SII-SWORD/CoKE huggingface dataset:
Knr4/Smi1-like domain superfamily (Knr4/Smi1-like_sf)
Type: Homologous_superfamily

This domain superfamily is found in the yeast cell wall assembly regulator Smi1 (also known as Knr4) .

Saccharomyces cerevisiae Knr4 has a regulatory role in chitin deposition and in cell wall assembly . It is believed to connect the PKC1-SLT2 MAPK pathway with cell proliferation. It has been shown to interact with Bck2, a gene involved in cell cycle progression in S. cerevisiae (forming a complex) to allow PKC1 to coordinate the cell cycle (cell proliferation) with cell wall integrity . Knr4 also interacts with the tyrosine-tRNA synthetase protein encoded by Tys1 and is involved in sporulation process .

Proteins containing this domain also include the animal F-box only protein 3 (FBXO3). In humans, FBXO3 is a substrate recognition component of the SCF (SKP1-CUL1-F-box protein)-type E3 ubiquitin ligase complex .

Interestingly, Smi1/Knr4 homologues from bacteria are potential immunity proteins in a subset of these contact-dependent inhibitory toxin systems .

Note: previously reported evidence that Knr4 may interact with nuclear matrix-association region may be due to an artefact .

This domain superfamily is also found in the Syd protein which interacts with the SecY protein.
LARG, RGS domain (LARG_RGS)
Type: Domain

The RGS domain is an essential part of the leukemia-associated RhoGEF protein (LARG, also known as Rho guanine nucleotide exchange factor 12), a member of the RhoGEF subfamily of the RGS protein family. The RhoGEFs are peripheral membrane proteins that regulate essential cellular processes, including cell shape, cell migration, cell cycle progression of cells, and gene transcription by linking signals from heterotrimeric G-alpha12/13 protein-coupled receptors to Rho GTPase activation, leading to various cellular responses, such as actin reorganization and gene expression .

The RhoGEF subfamily includes p115RhoGEF, LARG, PDZ-RhoGEF, and its rat specific splice variant GTRAP48. The RGS domain of RhoGEFs has very little sequence similarity with the canonical RGS domain of the RGS proteins and is often refered to as RH (RGS Homology) domain . In addition to being a G-alpha13 effector, the LARG protein also functions as a GTPase-activating protein (GAP) .
Heat shock protein beta-7, ACD domain (ACD_HspB7)
Type: Domain

This entry represents the alpha crystallin domain (ACD) found in mammalian small heat shock protein (sHsp) HspB7, also known as cardiovascular small heat shock protein (cvHsp).

Small Hsps are molecular chaperones that suppress protein aggregation and protect against cell stress, and are generally active as large oligomers consisting of multiple subunits . HspB7 is a 25kDa protein, preferentially expressed in heart and skeletal muscle . It is essential for fetal heart development by modulating actin filament assembly . It binds the cytoskeleton protein alpha-filamin (also known as actin-binding protein 280) . The expression of HspB7 is increased during rat muscle aging . As the human gene encoding HspB7 is mapped to chromosome 1p36.23-p34.3 it is a positional candidate for several dystrophies and myopathies .
p115RhoGEF, RGS domain (p115RhoGEF_RGS)
Type: Domain

The RGS (Regulator of G-protein Signaling) domain is an essential part of the p115RhoGEF protein, a member of the RhoGEF (Rho guanine nucleotide exchange factor) subfamily of the RGS protein family. The RhoGEFs are peripheral membrane proteins that regulate essential cellular processes, including cell shape, cell migration, cell cycle progression of cells, and gene transcription by linking signals from heterotrimeric G-alpha12/13 protein-coupled receptors to Rho GTPase activation, leading to various cellular responses, such as actin reorganization and gene expression .

The RhoGEF subfamily includes p115RhoGEF, LARG, PDZ-RhoGEF and its rat specific splice variant GTRAP48. The RGS domain of RhoGEFs has very little sequence similarity with the canonical RGS domain of the RGS proteins and is often refered to as RH (RGS Homology) domain. In addition to being a G-alpha13/12 effector, the p115RhoGEF protein also functions as a GTPase-activating protein (GAP) for G-alpha13 .
Rho guanine nucleotide exchange factor 11, RGS domain (PDZRhoGEF_RGS)
Type: Domain

The RGS domain is an essential part of the Rho guanine nucleotide exchange factor 11, also known as PDZ-RhoGEF (PDZ:Postsynaptic density 95, Disk large, Zona occludens-1; RhoGEF: Rho guanine nucleotide exchange factor; alias PRG), a member of RhoGEFs subfamily of the RGS protein family. The RhoGEFs are peripheral membrane proteins that regulate essential cellular processes, including cell shape, cell migration, and cell cycle progression, as well as gene transcription by linking signals from heterotrimeric G-alpha12/13 protein-coupled receptors to Rho GTPase activation, leading to various cellular responses, such as actin reorganization and gene expression .
KMT2D, SET domain (SET_KMT2D)
Type: Domain

Histone-lysine N-methyltransferase 2D (KMT2D, also known as MLL2;

) is a catalytic component of the MLL2/3 complex (also named ASCOM complex) and methylates 'Lys-4' of histone H3 (H3K4me). H3K4me represents a specific tag for epigenetic transcriptional activation. KMT2D is recruited by ESR1 and acts as a coactivator of the oestrogen receptor alpha . It functions as a scaffold protein for association with WRAD (WDR5, RbBP5, ASH2L, and DPY30), NCOA6, PTIP, PA1, and H3K27 demethylase UTX, being responsible for maintaining the stability of UTX. KMT2D plays critical roles in regulating development, differentiation, metabolism, and tumor suppression . KMT2D contains the catalytic domain SET, five plant homeodomain (PHD) fingers, two extended PHD (ePHD) fingers, a RING finger, an HMG (high-mobility group)-binding motif, and two FY-rich regions.
Immunity protein Cdil-like superfamily (Cdil-like_sf)
Type: Homologous_superfamily

Contact-dependent growth inhibition (CDI) toxins are expressed by Gram-negative bacteria as part of a mechanism to inhibit the growth of neighbouring bacteria. This entry includes the inhibitor (CdiI) of the CdiA effector protein from Escherichia coli EC869 (which is a DNAse). CdiA secretion is dependent on the outer membrane protein CdiB. Upon binding to a receptor on the surface of target bacteria, the CDI toxin is delivered. The inhibitors are intracellular proteins that inactivate the toxin/effector protein .

The structure of Cdil is composed of two β(3)-α motifs related by pseudo twofold symmetry, a single antiparrallel β-sheet, shaped into a half-barrel with a helical linker region.
SNX14, RGS domain (SNX14_RGS)
Type: Domain

This entry represents the RGS domain of SNX14 (Sorting Nexin14). RGS domain is a small α-helical structure that acts as GAPs for Galpha subunits of heterotrimeric G-proteins, and thus plays critical roles in attenuating G-protein coupled receptor (GPCR) signaling . SNX14 is believed to regulate membrane trafficking in motor neurons . It has been found localized to lysosomes and associated with phosphatidylinositol (3,5)-bisphosphate, a key component of late endosomes/lysosomes .
Calcyclin-binding Protein, CS domain (CS_CacyBP)
Type: Domain

This CS p23-like domain is found in the CacyBP/SIP protein (S100A6 binding protein and Siah-1 interacting protein) . CacyBP/SIP interacts with S100A6 (calcyclin), with some other members of the S100 family, with tubulin, and with Siah-1 and Skp-1 . The latter two are components of the ubiquitin ligase that regulates beta-catenin degradation. The beta-catenin gene is an oncogene participating in tumorigenesis in many different cancers. Overexpression of CacyBP/SIP, in part through its effect on the expression of beta-catenin, inhibits the proliferation, tumorigenicity, and invasion of gastric cancer cells . CacyBP/SIP is abundant in neurons and neuroblastoma NB2a cells. An extensive re-organization of microtubules accompanies the differentiation of NB2a cells. CacyBP/SIP may contribute to NB2a cell differentiation through binding to and increasing the oligomerization of tubulin. CacyBP/SIP is also implicated in differentiation of erythroid cells, rat neonatal cardiomyocytes, in mouse endometrial events, and in thymocyte development .
Dynein axonemal assembly factor 4, CS domain (CS_DYX1C1)
Type: Domain

This entry represents the CS p23-like domain found in dyslexia susceptibility 1 (DYX1) candidate 1 (C1) protein, DYX1C1, also known as dynein axonemal assembly factor 4 (DNAAF4). The human gene encoding this protein is a positional candidate gene for developmental dyslexia (DD), it is located on 15q21.3 by the DYX1 DD susceptibility locus (15q15-21) . Independent association studies have reported conflicting results . However, association of short-term memory, which plays a role in DD, with a variant within the DYX1C1 gene has been reported . Mutations in DYX1C1 have been found in patients with primary ciliary dyskinesia . Most proteins belonging to this group contain a C-terminal tetratricopeptide repeat (TPR) protein binding region .
NudC domain-containing protein 1 (NUDCD1)
Type: Family

NudCD1, also known as CML66 or OVA66, belongs to the NudC family, whose members share a conserved p23 domain. It is the more distant and less characterised family member. NudCD1 is a tumour associated antigen highly expressed in human leukaemia, some solid tumours and tumour cell lines . Its expression in normal tissues is restricted to testis . Different NudCD1 isoforms have unique interacting partners, with the first isoform binding to a putative RNA helicase named DHX15 involved in mRNA splicing .
SNX13, RGS domain (SNX13_RGS)
Type: Domain

This entry represents the RGS domain of SNX13 (Sorting Nexin13). RGS domain is a small α-helical structure that acts as GAPs for Galpha subunits of heterotrimeric G-proteins, and thus plays critical roles in attenuating G-protein coupled receptor (GPCR) signaling . Nexin13 binds and promotes GTPase activity of the trimeric G-protein subunit Galphas, and attenuate Galphas-mediated signaling . Snx13-null mice were embryonic lethal around midgestation which supports an essential role for SNX13 in mouse development and regulation of endocytosis dynamics .
NudC family (NudC_fam)
Type: Family

This family includes NudC (nuclear distribution gene C), NudC-like (NudCL) , NudC-like 2/NudC domain-containing protein 2 (NudCL2/NUDCD2), NudC domain-containing protein 3, and NudC domain protein BOBBER from plants . All members of the NudC family share a conserved p23 domain, which possesses chaperone activity both in conjunction with and independently of heat shock protein 90 (Hsp90) . NudC proteins play multiple roles in cell cycle progression, cell migration, inflammatory response, platelet production, carcinogenesis .
SNX25, PX domain (SNX25_PX)
Type: Domain

This entry represents the PX domain of SNX25.

Sorting nexins (SNXs) or phox homology (PX) domain containing proteins are central regulators of cell trafficking and signalling . Some PX domain proteins, namely SNX13, SNX14, and SNX25, also possess a regulator of G protein-coupled receptor signaling (RGS) domain and two unique PX-associated domains. SNX25 is a regulator of transforming growth factor (TGF-) signaling, binding to and promoting the lysosomal trafficking and degradation of TGF-receptors . The SNX25 PX domain has sequence alterations and may not be able to coordinate phosphoinositide-binding .
CISK, PX domain (CISK_PX)
Type: Domain

Cytokine-independent survival kinase (CISK also called SGK3) is a serine/threonine-protein kinase involved in the regulation of a wide variety of ion channels, membrane transporters, cell growth, proliferation, survival and migration . It phosphorylates and inhibits the proapoptotic proteins, Bad and FKHRL1 . CISK/SGK3 also regulates many transporters, ion channels, and receptors . It plays a critical role in hair follicle morphogenesis and hair cycling . N-terminal to a catalytic kinase domain, CISK contains a PX domain which binds highly phosphorylated PIs, directs membrane localization, and regulates the enzyme's activity .

This entry represents the PX domain of CISK.
HCLS1-binding protein 3, PX domain (HS1BP3_PX)
Type: Domain

Hematopoietic lineage cell-specific protein-1 (HS1) binding protein 3 (HS1BP3) associates with HS1 proteins through their SH3 domains, suggesting a role in mediating signaling. It has been reported that HS1BP3 might affect the IL-2 signaling pathway in hematopoietic lineage cells . Mutations in HS1BP3 may also be associated with familial Parkinson disease and essential tremor .

This entry represents the PX domain of HS1BP3. In general, the PX domain interacts with PIs and plays a role in targeting proteins to PI-enriched membranes .
NudC domain-containing protein 2, p23 domain (p23_NUDCD2)
Type: Domain

NudC-like 2/NudC domain-containing protein 2 (NudCL2/NUDCD2) regulates the LIS1/dynein pathway by stabilizing LIS1 with Hsp90 chaperone. LIS1 is a key regulator of cytoplasmic dynein, and is critical for cell proliferation, survival, and neuronal migration . Like other members of the NudC family, NUDCD2 has a conserved p23 domain, which possesses chaperone activity both in conjunction with and independently of Hsp90 . This entry represents the p23 domain of NUDCD2.
MONaKA, PX domain (MONaKA_PX)
Type: Domain

MONaKA (Modulator of Na,K-ATPase), also known as PXK, binds the plasma membrane ion transporter, Na,K-ATPase, and modulates its enzymatic and ion pump activities. It modulates brain Na,K-ATPase and may be involved in regulating electrical excitability and synaptic transmission . MONaKA contains an N-terminal PX domain and a C-terminal kinase domain that lacks several residues necessary for intrinsic catalytic activity . This entry represents the PX domain of MONaKA.

In general, the PX domain interacts with PIs and plays a role in targeting proteins to PI-enriched membranes .
Nischarin, PX domain (Nischarin_PX)
Type: Domain

Nischarin, also known as Imidazoline Receptor Antisera-Selected (IRAS), contains an N-terminal PX domain, leucine rich repeats, and a predicted coiled coil domain. The PX domain of IRAS binds to phosphatidylinositol-3-phosphate in membranes. Together with the coiled coil domain, it is essential for the localization of IRAS to endosomes . IRAS has been shown to interact with integrin and inhibit cell migration . Its interaction with alpha5 integrin causes a redistribution of the receptor from the cell surface to endosomal structures, suggesting that IRAS may function as a sorting nexin (SNX) which regulates the endosomal trafficking of integrin .

This entry represents the PX domain of nischarin/IRAS.
NudC domain-containing protein 3, p23 domain (p23_NUDCD3)
Type: Domain

NudC domain-containing protein 3 (NUDCD3) has not been characterised. It is a member of the NudC family. All members of the NudC family share a conserved p23 domain, which possesses chaperone activity both in conjunction with and independently of heat shock protein 90 (Hsp90) . NudC proteins play multiple roles in cell cycle progression, cell migration, inflammatory response, platelet production, carcinogenesis .
Vps17, PX domain (Vps17_PX)
Type: Domain

Vps17 belongs to the sorting nexin family, which contains a conserved PX domain . Vps17 is a component of the membrane-associated retromer complex (consists of Vps29, Vps26, Vps35, Vps5 and Vps17), which is essential in endosome-to-Golgi retrograde transport. It forms a retromer subcomplex with Vps5 that may assemble onto the membrane to promote vesicle formation .

Similar to Vps5 and SNX1, Vps17 harbours a Bin/Amphiphysin/Rvs (BAR) domain, which detects membrane curvature, C-terminal to the PX domain. The PX-BAR structural unit helps determine specific membrane localization. This entry represents the PX domain of Vps17 .
Cytochrome b5 reductase 4, p23 domain (p23_NCB5OR)
Type: Domain

NAD(P)H cytochrome b5 oxidoreductase (NCB5OR) is widely expressed in human organs and tissues and is localized in the ER (endoplasmic reticulum) . It appears to play a critical role in maintaining viable pancreatic beta cells . Mice homozygous for a targeted knockout (KO) of the gene encoding NCB5OR develop an early-onset nonautoimmune diabetes phenotype with a non-inflammatory beta-cell deficiency. The role of NCB5OR in beta cells may be in maintaining or regulating their redox status . The gene encoding NCB5OR has been considered as a positional candidate for type II diabetes and other diabetes subtypes related to B-cell dysfunction; however, variation in its coding region does not appear not to be a major contributor to the pathogenesis of these diseases .

This entry represents the CS p23-like domain found in NCB5OR. In addition to a p23-like domain NCB5OR contains an N-terminal cytochrome b5 domain and a C-terminal cytochrome b5 oxidoreductase domain .
SNX19, PX domain (SNX19_PX)
Type: Domain

Sorting nexins (SNXs) or phox homology (PX) domain-containing proteins are central regulators of cell trafficking and signalling . SNX19, like SNX13, SNX14, and SNX25, possesses two unique PX-associated domains, but lacks the G protein-coupled receptor signaling (RGS) domain present in the others . It plays a critical role in cartilage formation (chondrogenesis) and may be a protective factor against the progression of cartilage degradation in osteoarthritis . SNX19 is related to several diseases, including thyroid tumors and coronary heart disease .

This entry represents the PX domain of SNX19.
SNX16, PX domain (SNX16_PX)
Type: Domain

SNX16 contains a central PX domain followed by a coiled-coil region. SNX16 is localized in early and recycling endosomes through the binding of its PX domain to phosphatidylinositol-3-phosphate (PI3P). It plays a role in epidermal growth factor (EGF) signaling by regulating EGF receptor membrane trafficking .
Microspherule protein 1 (MCRS1)
Type: Family

Microspherule protein 1 (MCRS1 or MSP58) is an RNA-binding protein that interacts with Daxx transcriptional regulator, relieving its repressor activity. Overexpression of MCRS1 leads to translocation of Daxx to the enlarged nucleoli in COS-1 or 293 cells . It also interacts with fragile X messenger ribonucleoprotein 1 (FMRP), which represses specific mRNAs being transported as silent ribonucleoparticles from the cell body of a neuron to the distant synapse. MCRS1 binds to the G-quadruplex structures of the mRNA . MCRS1 is a component of the NSL complex , the MLL1/MLL complex , and is a putative regulatory component in the chromatin remodeling INO80 complex . The isoform MCRS2 is a cell-cycle-dependent protein which accumulates in the early S phase, and interacts with the telomerase-inhibitory protein LPTS/PinX1 .
Small heat shock protein IbpA/IbpB, ACD domain (ACD_IbpA/B)
Type: Domain

This is the alpha-crystallin domain (ACD) found in Escherichia coli inclusion body-associated proteins IbpA and IbpB, and similar proteins. This domain is also found in class A small heat shock proteins from Bradyrhizobium, which consists of proteins that show similarity to E. coli IbpA and IbpB .

IbpA and IbpB are 16kDa small heat shock proteins (sHsps). sHsps are molecular chaperones that suppress protein aggregation and protect against cell stress, and are generally active as large oligomers consisting of multiple subunits. They all contain a conserved alpha-crystallin domain flanked by variable N- and C-terminal tails . IbpA and IbpB are produced during high-level production of various heterologous proteins, specifically human prorenin, renin and bovine insulin-like growth factor 2 (bIGF-2), and are strongly associated with inclusion bodies containing these heterologous proteins . IbpA and IbpB work as an integrated system to stabilize thermally aggregated proteins in a disaggregation competent state . The chaperone activity of IbpB is also significantly elevated as the temperature increases from normal to heat shock. The high temperature results in the disassociation of 2-3-MDa IbpB oligomers into smaller approximately 600kDa structures. This elevated activity seen under heat shock conditions is retained for an extended period of time after the temperature is returned to normal . IbpA also forms multimers .
SpoVT-AbrB domain superfamily (SpoVT-AbrB_sf)
Type: Homologous_superfamily

The SpoVT-AbrB domain is a DNA-binding domain found in a large protein superfamily , which includes:

Bacterial antibiotic resistance protein B (AbrB), a transition-state regulator.

Bacterial SpoVT, a late sporulation factor that modulates forespore-specific sigma G-dependent transcription.

Bacterial PrlF, an antitoxin component of a toxin-antitoxin (TA) module.

Bacterial transcription factors (antitoxins) of plasmid maintenance systems (VapB, MvpT, VppA ,VagC, PemI, MazE, ChpS).

Bacterial transcriptional regulator MraZ, involved in the expression of the division and cell wall (dcw) cluster. It contains two copies of the SpoVT-AbrB domain.

Sulfolobus solfataricus repressor-like proteins SSo7c3 and SSo7c4.

The SpoVT-AbrB domain contains four β strands and one α helix and can be described as a pair of β hairpins linked by the α helix .
SNX29, PX domain (SNX29_PX)
Type: Domain

SNX29 contains an N-terminal RUN domain and a C-terminal PX domain. This entry represents the PX domain. In addition to protein-lipid interaction, the PX domain may also be involved in protein-protein interaction . The RUN domain is found in GTPases in the Rap and Rab families and may play a role in Ras-like signaling pathways .
Ypt35, PX domain (Ypt35_PX)
Type: Domain

The PX domain of Ypt35 binds to phosphatidylinositol 3-phosphate (PI3P). It also serves as a protein interaction domain, binding to the Yip1 protein family members, which localize to the ER and Golgi. Ypt35 is mainly associated with endosomes and together with Yip1p proteins, may be involved in a specific function in the endocytic pathway . Ypt35 recruits the lipid transfer protein VPS13 to endosomal and vacuolar membranes .
SNX2, PX domain (SNX2_PX)
Type: Domain

Sorting nexin-2 (SNX2) belongs to the sorting nexin family, which contains a conserved PX (phox homology) domain that is responsible for binding to specific phosphoinositides . SNX1 and SNX2 are orthologues of yeast Vps5, which is a component of retromer complex that is essential in endosome-to-Golgi retrograde transport .

This entry represents the PX domain of SNX2.
UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase 110kDa subunit (OGT)
Type: Family

The UDP-N-acetylglucosamine--peptide N-acetylglucosaminyltransferase (OGT;

) is a heterotrimer of one 78kDa subunit and two 110kDa subunits. OGT catalyzes the transfer of a single N-acetylglucosamine from UDP-GlcNAc to a serine or threonine residue in a protein. Substrate proteins include histone H2B, AKT1, EZH2, PFKL, KMT2E/MLL5, MAPT/TAU and HCFC1. The consequences of this form of glycosylation are diverse, including insulin resistance in muscle and adipocyte cells (brought about by inhibiting the 'Thr-308' phosphorylation of AKT1) ; regulation of glycolysis by inhibiting PFKL activity ; in the cell cycle O-glycosylation stabilizes ARNTL/BMAL1 and CLOCK, preventing their ubiquitination and subsequent degradation ; glycosylation of HCFC1 and interaction with TET proteins promotes binding of the SET1/COMPASS methyltransferase SETD1A to chromatin ; and H2B GlcNAcylation is a histone modification that facilitates H2BK120 monoubiquitination . It is a component of several complexes, including MLL5-L, NSL and THAP1/THAP3-HCFC1-OGT .

This entry represents the 110kDa subunit which has thirteen tetratricopeptide (TPR) repeats that are required for substrate binding and oligomerization .

The NSL complex is involved in acetylation of nucleosomal histone H4 on several lysine residues and therefore may be involved in the regulation of transcription. The complex is composed of at least MOF/KAT8, KANSL1, KANSL2, KANSL3, MCRS1, PHF20, OGT1/OGT, WDR5 and HCFC1 .