotidyl transfer reaction is repeated with subsequent NTPs to generate the complementary RNA product .

This entry represents RNA-directed RNA polymerase (also known as the large structural protein) from various Rhabdoviruses, such as Vesicular stomatitis Indiana virus . The large structural protein (or L protein) carries four enzymatic activities: RNA-directed RNA polymerase (

), mRNA (guanine-N(7)-)-methyltransferase (

), mRNA guanylyltransferase (

), and poly(A) synthetase. The viral mRNA guanylyl transferase displays a different biochemical reaction than the cellular enzyme. The template is composed of the viral RNA tightly encapsidated by the nucleoprotein (N). The protein can function either as transcriptase or as replicase. The transcriptase synthesises subsequently five subgenomic RNAs, assuring their capping and polyadenylation by a stuttering mechanism. The replicase mode is dependent on intracellular N protein concentration. In this mode, the polymerase replicates the whole viral genome without recognizing the transcriptional signals.
RNA-directed RNA polymerase L, filovirus (RNA-dir_pol_L_filovirus)
Type: Family

RNA-directed RNA polymerase (RdRp) (

) is an essential protein encoded in the genomes of all RNA containing viruses with no DNA stage . It catalyses synthesis of the RNA strand complementary to a given RNA template, but the precise molecular mechanism remains unclear.
The postulated RNA replication process is a two-step mechanism. First, the initiation step of RNA synthesis begins at or near the 3' end of the RNA template by means of a primer-independent (de novo) mechanism. The de novo initiation consists in the addition of a nucleotide tri-phosphate (NTP) to the 3'-OH of the first initiating NTP. During the following so-called elongation phase, this nucleotidyl transfer reaction is repeated with subsequent NTPs to generate the complementary RNA product .

This entry represents RNA-directed RNA polymerase (also known as the large structural protein) from various Filoviruses . The large structural protein (or L protein) carries three enzymatic activities: RNA-directed RNA polymerase (

), mRNA (guanine-N(7)-)-methyltransferase (

), and mRNA guanylyltransferase (

). The viral mRNA guanylyl transferase displays a different biochemical reaction than the cellular enzyme. The template is composed of the viral RNA tightly encapsidated by the nucleoprotein (N). The protein can function either as transcriptase or as replicase. The transcriptase synthesises subsequently subgenomic RNAs, assuring their capping and polyadenylation by a stuttering mechanism. The replicase mode is dependent on intracellular N protein concentration. In this mode, the polymerase replicates the whole viral genome without recognizing the transcriptional signals.
Glycine/sarcosine/betaine reductase, component C, beta (Gly/sarc/bet/_Rdtase_C_bsu)
Type: Family

This group represents a glycine/sarcosine/betaine reductase complexes, C component, beta subunit.
rRNA (guanine-N2-)-methyltransferase, RlmG (rRNA_m2G-MeTrfase_RlmG)
Type: Family

This entry represents rRNA (guanine-N(2)-)-methyltransferase G (RlmG;

). This enzyme specifically methylates the guanine in position 1835 (m2G1835) of 23S rRNA . This modification specifically enhances association of ribosomal subunits and provides a significant advantage for bacteria in osmotic and oxidative stress .
Squamosa promoter-binding protein (SBP_fam)
Type: Family

This entry represents a group of DNA binding proteins, known as SBP (SQUAMOSA-pROMOTER BINDING PROTEIN) family. They are putative transcription factors characterised by a highly conserved SBP-box of 76 amino acids involved in DNA binding and nuclear localisation . They are involved in the control of early flower development . This entry includes Arabidopsis SPL3 and SPL4 . SPL3/SPL4 promote vegetative phase change and flowering, and are strongly repressed by miR156 .
Mitogen-activated protein (MAP) kinase kinase kinase Ste11, Cryptococcus (Ste11_Cryptococcus)
Type: Family

This group represents a MAP kinase kinase kinase (MAPKKK) STE11 from the jelly fungus Cryptococcus. It is similar to other fungal MAPKKK genes but is mating type specific .
Mitogen-activated protein (MAP) kinase kinase kinase Ssk2/Ssk22 (MAPKKK_Ssk2/Ssk22)
Type: Family

This entry includes a group of MAP kinase kinase kinase from fungi, including Ssk2/Ssk22 from budding yeasts and Win1/Wis4 from fission yeasts. They are kinases involved in a signal transduction pathway that is activated by environmental stress .
Toll-like receptor (Toll-like_receptor)
Type: Family

This entry represents toll-like receptors (TLRs), which are key regulators of immune responses. They recognise pathogen-associated molecular patterns (PAMPs) such as bacterial lipopeptides (TLR1/2/6), bacterial flagellin (TLR5), and lipopolysaccharide (TLR4) . In higher vertebrates, TLRs are essential not only for sensing microbes by the innate immune system, but also for inducing adaptive immune system responses mediated by B and T cells .

TLRs are expressed at the cell membrane and in subcellular compartments such as the endosome. TLRs are type-I transmembrane proteins with extracellular leucine-rich repeat (LRR) motifs and an intracellular Toll/interleukin-1 receptor (TIR) domain. Members of the TLR family contribute both to cell-cell interactions and to signalling, linking extracellular signals to specific gene-expression programmes . Binding of ligands to the extracellular domains causes rearrangement of the receptor complexes and triggers the recruitment of specific adaptor proteins to the intracellular TIR domain, leading to nuclear factor-kappa B (NF-kappaB) activation and initiation of both innate and adaptive immune responses. Signalling by TLRs involves five adaptor proteins known as MyD88, MAL, TRIF, TRAM and SARM .
BLOC-1 complex, pallidin subunit (BLOC-1_pallidin)
Type: Family

Lysosomes are membrane-bound organelles found in animals that are involved in degradation of endogenous and exogenous macromolecules . Lysosome-related organelles occur in specific cell types and fulfil specialised functions e.g. melanosomes which synthesise and store pigments in higher eukaryotes. Lysosome biogenesis is linked to the to the secretory and endocytic pathways for protein and lipid trafficking.

One of the protein complexes involved in this process is biogenesis of lysosome-related organelles complex 1 (BLOC-1). This complex consists of seven distinct subunits: dysbindin, pallidin, muted, snapin, cappuccino, and BLOS1-3 subunits . Apart from BLOCS3 all of these subunits are predicted to form coiled-coil structures. BLOC-1 can be found in the cytosol and also associated with membranes. Protein interaction studies suggest that this complex interacts with a number of proteins including syntaxin, filametous actin, dystrobrevin and mysopryn, though the molecluar function of this complex is not yet known. Mutations in BLOC-1 subunits are associated with Hermansky-Pudlak syndrome -a disorder characterised by deficiencies in melanosomes, platelet-dense granules and other lysosome-related organelles. Cells that lack lysosome-related organelles express BLOC-1 but do not appear to need it for lysosome biosynthesis. In concert with the AP-3 complex, the BLOC-1 complex is required to target membrane protein cargos into vesicles assembled at cell bodies for delivery into neurites and nerve terminals .

This group represents the pallidin subunit (or subunit 6) of BLOC-1 . BLOC-1 is composed in higher eukaryotes of blos1, blos2, blos3, blos4, dysb, muted, pallidin and snapin.
Biogenesis of lysosome-related organelles complex 1 subunit 5 (Bloc1s5)
Type: Family

Lysosomes are membrane-bound organelles found in animals that are involved in degradation of endogenous and exogenous macromolecules . Lysosome-related organelles occur in specific cell types and fulfil specialised functions e.g. melanosomes which synthesise and store pigments in higher eukaryotes. Lysosome biogenesis is linked to the to the secretory and endocytic pathways for protein and lipid trafficking.

One of the protein complexes involved in this process is biogenesis of lysosome-related organelles complex 1 (BLOC-1). This complex consists of seven distinct subunits: dysbindin, pallidin, muted, snapin, cappuccino, and BLOS1-3 subunits . Apart from BLOCS3 all of these subunits are predicted to form coiled-coil structures. BLOC-1 can be found in the cytosol and also associated with membranes. Protein interaction studies suggest that this complex interacts with a number of proteins including syntaxin, filametous actin, dystrobrevin and mysopryn, though the molecluar function of this complex is not yet known. Mutations in BLOC-1 subunits are associated with Hermansky-Pudlak syndrome -a disorder characterised by deficiencies in melanosomes, platelet-dense granules and other lysosome-related organelles. Cells that lack lysosome-related organelles express BLOC-1 but do not appear to need it for lysosome biosynthesis. In concert with the AP-3 complex, the BLOC-1 complex is required to target membrane protein cargos into vesicles assembled at cell bodies for delivery into neurites and nerve terminals .

This group represents the subunit 5 (also known as the muted subunit) of BLOC-1 . In mice, defects in this protein are the cause of the Muted (mu) mutant, which is characterised by light eyes at birth, hypopigmentation of the coat, platelet storage pool deficiency and lysosomal hyposecretion .
Ribosomal RNA large subunit methyltransferase K/L (23SrRNA_methyltr_KL)
Type: Family

This entry represents bacterial Ribosomal RNA large subunit methyltransferase K/L, which specifically methylates the guanine in position 2445 (m2G2445) and the guanine in position 2069 (m7G2069) of 23S rRNA. The methylation occurs before assembly of 23S rRNA into 50S subunits.
BLOC-1 complex, subunit 3 (BLOC-1_complex_su-3)
Type: Family

Lysosomes are membrane-bound organelles found in animals that are involved in degradation of endogenous and exogenous macromolecules . Lysosome-related organelles occur in specific cell types and fulfil specialised functions e.g. melanosomes which synthesise and store pigments in higher eukaryotes. Lysosome biogenesis is linked to the to the secretory and endocytic pathways for protein and lipid trafficking.

One of the protein complexes involved in this process is biogenesis of lysosome-related organelles complex 1 (BLOC-1). This complex consists of seven distinct subunits: dysbindin, pallidin, muted, snapin, cappuccino, and BLOS1-3 subunits . Apart from BLOCS3 all of these subunits are predicted to form coiled-coil structures. BLOC-1 can be found in the cytosol and also associated with membranes. Protein interaction studies suggest that this complex interacts with a number of proteins including syntaxin, filametous actin, dystrobrevin and mysopryn, though the molecluar function of this complex is not yet known. Mutations in BLOC-1 subunits are associated with Hermansky-Pudlak syndrome -a disorder characterised by deficiencies in melanosomes, platelet-dense granules and other lysosome-related organelles. Cells that lack lysosome-related organelles express BLOC-1 but do not appear to need it for lysosome biosynthesis. In concert with the AP-3 complex, the BLOC-1 complex is required to target membrane protein cargos into vesicles assembled at cell bodies for delivery into neurites and nerve terminals .

This group represents subunit 3 of the BLOC-1 complex, also known as BLOS3 .
Snapin (Snapin)
Type: Family

Snapin is a component of the biogenesis of lysosomal organelles complex-1 (BLOC-1), a complex required for the normal biogenesis of lysosome-related organelles, such as melanosomes and platelet dense granules , and endosomal cargo sorting .

Snapin binds to SNAP-25, part of the SNARE complex that mediates the synaptic vesicle docking and fusion . Snapin may modulate a step between vesicle priming, fusion and calcium-dependent neurotransmitter release through its ability to potentiate the interaction of synaptotagmin with the SNAREs and the plasma-membrane-associated protein SNAP25 . Its phosphorylation state influences exocytotic protein interactions and may regulate synaptic vesicle exocytosis . It may also have a role in the mechanisms of SNARE-mediated membrane fusion in non-neuronal cells .
UBX domain-containing protein 8 (UBXN8)
Type: Family

UBX domain-containing protein 8 is involved in endoplasmic reticulum-associated degradation (ERAD) for misfolded lumenal proteins, possibly by tethering VCP to the endoplasmic reticulum membrane .
HS1-associating protein X-1 (HAX-1)
Type: Family

HS1-associating protein X-1 (HAX-1) promotes cell survival and is involved in the clathrin-mediated endocytosis pathway . It has been implicated in severe congenital neutropenia (SCN), neurological disorders and cancer . The voltage-dependent Kv3.3 potassium channel has been shown to bind to HAX-1 to induce Arp2/3 (actin-related protein 2/3 complex) dependent actin filament nucleation at the plasma membrane .
Activator of apoptosis harakiri (Apoptosis_activator_harakiri)
Type: Family

Apoptosis, or programmed cell death (PCD), is a common and evolutionarily conserved property of all metazoans . In many biological processes, apoptosis is required to eliminate supernumerary or dangerous (such as pre-cancerous) cells and to promote normal development. Dysregulation of apoptosis can, therefore, contribute to the development of many major diseases including cancer, autoimmunity and neurodegenerative disorders. In most cases, proteins of the caspase family execute the genetic programme that leads to cell death.

The protein harakiri (Hrk, also called death protein 5, DP5) is a pro-apoptotic Bcl-2 homology domain 3-only (BH3-only) member protein, which belongs to the Bcl-2 family. Hrk is associated to the mitochondrial outer membrane via a putative trans-membrane domain at the C-terminal, which adopts a predominantly α-helical structure. This domain is able to insert itself into membranes where it perturbs the physical properties of the membrane considerably .

It can be activated by a diverse array of developmental cues or experimentally applied stress stimuli. Hrk contributes to apoptosis signalling elicited by trophic factor withdrawal in certain neuronal cells but is not critical for apoptosis of haematopoietic cells . DP5 is important in neuronal cell death that can be induced by axotomy and neuronal growth factor (NGF) deprivation. It acts by regulating the mitochondrial function and caspase-3 activation .
Histone deacetylase complex subunit SAP18 (Hist_deAcase_cplx_SAP18)
Type: Family

Histone acetylation plays a key role in the regulation of gene expression. The chromatin structure and accessibility of genes to transcription factors is regulated by enzymes that acetylate and deacetylate histones. The Sin3A-histone deacetylase (HDAC) co-repressor complex consists of multiple proteins and regulates gene expression by deacetylating histones.

This group represents the Histone deacetylase complex subunit SAP18 (Sin3A associated protein 18) . SAP18 adopts an ubiquitin-like fold with several large loop insertions .
Apoptotic protease-activating factor 1 (Apaf-1)
Type: Family

Apoptotic protease activating factor-1 (Apaf-1) is a component protein of the apoptosome . During apoptosis, cytochrome c is released from mitochondria to the cytosol and binds Apaf-1. Binding of cytochrome c to Apaf-1 allows the recruitment and activation of caspase-9 within the apoptosome .
Dynein regulator LIS1 (Dynein_regulator_LIS1)
Type: Family

This entry represents Lissencephaly-1 (LIS1) and homologues. LIS1 is required for nuclear migration in fungi, cell cycle progression in mammals, and the formation of a folded cerebral cortex in humans. They appear to regulate the mechanical behaviour of cytoplasmic dynein, the primary minus-end-directed microtubule motor . Proteins in this entry include:

Platelet-activating factor acetylhydrolase IB subunit alpha, also known as Lissencephaly-1 protein .

Nuclear distribution protein PAC1 from budding yeasts .

Fungal nuclear distribution protein nudF .

Mutations in the LIS1 gene cause Lissencephaly-1, a classical lissencephaly characterised by agyria or pachygyria and disorganization of the clear neuronal lamination of normal six-layered cortex .