SII-SWORD/CoKE huggingface dataset:
Synaptotagmin-14/14L/16 (SYT14/14L/16)
Type: Family

This entry includes Synaptotagmin-14/14L/16 proteins. They belong to the synaptotagmin family, which is a group of membrane-trafficking proteins that contain two C-terminal C2 domains (known as C2A and C2B domains). The C2 domain is a Ca2-dependent membrane-targeting module. Most of the synaptotagmins have a unique N-terminal domain (transmembrane region) that is involved in membrane anchoring or specific ligand binding .

The 3D structure of the C2 domain of synaptotagmin has been reported . The domain forms an eight-stranded β sandwich constructed around a conserved 4-stranded motif, designated a C2 key . Calcium binds in a cup-shaped depression formed by the N- and C-terminal loops of the C2-key motif. Structural analyses of several C2 domains have shown them to consist of similar ternary structures in which three Ca2-binding loops are located at the end of an 8 stranded antiparallel β sandwich.

In mammals Synaptotagmin-14 (SYT14) is expressed in brain (especially in the cerebellum) . Mutations in SYT14 gene cause spinocerebellar ataxia, autosomal recessive, 11 (SCAR11), which is a clinically and genetically heterogeneous group of cerebellar disorders .

This entry also includes synaptotagmin-14-like protein (SYT14L, also known as sytdep) from human, which is highly expressed in mature peripheral blood neutrophils .

SYT16 is Ca2-independent and may be involved in membrane trafficking in specific tissues outside the brain .
Pappalysin-1/2 (PAPPA/PAPPA2)
Type: Family

Pappalysin-1 (also known as pregnancy-associated plasma protein-A (PAPP-A); MERIOPS identifier M43.004) is a metalloendopeptidase that belongs to the MEROPS peptidase family M43B. It was first found in high concentrations in the blood of pregnant women. Later, it was identified as a proteinase responsible for cleavage of insulin-like growth factor binding protein (IGFBP)-4, an inhibitor of IGF action that mediates cell growth and survival signals. PAPP-A is expressed by different cell types, and thus no longer could be considered to be just "pregnancy-associated" . It is involved in rapid yet strictly controlled growth and development, including wound healing, bone remodelling, folliculogenesis, placental development, and atherosclerosis .

Pappalysin-2 is a zinc binding metalloproteinase which specifically cleaves insulin-like growth factor-binding protein 5 (IGFBP-5). It shows limited proteolysis toward IGFBP-3 .

This entry includes Pappalysin-1/2 (PAPPA/PAPPA2). They are metalloproteinases that cleave insulin-like growth factor binding proteins. This entry also includes a group of uncharacterised bacterial proteins.
Sorting nexin-10/11 (SNX10/11)
Type: Family

This entry includes SNX10/11. They belong to the nexin family, which contains a conserved PX (phox homology) domain that is responsible for binding to specific phosphoinositides .

SNX10 is involved in intracellular vesicular trafficking . It has been linked to osteopetrosis . SNX11 is involved in protein sorting and membrane trafficking in endosomes .
Glutamate receptor-interacting protein 1/2 (GRIP1/2)
Type: Family

Glutamate receptor-interacting proteins (GRIPs) are multi-PDZ domain scaffolding proteins required for dendrite development. There are two members of the GRIP family: GRIP1 and GRIP2/ABP (AMPA receptor binding protein) . GRIPs regulate AMPAR receptor trafficking and neuronal plasticity . They also bind various receptor and signalling proteins, such as EphB receptors, ephrinB ligands, the proteoglycan NG2, the Fraser syndrome protein Fras1, and matrix metalloproteinase 5 .

This entry includes glutamate receptor-interacting protein 1/2 (GRIP1/2).
Vesicle-trafficking protein Sec22a/c (Sec22a/c)
Type: Family

Sec22a is a multi-pass membrane protein that may be involved in vesicle transport between the ER and the Golgi complex . Sec22c is an endoplasmic reticulum (ER)-localised transmembrane protein involved in regulation of the vesicle transport between the ER and the Golgi .

This entry includes Sec22a and Sec22c. They belong to the synaptobrevin family.
Mimecan/Epiphycan/Opticin (Mimecan/Epiphycan/Opticin)
Type: Family

Proteoglycans are heavily glycosylated proteins that can be divided into large hyaluronan-binding proteoglycans like aggrecan, and small proteoglycans including the small leucine-rich repeat protein (SLRP) superfamily. The SLRP family is divided into five classes (class I-V) of structurally and genetically related molecules which may play a role in the regulation of the extracellular matrix architecture . This entry includes SLRP family class III proteins, which includes mimecan, epiphycan and opticin which are characterised by a relatively low number of LRRs .

Mimecan, also known as osteoglycin, induces bone formation in conjunction with TGF-beta-1 or TGF-beta-2 . Its expression can be modulated by growth factors and cytokines. It may play roles in many biological processes, including cellular growth, angiogenesis, and inflammation .

Epiphycan may have a role in bone formation and also in establishing the ordered structure of cartilage through matrix organisation .

Opticin inhibits angiogenesis in the vitreous humor of the eye, and therefore represses neovascularization and may be involved in collagen fibre organisation via regulation of other members of the SLRP superfamily .
1-phosphatidylinositol-3phosphate-5-kinase (PIKfyve)
Type: Family

The PI(3,5)P2 regulatory complex regulates both the synthesis and turnover of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2). It catalyzes the phosphorylation of phosphatidylinositol 3-phosphate on the fifth hydroxyl of the myo-inositol ring, to form phosphatidylinositol 3,5-bisphosphate. The dynamic interconversion of PI3P and PI(3,5)P2 is regulated by a protein complex which is conserved from yeast to mammals. It includes at least five proteins in yeast, located in the vacuole membrane: the lipid kinase Fab1p, lipid phosphatase Fig4p, the Fab1p activator Vac7p, the Fab1p inhibitor Atg18p, and Vac14p. Homologues of Fab1p, Vac14p and Fig4p are found in all eukaryotes which in mammalian cells, are known as Fab1/PIKfyve/PIP5K3, Fig4/Sac3, and Vac14/ArPIKfyve, located on early and late endosomes. Fab1, Vac14, and Fig4 form a ternary complex where Fab1 lipid kinase and Fig4 lipid phosphatase bind to opposite ends of Vac14. A conformational change of Vac14 allows a quick effect on kinase and phosphatase activities. This complex is required for endocytic-vacuolar pathway and nuclear migration. It plays a role in the biogenesis of endosome carrier vesicles (ECV)/ multivesicular bodies (MVB) transport intermediates from early endosomes in mammals, being essential for nervous tissue function. It has been shown that alterations in this complex leads to reduced intracellular levels of PI(3,5)P2, cytoplasmic vacuolisation and neurodegeneration .

This entry represents the 1-phosphatidylinositol-3phosphate-5-kinase (PIKfyve) found in eukaryotes.
C2 calcium-dependent domain-containing protein 4C/4D (C2C4C/C2C4D)
Type: Family

The function of C2 calcium-dependent domain-containing protein 4C/4D is not known. The C2 domain is a Ca2 -dependent membrane-targeting module found in many cellular proteins involved in signal transduction or membrane trafficking.
Histone-lysine N-methyltransferase EHMT1/EHMT2 (EHMT1/EHMT2)
Type: Family

This entry includes Histone-lysine N-methyltransferase EHMT1 and Histone-lysine N-methyltransferase EHMT2 (

). EHMT1 and EHMT2 mono- and dimethylate 'Lys-9' of histone H3 (H3K9me1 and H3K9me2, respectively) in euchromatin . H3K9me is a specific tag for repression of epigenetic transcription, recruiting HP1 proteins to methylated histones. EHMT1 also methylates 'Lys-27' of histone H3 (H3K27me), but weakly , while EHMT2 also monomethylates 'Lys-56' of histone H3 (H3K56me1) during the G1 phase of the cell cycle , and methylates 'Lys-27' of histone H3 (H3K27me) . EHMT1 and EHMT2 also dimethylate other proteins, including 'Lys-373' of p53 .

EHMT1 forms a heterodimer with EHMT2 , and is a component of the E2F6.com-1 complex in G0 phase . EHMT1 and EHMT2 contain ankyrin repeats (eight and seven ankyrin repeats, respectively), which bind the monomethylated RELA subunit of NF-kappa-B, a SET domain which interacts with WIZ , and a pre-SET domain that binds three zinc ions via cysteine residues .
SNF1-related protein kinase regulatory subunit beta (KINB)
Type: Family

This family represents the regulatory beta subunits of the plant SNF1-related protein kinase (SnRK) complex, probably a trimeric complex consisting of an alpha catalytic subunit, and a beta and a gamma non-catalytic regulatory subunits . In Arabidopsis, there are two isoforms of the catalytic subunit (AKIN10 and AKIN11), three beta subunits (AKINbeta1, AKINbeta2, and AKINbeta3) and one gamma subunit (AKINg) . The SnRK complex in higher plants plays a role in signal transduction cascades regulating gene expression, carbohydrate and nitrogen metabolism . Some known SnRK1 substrates are key metabolic enzymes such as sucrose phosphate synthase, nitrate reductase, and HMG-CoA reductase , while others are transcription factors . Its physical interaction with nitrate reductase specifically occurs via the AKINbeta1 subunit .

Beta subunits show conserved domains in different organisms. These domains include the Association with the SNF1 Complex (ASC) domain, which is important for interaction with the alpha and gamma subunits, and a specialised carbohydrate-binding module named the Glycogen Binding Domain (GBD). In Arabidopsis, only AKINbeta1 and AKINbeta2 exhibit both the GBD and the ASC domains . AKINbeta3 could be a plant specific subunit .
Sushi repeat-containing protein SRPX-like (SRPX-like)
Type: Family

Sushi repeat-containing protein SRPX2 is a multifunctional protein that is involved in seizure disorders, angiogenesis and cellular adhesion . It acts as a ligand for the urokinase plasminogen activator surface receptor . The overexpression of SRPX2 enhances cellular migration and adhesion in gastric cancer cells . Mutations in SRPX2 gene cause rolandic epilepsy with speech dyspraxia and mental retardation X-linked (RESDX) .

Sushi repeat-containing protein SRPX is deleted in patients with X-linked retinitis pigmentosa .

This entry includes SRPX and SRPX2.
StAR-related lipid transfer protein 5/6 (StARD5/6)
Type: Family

The steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domain is a protein module of approximately 210 residues that binds lipids, including sterols. The START domain consists of an α/β helix-grip fold. Fifteen mammalian proteins, STARD1-STARD15, possess a START domain . This entry includes StARD5 and StARD6.

StAR-related lipid transfer protein 5 (StARD5) contains a START domain that binds lipids, including sterols . StARD5 primary binds bile acids, and may be involved in the transport of bile acids rather than cholesterol .

StARD6 can bind cholesterol. It has cholesterol-transfer activity and StAR-like activity. STARD6 is restricted to the testes and is expressed during spermatogenesis in spermatids but not in steroidogenic cells .
Dermcidin/Lacritin (Dermcidin/Lacritin)
Type: Family

Dermcidin is an antibiotic peptide secreted by sweat glands. It is proteolytically processed to generate a 47-amino acid peptide with antimicrobial activity in response to a variety of pathogenic microorganisms .

Lacritin is a tear glycoprotein that induces tear secretion and promotes epithelial homeostasis . Lacritin has anti-microbial, cytoprotective and wound-healing properties . It is down-regulated in conditions such as dry eye , keratitis , and other eye pathologies. Lacritin is highly expressed in human lacrimal gland and moderately in major and minor salivary glands .

This entry include a group of anti-microbial proteins, including Dermcidin and Lacritin.
Transcription factor LHW-like (LHW-like)
Type: Family

Transcription factor LHW is a transcription activator that regulates root development. It shows weak sequence similarity to basic helix-loop-helix (bHLH)-domain proteins . LHW coordinately controls the number of all vascular cell types by regulating the size of the pool of cells from which they arise .

This entry represents a group of transcription factors from plants, including LHW and LHWL1/2/3 from Arabidopsis.
Retinal homeobox protein RAX/RAX2 (RAX/RAX2)
Type: Family

This entry includes a group of homeobox proteins, including RAX and RAX2.

RAX is a transcription factor that plays a critical role in the eye and forebrain development of vertebrate species. It is involved in the establishment of the retina . Mutations in the RAX gene cause microphthalmia, isolated 3, which is a disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues . Homeobox protein ceh-8 is the RAX orthologue from C. elegans required for cell specification of the RIA interneurons .

Retina and anterior neural fold homeobox protein 2 (RAX2) is known to bind to the Ret-1 and Bat-1 element within the rhodopsin promoter and may be involved in modulating the expression of photoreceptor specific genes .

This entry also includes ceh-8 from Caenorhabditis elegans required for cell specification of the RIA interneurons .
Nuclear body protein Sp110/Sp140/Sp140L-like (Sp110/Sp140/Sp140L-like)
Type: Family

This entry includes a group of nuclear dot-associated proteins, including Sp110/Sp140/Sp140L and autoimmune regulator from humans. They are proteins with a constituent of nuclear domains, also known as nuclear dots (NDs). Sequences similar to the Sp100 homodimerization/ND-targeting region occur in several other proteins and constitute a novel protein motif, termed HSR domain (for homogeneously-staining region) .

Sp110 is a leukocyte-specific component of the nuclear body . It may function as a nuclear hormone receptor transcriptional coactivator that may play a role in inducing differentiation of myeloid cells . It is also involved in resisting intracellular pathogens and functions as an important drug target for preventing intracellular pathogen diseases, such as tuberculosis, hepatic veno-occlusive disease, and intracellular cancers . Sp110 gene polymorphisms may be associated with susceptibility to tuberculosis in Chinese population .

The function of nuclear protein Sp140 is not known, though it contains several chromatin related modules such as plant homeodomain (PHD), bromodomain (BRD) and SAND domain, which suggests a role in chromatin-mediated regulation of gene expression . It also harbours a nuclear localisation signal and a dimerisation domain (HSR or CARD domain). The PHD finger of Sp140 presents an atypical fold which does not bind to histone H3 tails but binds to peptidylprolyl isomerase Pin1. Pin1 catalyses the isomerisation of a phospho-Threonine-Proline bond in Sp140-PHD and thus may modulate Sp140 function .

Human Sp140 is an interferon inducible nuclear leukocyte-specific protein that may be involved in the pathogenesis of acute promyelocytic leukemia and viral infection . It localises to LYSP100-associated nuclear dots and is also a component of the promyelocytic leukemia nuclear body (PML-NBs) . The Sp140 locus has been identified as a lymphocytic leukemia (CLL) risk locus .

This family also includes protein Sp140-like (SP140L) .
PAX family (PAX_fam)
Type: Family

PAX family members are transcription factors characterised by a ~128-amino-acid DNA-binding paired domain that makes sequence specific contacts with DNA . In mammals, there are nine Pax proteins (PAX1-9). They regulate the morphogenesis of a wide range of organs and are key factors for the development of mammalian sensory organs such as the eye (Pax6, Pax2), nose (Pax6) and ears (Pax2, Pax8) .
Rabphilin/Doc2/Noc2 (Rabphilin/DOC2/Noc2)
Type: Family

This entry includes Rabphilin and Doc2. Rabphilin and Doc2s share highly homologous tandem C2 domains, although their N-terminal structures are completely different: Rabphilin contains an N-terminal Rab-binding domain (RBD), whereas Doc2 contains an N-terminal Munc13-1-interacting domain (MID) . This entry also includes Noc2 (also known as Rabphilin-3A-like protein), which is a potential effector of Ras-associated binding proteins Rab3A and Rab27A. Noc2 contains an N-terminal Rab3A effector domain which harbors a conserved zinc finger, but lacks tandem C2 domains .
Synaptotagmin-like 1-5, C2B domain (SYTL1-5_C2B)
Type: Domain

Synaptotagmin-like proteins (Slps) contain a N-terminal RabBD (Rab-binding) domain and two C-terminal C2 domains, C2A and C2B . The characteristic feature of the Slp family is the N-terminal domain (referred to as SHD for Slp Homology Domain), which is not found in other C-type tandem C2 proteins . SHD functions as a specific Rab27A/B-binding domain . This entry represents the C2B domain.

The C2 domain is a Ca
2+
-dependent membrane-targeting module found in many cellular proteins involved in signal transduction or membrane trafficking. C2 domains are unique among membrane targeting domains in that they show wide range of lipid selectivity for the major components of cell membranes, including phosphatidylserine and phosphatidylcholine. This C2 domain is about 116 amino-acid residues and is located between the two copies of the C1 domain in Protein Kinase C and the protein kinase catalytic domain . Regions with significant homology to the C2-domain have been found in many proteins. The C2 domain is thought to be involved in calcium-dependent phospholipid binding and in membrane targetting processes such as subcellular localisation.

The 3D structure of the C2 domain of synaptotagmin has been reported , the domain forms an eight-stranded β-sandwich constructed around a conserved 4-stranded motif, designated a C2 key . Calcium binds in a cup-shaped depression formed by the N- and C-terminal loops of the C2-key motif. Structural analyses of several C2 domains have shown them to consist of similar ternary structures in which three Ca
2+
-binding loops are located at the end of an 8 stranded antiparallel β-sandwich.
Polyphosphoinositide phosphatase Fig4-like (Fig4-like)
Type: Family

This entry represents a group of polyphosphoinositide phosphatases, including fungal Fig4 and its homologues from animals and plants. They contain a SAC (suppressor of actin) domain. Fig4 is part of the PtdIns(3,5)P2-synthesising complex of yeast at the vacuole membrane and is involved in regulating both the acute rise and subsequent fall in PI3,5P(2) levels .

In Arabidopsis there are five Fig4 homologues, known as SAC1-5. They play an important role in vacuolar trafficking, vacuolar morphology and function in plants .

In humans, mutations of the FIG4 gene cause Charcot-Marie-Tooth disease 4J (CMT4J), a recessive demyelinating form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system .
Caspase recruitment domain-containing protein 19 (CARD19)
Type: Family

Caspase recruiment domain-containing proteins (CARDs) are death domains (DDs) found associated with caspases . They are known to be important in the signalling pathways for apoptosis, inflammation, and host-defense mechanisms .

This entry includes the Caspase-recruitment domain-containing protein 19 (CARD19), also known as Bcl10-interacting protein with CARD (BinCARD) which interacts with apoptosis inducer CARD protein Bcl10 through CARD. It inhibits Bcl10-mediated activation of NF-kappa B and to suppress Bcl10 phosphorylation .
Macrophage stimulating protein (MSP_HGFL)
Type: Family

Macrophage stimulating protein (MSP; also known as hepatocyte growth factor-like protein) and its close relative hepatocyte growth factor (

) are non-peptidase homologues belonging to MEROPS peptidase family S1 (chymotrypsin family, clan PA(S)), subfamily S1A.

MSP is a plasma protein that is secreted from the liver into the circulation as a single-chain, biologically inactive pro-protein. Proteolytic cleavage at a single site yields the active molecule composed of disulphide-linked alpha and beta chains. The MSP receptor is a transmembrane tyrosine kinase found in murine resident peritoneal macrophages but not exudate macrophages or blood monocytes. MSP induces phosphorylation of the receptor cytoplasmic domain, association of phosphatidylinositol (PI)-3 kinase with the receptor, and phosphorylation of receptor-bound PI-3 kinase. MSP may function in tissue injury or wound healing .
Predicted galactose-1-phosphate uridylyltransferase, Corynebacterium type (GalT_Corynebac)
Type: Family

This group represents a predicted galactose-1-phosphate uridylyltransferase, Corynebacterium type.
Asparaginyl endopeptidase (AE)
Type: Family

This entry represents a group of asparagine-specific endopeptidases, including Legumain from mammals, Hemoglobinase from Schistosoma mansoni (Blood fluke) and Vacuolar-processing enzyme from plants.

Asparaginyl endopeptidase is a family of cysteine proteases found in many organisms. This group of cysteine peptidases belong to the MEROPS peptidase family C13 (legumain family, clan CD). A type example is legumain from Canavalia ensiformis (Jack bean, Horse bean) . Although legumains were first described from beans (also known as Vacuolar Processing Enzymes), homologues have been identified in plants, protozoa, vertebrates, and helminths . In blood-feeding helminths, asparaginyl endopeptidases (sometimes described as hemoglobinases) have been located in the gut and are considered to be involved in host hemoglobin digestion .
Cutinase, aspartate and histidine active sites (CUTINASE_2)
Type: Conserved_site

Cutinase is an extracellular fungal enzyme that catalyses the hydrolysis of cutin, an insoluble lipid-polyester that forms the structure of plant
cuticle. Cutinase allows pathogenic fungi to penetrate through the host plant cuticular barrier during the initial stage of fungal infection. Cutinase is a
serine esterase which contains the classical catalytic triad (Asp, Ser, and His) found in the serine hydrolases .

Two cutinase-like proteins (MtCY39.35 and MtCY339.08c) have been found in the genome of the bacteria Mycobacterium tuberculosis.

The sequence around the catalytic residues is well conserved in the sequence of the known fungal cutinases.
Cutinase, serine active site (CUTINASE_1)
Type: Conserved_site

Cutinase is an extracellular fungal enzyme that catalyses the hydrolysis of cutin, an insoluble lipid-polyester that forms the structure of plant
cuticle. Cutinase allows pathogenic fungi to penetrate through the host plant cuticular barrier during the initial stage of fungal infection. Cutinase is a
serine esterase which contains the classical catalytic triad (Asp, Ser, and His) found in the serine hydrolases .

Two cutinase-like proteins (MtCY39.35 and MtCY339.08c) have been found in the genome of the bacteria Mycobacterium tuberculosis.

The sequence around the catalytic residues is well conserved in the sequence of the known fungal cutinases.
Axin-like (Axin-like)
Type: Family

This entry includes Axin-1 and Axin-2 from vertebrates and related proteins from invertebrates. Axin is a central component of the canonical Wnt signaling pathway that interacts with the adenomatous polyposis coli protein APC and the kinase GSK3beta to downregulate the effector beta-catenin .

Axin-1 (axis inhibition protein 1) is a scaffold protein that is involved in many signalling pathways, including the Wnt, transforming growth factor-beta, MAP kinase pathways, as well as p53 activation cascades . It controls many biological processes ranging from sugar intake, cell proliferation, and organ development to cell death .

Mutations in Axin-1 gene cause hepatocellular carcinoma (HCC), a primary malignant neoplasm of epithelial liver cells , and caudal duplication anomaly (CADUA), a condition characterised by the occurrence of duplications of different organs in the caudal region .

Like its mammalian counterpart, Drosophila Axin homologue, Daxin, acts as a negative regulator of wg/Wnt signaling .

In C. elegans AXL-1 functions redundantly with its ortholog, PRY-1, in negatively regulating BAR-1/beta-catenin signaling in the developing vulva and the Q neuroblast lineage. AXL-1 also functions independently of PRY-1 in negatively regulating canonical Wnt signaling during excretory cell development .