SII-SWORD/CoKE huggingface dataset:
SFRP5, cysteine-rich domain (SFRP5_CRD)
Type: Domain

The cysteine-rich domain (CRD) is an essential part of the secreted frizzled-related Protein 5 (SFRP5), which is a positive regulator of BMP and Wnt signaling during retinal and gastrointestinal development .

In general, SFRPs antagonize the activation of Wnt signaling by binding to the CRD domains of frizzled (Fz) proteins, thereby preventing Wnt proteins from binding to these receptors. SFRPs are also known to have functions unrelated to Wnt, as enhancers of procollagen cleavage by the TLD proteinases . SFRPs and Fz proteins both contain CRD domains, but SFRPs lack the seven-pass transmembrane domain which is an integral part of Fzs .
Corin, cysteine-rich domain 1 (Corin_CRD_1)
Type: Domain

The cysteine-rich domain (CRD) is an essential component of corin, a type II transmembrane serine protease which functions as the convertase of the pro-atrial natriuretic peptide (pro-ANP) in the heart . Corin contains two CRDs in its extracellular region, which play an important role in recognition of the physiological substrate, pro-ANP. This entry represents the first (N-terminal) CRD .
Corin, cysteine-rich domain 2 (Corin_CRD_2)
Type: Domain

The cysteine-rich domain (CRD) is an essential component of corin, a type II transmembrane serine protease which functions as the convertase of the pro-atrial natriuretic peptide (pro-ANP) in the heart . Corin contains two CRDs in its extracellular region, which play an important role in recognition of the physiological substrate, pro-ANP. This entry represents the second (C-terminal) CRD .
SFRP2, cysteine-rich domain (SFRP2_CRD)
Type: Domain

The cysteine-rich-domain (CRD) is an essential part of the secreted frizzled related protein 2 (SFRP2), which has a role in development of the neural system, eyes, muscles and limbs. As a Wnt antagonist, SFRP2 regulates Nkx2.2 expression in the ventral spinal cord and anteroposterior axis elongation .

In general, SFRPs antagonize the activation of Wnt signaling by binding to the CRD domains of frizzled (Fz) proteins, thereby preventing Wnt proteins from binding to these receptors. SFRPs are also known to have functions unrelated to Wnt, as enhancers of procollagen cleavage by the TLD proteinases . SFRPs and Fz proteins both contain CRD domains, but SFRPs lack the seven-pass transmembrane domain which is an integral part of Fzs .
Frizzled 4, cysteine-rich domain (FZ4_CRD)
Type: Domain

The cysteine-rich domain (CRD) is an essential extracellular portion of the frizzled 4 (Fz4) receptor, and is required for binding Wnt proteins, which play fundamental roles in many aspects of early development, such as cell and tissue polarity, neural synapse formation, and the regulation of proliferation. Fz proteins serve as Wnt receptors for multiple signal transduction pathways, including both beta-catenin dependent and -independent cellular signalling, as well as the planar cell polarity pathway and the Ca(2+) modulating signalling pathway . CRD containing Fzs have been found in diverse species from amoebas to mammals. 10 different frizzled proteins are found in vertebrata.

Frizzled 4 (Fz4) activates the Ca(2+)/calmodulin-dependent protein kinase II and protein kinase C of the Wnt/Ca(2+) signalling pathway during retinal angiogenesis. Mutations in Fz4 lead to familial exudative vitreoretinopathy (FEVR), a hereditary ocular disorder characterised by failure of the peripheral retinal vascularisation . In addition, the interplay between Fz4 and norrin as a receptor-ligand pair plays an important role in vascular development in the retina and inner ear in a Wnt-independent manner .
PA3087-like (PA3087-like)
Type: Family

This entry consists of Pseudomonas aeruginosa PA3087 and related proteins. PA3087 is an uncharacterised protein from Pseudomonas aeruginosa with a metallophosphatase domain that belongs to the phosphoprotein phosphatase (PPP) family.

The PPP family also includes: PP1, PP2A, PP2B (calcineurin), PP4, PP5, PP6, PP7, Bsu1, RdgC, PrpE, PrpA/PrpB, and ApA4 hydrolase. The PPP catalytic domain is defined by three conserved motifs (-GDXHG-, -GDXVDRG- and -GNHE-). The PPP enzyme family is ancient with members found in all eukaryotes, and in most bacterial and archaeal genomes. Dephosphorylation of phosphoserines and phosphothreonines on target proteins plays a central role in the regulation of many cellular processes .
Tyrosine-protein phosphatase (RLPH)
Type: Family

Rhilphs (Rhizobiales/ Rhodobacterales/ Rhodospirillaceae-like phosphatases) are a phylogenetically distinct group of PPP (phosphoprotein phosphatases), found only in land plants. They are named for their close relationship to to PPP phosphatases from alpha-Proteobacteria, including Rhizobiales, Rhodobacterales and Rhodospirillaceae . This entry includes tyrosine-protein phosphatase 2 (RLPH2) from Arabidopsis .
Frizzled 3, cysteine-rich domain (FZ3_CRD)
Type: Domain

The cysteine-rich domain (CRD) is an essential extracellular portion of the frizzled 3 (Fz3) receptor, and is required for binding Wnt proteins, which play fundamental roles in many aspects of early development, such as cell and tissue polarity, neural synapse formation, and the regulation of proliferation. Fz proteins serve as Wnt receptors for multiple signal transduction pathways, including both beta-catenin dependent and -independent cellular signaling, as well as the planar cell polarity pathway and Ca(2+) modulating signaling pathway. CRD containing Fzs have been found in diverse species from amoebas to mammals. 10 different frizzled proteins are found in vertebrata . Fz3 plays a vital role in the anterior-posterior guidance of commissural axons. Knockout mice without Fz3 show defects in fibre tracts in the rostral CNS .
Frizzled 6, cysteine-rich domain (FZ6_CRD)
Type: Domain

The cysteine-rich domain (CRD) is an essential extracellular portion of the frizzled 6 (Fz6) receptor, and is required for binding Wnt proteins, which play fundamental roles in many aspects of early development, such as cell and tissue polarity, neural synapse formation, and the regulation of proliferation. Fz proteins serve as Wnt receptors for multiple signal transduction pathways, including both beta-catenin dependent and -independent cellular signaling, as well as the planar cell polarity pathway and Ca(2+) modulating signaling pathway. CRD containing Fzs have been found in diverse species from amoebas to mammals. 10 different frizzled proteins are found in vertebrata . Frizzled 6 (Fz6) is involved in the neural tube closure and plays a role in the regulation of the establishment of planar cell polarity (PCP), particularly in the orientation of asymmetric bundles of stereocilia on the apical faces of a subset of auditory and vestibular sensory cells located in the inner ear .
Smoothened, cysteine-rich domain (SMO_CRD)
Type: Domain

The cysteine-rich domain (CRD) is part of the smoothened receptor (Smo), an integral membrane protein and one of the key players in the Hedgehog (Hh) signaling pathway, critical for development, cell growth and migration, as well as stem cell maintenance. The CRD of Smo is conserved in vertebrates and can also be identified in invertebrates. The precise function of the CRD in Smo is unknown . Mutations in the Drosophila CRD disrupt Smo activity in vivo, while deletion of the CRD in mammalian cells does not seem to affect the activity of overexpressed Smo .
Sizzled, cysteine-rich domain (Sizzled_CRD)
Type: Domain

The cysteine-rich domain (CRD) is an essential part of the sizzled protein, which regulates bone morphogenetic protein (Bmp) signaling by stabilizing chordin, and plays a critical role in the patterning of vertebrate and invertebrate embryos. Sizzled also functions in the ventral region as a Wnt inhibitor and modulates canonical Wnt signaling. Sizzled proteins belong to the secreted frizzled-related protein family (SFRP), and have be identified in the genomes of birds, fishes and frogs, but not mammals .
Crescent, cysteine-rich domain (Crescent_CRD)
Type: Domain

The cysteine-rich domain (CRD) is an essential part of the crescent protein, a member of the secreted frizzled-related protein (SFRP) family, which regulates convergent extension movements (CEMs) during gastrulation and neurulation. Xenopus laevis crescent efficiently forms inhibitory complexes with Wnt5a and Wnt11, but this effect is cancelled in the presence of another member of the SFRP family, Frzb1. A potential role for Crescent in head formation is to regulate a non-canonical Wnt pathway positively in the adjacent posterior mesoderm, and negatively in the overlying anterior neuroectoderm .
LIN-17, cysteine-rich domain (LIN-17_CRD)
Type: Domain

A cysteine-rich domain (CRD) is an essential component of a number of cell surface receptors, which are involved in multiple signal transduction pathways, particularly in modulating the activity of the Wnt proteins, which play a fundamental role in the early development of metazoans. CRD is also found in secreted frizzled related proteins (SFRPs), which lack the transmembrane segment found in the frizzled protein. The CRD domain is also present in the alpha-1 chain of mouse type XVIII collagen, in carboxypeptidase Z, several receptor tyrosine kinases, and the mosaic transmembrane serine protease corin. The CRD domain is well conserved in metazoans - 10 frizzled proteins have been identified in mammals, 4 in Drosophila and 3 in Caenorhabditis elegans. CRD domains have also been identified in multiple tandem copies in a Dictyostelium discoideum protein. Very little is known about the mechanism by which CRD domains interact with their ligands. The domain contains 10 conserved cysteines.

This entry represents the CRD domain of lin-17, a protein involved in cell type specification during Caenorhabditis elegans vulval development .
Ror-like, cysteine-rich domain (Ror-like_CRD)
Type: Domain

The cysteine-rich domain (CRD) is an essential part of the tyrosine kinase-like orphan receptor (Ror) proteins, a conserved family of tyrosine kinases that function in various processes, including neuronal and skeletal development, cell polarity, and cell movement. Ror proteins are receptors of Wnt proteins, which are key players in a number of fundamental cellular processes in embryogenesis and postnatal development. In different cellular contexts, Ror proteins can either activate or repress transcription of Wnt target genes, and can modulate Wnt signaling by sequestering Wnt ligands. In addition, a number of Wnt-independent functions have been proposed for both Ror1 and Ror2 . Proteins containing this domain also include CAM-1 from C. elegans. CAM-1 is a ROR receptor tyrosine kinase that inhibits the Wnt pathway .
Frizzled 8, cysteine-rich domain (FZ8_CRD)
Type: Domain

The cysteine-rich domain (CRD) is an essential extracellular portion of the frizzled 8 (Fz8) receptor, and is required for binding Wnt proteins, which play fundamental roles in many aspects of early development, such as cell and tissue polarity, neural synapse formation, and the regulation of proliferation. Fz proteins serve as Wnt receptors for multiple signal transduction pathways, including both beta-catenin dependent and -independent cellular signaling, as well as the planar cell polarity pathway and Ca(2+) modulating signaling pathway. CRD containing Fzs have been found in diverse species from amoebas to mammals. 10 different frizzled proteins are found in vertebrata . Xenopus Fz8 is important in Wnt/beta-catenin signaling pathways controlling the transcriptional activation of target genes Siamois and Xnr3 in the animal caps of late blastula .
Frizzled 9, cysteine-rich domain (FZ9_CRD)
Type: Domain

The cysteine-rich domain (CRD) is an essential extracellular portion of the frizzled 9 (Fz9) receptor, and is required for binding Wnt proteins, which play fundamental roles in many aspects of early development, such as cell and tissue polarity, neural synapse formation, and the regulation of proliferation. Fz proteins serve as Wnt receptors for multiple signal transduction pathways, including both beta-catenin dependent and -independent cellular signaling, as well as the planar cell polarity pathway and Ca(2+) modulating signaling pathway. CRD containing Fzs have been found in diverse species from amoebas to mammals. 10 different frizzled proteins are found in vertebrata . Fz9 plays an important role in hippocampal development . Mutation of the Fz9 gene has been linked to Williams-Beuren Syndrome, a genetic neurodevelopmental disorder characterised by an uncommon hypersociability and a mosaic of retained and compromised linguistic and cognitive abilities .
Frizzled 2, cysteine-rich domain (FZ2_CRD)
Type: Domain

The cysteine-rich domain (CRD) is an essential extracellular portion of the frizzled 2 (Fz2) receptor, and is required for binding Wnt proteins, which play fundamental roles in many aspects of early development, such as cell and tissue polarity, neural synapse formation, and the regulation of proliferation. Fz proteins serve as Wnt receptors for multiple signal transduction pathways, including both beta-catenin dependent and -independent cellular signaling, as well as the planar cell polarity pathway and Ca(2+) modulating signaling pathway. CRD containing Fzs have been found in diverse species from amoebas to mammals. 10 different frizzled proteins are found in vertebrata . Fz2 is involved in the Wnt/beta-catenin signaling pathway and in the activation of protein kinase C and calcium/calmodulin-dependent protein kinase (CaM kinase) .
FERM and PDZ domain-containing protein 1/3/4, FERM domain C-lobe (FRMPD1/3/4_FERM_C)
Type: Domain

FRMPD1, FRMPD3, and FRMPD4 contain an N-terminal PDZ domain and a C-terminal FERM domain. The PDZ domain helps anchor transmembrane proteins to the cytoskeleton and hold together signaling complexes. The PDZ domain also binds to a short region of the C terminus of other specific proteins. The FERM domain is composed of three subdomains: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3), which form a clover leaf fold. The C-lobe/F3 within the FERM domain is part of the PH domain superfamily. The FERM domain is found in the cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases (PTPs) , the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites .

This entry represents the C-lobe of the FERM domain found in FRMPD1/3/4. FRMPD1 regulates the subcellular location of activator of G-protein signaling 3 and its interaction with G-proteins . FRMPD4 has been shown to regulates dendritic spine morphogenesis . The function of FRMPD3 is not clear.
PrpE-like, metallophosphatase domain (MPP_PrpE-like)
Type: Domain

This entry represents the metallophosphatase domain of Bacillus subtilis PrpE and related proteins. PrpE (protein phosphatase E) is a bacterial member of the PPP (phosphoprotein phosphatase) family of serine/threonine phosphatases and a key signal transduction pathway component controlling the expression of spore germination receptors GerA and GerK in Bacillus subtilis. PrpE is closely related to ApaH (also known symmetrical Ap(4)A hydrolase and bis(5'nucleosyl)-tetraphosphatase). PrpE has specificity for phosphotyrosine only, unlike the serine/threonine phosphatases to which it is related . The Bacilli members of this family are single domain proteins while the other members have N- and C-terminal domains in addition to this phosphatase domain. Polynucleotide kinase/phosphatase (Pnkp) is the end-healing and end-sealing component of an RNA repair system present in bacteria . It is composed of three catalytic modules: an N-terminal polynucleotide 5' kinase, a central 2',3' phosphatase, and a C-terminal ligase. Pnkp is a Mn(2+)-dependent phosphodiesterase-monoesterase that dephosphorylates 2',3'-cyclic phosphate RNA ends. An RNA binding site is suggested by a continuous tract of positive surface potential flanking the active site .

The PPP (phosphoprotein phosphatase) family, to which PrpE belongs, is one of two known protein phosphatase families specific for serine and threonine. The PPP family also includes: PP1, PP2A, PP2B (calcineurin), PP4, PP5, PP6, PP7, Bsu1, RdgC, PrpA/PrpB, and ApA4 hydrolase. The PPP catalytic domain is defined by three conserved motifs (-GDXHG-, -GDXVDRG- and -GNHE-). The PPP enzyme family is ancient with members found in all eukaryotes, and in most bacterial and archeal genomes. Dephosphorylation of phosphoserines and phosphothreonines on target proteins plays a central role in the regulation of many cellular processes . PPPs belong to the metallophosphatase (MPP) superfamily.
FERM domain-containing protein 6, FERM domain C-lobe (FRMD6-FERM_C)
Type: Domain

This entry represents the C-lobe of FERM domain found in FRMD6. The Drosophilla FRMD6 homologue, Ex, is a regulator of the Hippo/SWH (Sav/Wts/Hpo) signaling pathway, which plays a pivotal role in organ size control and is tumour suppression by restricting proliferation and promoting apoptosis . However, human FRMD6 is thought to function independently of the Hippo pathway. Instead it may inhibit progression through the S phase of the cell cycle by upregulating p21(Cip1) and downregulating Cyclin A . It has been implicated in the progression of Alzheimer disease . FRMD6 contains a single FERM domain which has a cloverleaf tripart structure composed of: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3). The C-lobe is a member of the PH domain superfamily. The FERM domain is found in the cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases (PTPs) , the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites .
PTPN14/21, FERM domain C-lobe (PTPN14/21_FERM_C)
Type: Domain

This entry represents the C-lobe of FERM domain found in protein-tyrosine phosphatases non-receptor type-14 (PTPN14, also known as Pez) and type-21 (PTPN21). A number of mutations in Pez/PTPN14 have been shown to be associated with breast and colorectal cancer . PTPN14 and PTPN21 contain an N-terminal FERM domain and a C-terminal PTP catalytic domain.

The FERM domain has a cloverleaf tripart structure composed of: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. Like most other ERM members they have a phosphoinositide-binding site in their FERM domain. The FERM C domain is the third structural domain within the FERM domain. The FERM domain is found in the cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases (PTPs) , the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites .
PTPN3/4, FERM domain C-lobe (PTPN3/4_FERM_C)
Type: Domain

Tyrosine-protein phosphatase non-receptor type-4 (PTPN4, also known as PTPMEG) is a cytoplasmic protein-tyrosine phosphatase (PTP) thought to play a role in cerebellar function. PTPMEG-knockout mice have impaired memory formation and cerebellar long-term depression . Tyrosine-protein phosphatase non-receptor type-3 (PTPN3/PTPH1) is a membrane-associated PTP implicated in regulating tyrosine phosphorylation of growth factor receptors, p97 VCP (valosin-containing protein, or Cdc48 in Saccharomyces cerevisiae), and HBV (Hepatitis B Virus) gene expression; it is mutated in a subset of colon cancers . PTPN3 and PTPN4 contain an N-terminal FERM domain, a middle PDZ domain, and a C-terminal phosphatase domain. Tyrosine-protein phosphatase 1/PTP1 from nematodes is also included in this entry.

The FERM domain has a cloverleaf tripart structure composed of: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3). The C-lobe/F3 within the FERM domain is part of the PH domain family. Like most other ERM members they have a phosphoinositide-binding site in their FERM domain. The FERM C domain is the third structural domain within the FERM domain. The FERM domain is found in the cytoskeletal-associated proteins such as ezrin, moesin, radixin, 4.1R, and merlin. These proteins provide a link between the membrane and cytoskeleton and are involved in signal transduction pathways. The FERM domain is also found in protein tyrosine phosphatases (PTPs) , the tyrosine kinases FAK and JAK, in addition to other proteins involved in signaling. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites .
FAK1/PYK2, FERM domain C-lobe (FAK1/PYK2_FERM_C)
Type: Domain

FAK1 (focal adhesion kinase 1) is a non-receptor tyrosine kinase that localizes to focal adhesions in adherent cells. It has been implicated in diverse cellular roles including cell locomotion, mitogen response and cell survival . The N-terminal region of FAK1 contains a FERM domain, a linker, a kinase domain, and a C-terminal FRNK (FAK-related-non-kinase) domain. Three subdomains of FERM: (1) FERM_N (A-lobe or F1); (2) FERM_M (B-lobe, or F2); and (3) FERM_C (C-lobe or F3), form a cloverleaf fold, similar to those of known FERM structures despite the low sequence conservation. The phosphoinositide-binding site found in ERM family proteins is not present in the FERM domain of FAK1 . The adjacent Src SH3 and SH2 binding sites in the linker of FAK1 associates with the F3 and F1 lobes and are thought to be involved in regulation. The FERM domain of FAK1 can inhibit enzymatic activity and repress FAK signaling. In an inactive state of FAK1, the FERM domain is thought to interact with the catalytic domain of FAK1 to repress its activity. Upon activation this interaction is disrupted and its kinase activity restored. The FRNK domain is thought to function as a negative regulator of kinase activity. This entry represents the C-lobe/F3 domain, which is the third structural domain within the FERM domain. This domain is structurally similar to the PH and PTB domains and consequently is capable of binding to both peptides and phospholipids at different sites .