SII-SWORD/CoKE huggingface dataset:
Plasmodium RESA, N-terminal (PRESA_N)
Type: Domain

This entry represents the N-terminal domain of RESA (ring-infected erythrocyte surface antigen) from Plasmodium falciparum, the apicomplexan parasite that causes the most severe form of malaria in humans.

The short, four-helical domain first identified in the Plasmodium export proteins PHISTa and PHISTc has been identified in the P. falciparum-specific RESA-type (Ring-infected erythrocyte surface antigen) proteins in association with the DnaJ domain. Overall, at least 67 proteins have been detected in P. falciparum with complete copies of the PRESAN domain. No versions of this domain were detected in other apicomplexan genera, suggesting that the domain was 'invented' after the divergence of the lineage leading to the genus Plasmodium undergoing a dramatic proliferation only in P. falciparum. The structure of this domain has been solved. It contains a short initial helix (alpha1) followed by an antiparallel bundle of 3 long helices (alpha2-alpha4) .
Chaperone lipoprotein, PulS/OutS-like (Chap_lipoprot_PulS/OutS-like)
Type: Family

This family comprises lipoproteins from gamma proteobacterial species: pullulanase secretion protein PulS protein of Klebsiella pneumoniae (

), the lipoprotein OutS protein of Erwinia chrysanthemi (

) and the functionally uncharacterised type II secretion protein EtpO (

) from Escherichia coli O157:H7. PulS and OutS have been shown to interact with and facilitate insertion of secretins into the outer membrane, suggesting a chaperone-like, or piloting function for members of this family. These proteins consist of 4 α helices arranged into a slightly elongated, C-shaped helical bundle. Within PulS, the helices form a binding groove which interact with a disordered region on another protein, PulD, to form a PulS-PulD complex. PulD then oligomerises into a dodecameric outer membrane complex in the formation of a type II secretion system .

In addition to the PulS/OutS proteins this entry also includes other functionally uncharacterised proteins, such as YacC from Escherischia coli (

).
CRISPR-associated protein, Cmr3 (CRISPR-assoc_protein_Cmr3)
Type: Family

The CRISPR-Cas system is a prokaryotic defence mechanism against foreign genetic elements. The key elements of this defence system are the Cas proteins and the CRISPR RNA.

This entry represents a highly divergent family of Cas proteins, found in at least ten different archaeal and bacterial species, including TM1793 from Thermotoga maritima.
CRISPR-associated protein, CXXC-CXXC domain (CRISPR-assoc_CXXC-CXXC_dom)
Type: Domain

The CRISPR-Cas system is a prokaryotic defence mechanism against foreign genetic elements. The key elements of this defence system are the Cas proteins and the CRISPR RNA.

This entry represents a conserved domain of about 65 amino acids found in otherwise highly divergent proteins encoded in CRISPR-associated regions. This domain features two CXXC motifs.
Exosortase (Exosortase)
Type: Family

Proteins in this family are mostly designated exosortase, analogous to the sortase in cell wall sorting mediated by LPXTG domains in Gram-positive bacteria. Members of this family are integral membrane proteins with eight predicted transmembrane helices in common. The best characterised protein in this entry is EpsH of Methylobacillus sp. 12S, where it is part of a locus associated with biosynthesis of the exopolysaccharide methanolan .
Sister chromatid cohesion protein Dcc1 (Dcc1)
Type: Family

Sister chromatid cohesion protein Dcc1 is a component of the RFC-like complex Ctf18-RFC. This complex is required for the efficient establishment of chromosome cohesion during S-phase and may load or unload Pol30/PCNA. During a clamp loading circle, the RFC:clamp complex binds to DNA and the recognition of the double-stranded/single-stranded junction stimulates ATP hydrolysis by RFC. The complex presumably provides bipartite ATP sites in which one subunit supplies a catalytic site for hydrolysis of ATP bound to the neighbouring subunit. Dissociation of RFC from the clamp leaves the clamp encircling DNA .
Folate-sensitive fragile site protein Fra10Ac1 (Folate-sensitive_fs_Fra10Ac1)
Type: Family

This entry represents the full-length proteins in which, in higher eukaryotes, the nested domain EDSLL lies. Fra10Ac1 is a highly conserved nuclear protein of unknown function that is highly expressed in brain tissue .
Macoilin (Macoilin)
Type: Family

Macoilin has several highly conserved predicted transmembrane domains towards the N terminus and the coiled-coil regions at the C terminus. It is a conserved nervous system-specific ER membrane protein that regulates neuronal functions .
Cortactin-binding protein-2, N-terminal (Cortactin-binding_p2_N)
Type: Domain

This entry represents a N-terminal domain found in cortactin-binding protein 2 and in filamin A interacting protein 1 (Filip1).

In addition to being a positional candidate for autism, cortactin-binding protein 2 is expressed at highest levels in the brain in humans. Towards the C-terminal end of this protein are a series of proline-rich regions which are likely to be the points of interaction with the SH3 domain of cortactin. The human protein has six associated ankyrin repeat domains (

) towards the C terminus of the protein which act as protein-protein interaction domains .
MICOS complex subunit MIC60 (MIC60)
Type: Family

MICOS complex subunit MIC60 (also known as Mitofilin) is a component of the MICOS complex which controls mitochondrial cristae morphology, maintenance of junctions, inner membrane architecture, and formation of contact sites to the outer membrane . Mitofilin is enriched in the narrow space between the inner boundary and the outer membranes, where it forms a homotypic interaction and assembles into a large multimeric protein complex . The first 78 amino acids contain a typical amino-terminal-cleavable mitochondrial presequence (residues 1-43) rich in positive-charged and hydroxylated residues and a membrane anchor domain (residues 47-66). In addition, it has three centrally located coiled coil domains (residues 200-240, 280-310 and 400-420) .
Splicing factor Cactin, C-terminal (Cactin_C)
Type: Domain

This entry represents the C-terminal β-sandwich domain of the splicing factor cactin , which is necessary for the association of cactin with the IkappaB protein cactus, as one of the intracellular members of the Rel complex. The Rel (NF-kappaB) pathway is conserved in invertebrates and vertebrates. In mammals, it controls the activities of the immune and inflammatory response genes as well as viral genes, and is critical for cell growth and survival . In Drosophila, the Rel pathway functions in the innate cellular and humoral immune response, in muscle development and in the establishment of dorsal-ventral polarity in the early embryo . Members of this entry play a role in pre-mRNA splicing by facilitating excision of a subset of introns .

Most members of the family also have the conserved mid region of cactin (

) further upstream.
Polycomb protein, VEFS-Box (Polycomb_protein_VEFS-Box)
Type: Domain

The VEFS-Box is found in the the C-terminal region of the VRN2, EMF2, FIS2, and Su(z)12 polycomb proteins. This domain is characterised by an acidic cluster and a tryptophan/methionine-rich sequence, the acidic-W/M domain . In some proteins the VEFS-Box is associated with a zinc-finger domain located roughly 100 residues towards the N terminus. These proteins are part of the polycomb cluster of proteins which control HOX gene transcription as it functions in heterochromatin-mediated repression .
Transcription factor IIIC subunit 5, HTH domain (TF_IIIC_su-5_HTH)
Type: Domain

Transcription factor IIIC (TFIIIC) is a multisubunit DNA binding factor that serves as a dynamic platform for assembly of pre-initiation complexes on class III genes. This entry represents subunit Tfc1/Sfc1 (also known as the tau 95 subunit) which holds a key position in TFIIIC, exerting both upstream and downstream influence on the TFIIIC-DNA complex by rendering the complex more stable . Once bound to tDNA-intragenic promoter elements, TFIIIC directs the assembly of TFIIIB on the DNA, which in turn recruits the RNA polymerase III (pol III) and activates multiple rounds of transcription.

This entry represents the HTH domain of transcription factor IIIC subunit 5.
Nck-associated protein 1 (Nck-associated_protein-1)
Type: Family

Nck-associated protein 1 is part of lamellipodial complex that controls Rac-dependent actin remodeling . It associates preferentially with the first SH3 domain of Nck and is a component of the WAVE2 complex composed of ABI1, CYFIP1/SRA1, NCKAP1/NAP1 and WASF2/WAVE2. It is also a component of the WAVE1 complex composed of ABI2, CYFIP2, C3orf10/HSPC300, NCKAP1 and WASF1/WAVE1. CYFIP2 binds to activated RAC1 which causes the complex to dissociate, releasing activated WASF1. The complex can also be activated by NCK1. Expression of this protein was found to be markedly reduced in patients with Alzheimer's disease .
De-etiolated protein 1, Det1 (De-etiolated_protein_1_Det1)
Type: Family

This entry represents Det1 family proteins . Det1 (de-etiolated-1) is an essential negative regulator of plant light responses, and it is a component of the Arabidopsis CDD complex containing DDB1 and COP10 ubiquitin E2 variant. Mammalian Det1 forms stable DDD-E2 complexes, consisting of DDB1, DDA1 (DET1, DDB1 Associated 1), is a member of the UBE2E group of canonical ubiquitin conjugating enzymes and modulates Cul4A function .
Leucine-rich repeat flightless-interacting protein 1/2 (LRRFIP1/2)
Type: Family

Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1) is a transcriptional repressor which preferentially binds to the GC-rich consensus sequence (5'-AGCCCCCGGCG-3') and may regulate expression of TNF, EGFR and PDGFA . It may control smooth muscle cell proliferation following artery injury through PDGFA repression and may also bind double-stranded RNA. It interacts with the leucine-rich repeat domain of human flightless-I (FliI) protein .

Leucine-rich repeat flightless-interacting protein 2 (LRRFIP2) may function as activator of the canonical Wnt signaling pathway, in association with DVL3, upstream of CTNNB1/beta-catenin . It positively regulates Toll-like receptor (TLR) signalling in response to agonist probably by competing with the negative FLII regulator for MYD88-binding .
Mini-chromosome maintenance complex-binding protein (MCM_complex-bd)
Type: Family

This entry represents a family of proteins which are approximately 600 residues in length and contain alternating regions of conservation and low complexity. They are associated components of the mini-chromosome maintenance (MCM) complex that acts as a regulator of DNA replication. They bind to the MCM complex during late S phase and promotes the disassembly of the MCM complex from chromatin, thereby acting as a key regulator of pre-replication complex (pre-RC) unloading from replicated DNA. Can dissociate the MCM complex without addition of ATP; probably acts by destabilising interactions of each individual subunits of the MCM complex. Required for sister chromatid cohesion .
Protein of unknown function DUF2045 (DUF2045)
Type: Family

This entry is the conserved 250 residues of proteins of approximately 450 amino acids. It contains several highly conserved motifs including a CVxLxxxD motif. The function is unknown.
Dymeclin (Dymeclin)
Type: Family

Dymeclin (Dyggve-Melchior-Clausen syndrome protein) contains a large number of leucine and isoleucine residues and a total of 17 repeated dileucine motifs. It is characteristically about 700 residues long and present in plants and animals. Human dymeclin is necessary for correct organisation of Golgi apparatus and is involved in bone development . Mutations in the dymeclin gene cause Dyggve-Melchior-Clausen syndrome (DMC, MIM 223800), an autosomal-recessive disorder characterised by the association of spondylo-epi-metaphyseal dysplasia and mental retardation .
Membralin (Membralin)
Type: Family

Membralin is evolutionarily highly conserved, though it appears to represent a unique protein family. The protein appears to contain several transmembrane regions. In humans it is expressed in certain cancers, particularly ovarian cancers . Membralin-like gene homologues have been identified in plants including grape, cotton and tomato .
Mediator complex, subunit Med10 (Mediator_Med10)
Type: Family

The Mediator complex is a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. The Mediator complex, having a compact conformation in its free form, is recruited to promoters by direct interactions with regulatory proteins and serves for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. On recruitment the Mediator complex unfolds to an extended conformation and partially surrounds RNA polymerase II, specifically interacting with the unphosphorylated form of the C-terminal domain (CTD) of RNA polymerase II. The Mediator complex dissociates from the RNA polymerase II holoenzyme and stays at the promoter when transcriptional elongation begins.

The Mediator complex is composed of at least 31 subunits: MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11.

Med10 is one of the protein subunits of the Mediator complex, tethered to Med14 (Rgr1) protein. Med10 specifically mediates basal-level HIS4 transcription via Gcn4. In addition, there is a putative requirement for Med10 in Bas2-mediated transcription .
Suppressor of white apricot, N-terminal domain (SWAP_N_domain)
Type: Domain

This entry represents the conserved N-terminal region of SWAP (suppressor-of-white-apricot protein) splice factor proteins. This region contains two highly conserved motifs, viz: DRY and EERY, which appear to be the sites for alternative splicing of exons 2 and 3 of the SWAP mRNA . These proteins are thus thought to be involved in auto-regulation of pre-mRNA splicing.
Nuclear protein DGCR14/ESS-2 (Nuclear_protein_DGCR14_ESS-2)
Type: Family

This entry represents a family of proteins known variously as DiGeorge syndrome critical region 14 (DGCR14), DiGeorge syndrome protein I (DGSI), ES2 and ESS-2. In yeast the homologue is known as stress response protein Bis1.
Proteins in this family consist of approximately 500 residues with alternating regions of low complexity and conservation where the domain similarities are strong. They contain two predicted coiled-coil regions. ESS-2 has been shown to be involved in pre-mRNA splicing . Similarly DGCR14 has been shown to be a noncore component of the spliceosome C complex .
Alpha/beta hydrolase domain-containing protein 18 (ABHD18)
Type: Family

This entry represents alpha/beta hydrolase domain-containing protein 18 (ABHD18). Its function is not clear.
Vesicle transport protein, Use1 (Vesicle_transport_protein_Use1)
Type: Family

This entry represents a family of proteins, approximately 300 residues in length, involved in vesicle transport. They have a single C-terminal transmembrane domain and a SNARE [soluble NSF (N-ethylmaleimide-sensitive fusion protein) attachment protein receptor] domain of approximately 60 residues. The SNARE domains are essential for membrane fusion and are conserved from yeasts to humans. Use1 is one of the three protein subunits that make up the SNARE complex and it is specifically required for Golgi-endoplasmic reticulum retrograde transport .
Proteasome assembly chaperone 2 (Proteasome_assmbl_chaperone_2)
Type: Family

This PAC2 (Proteasome assembly chaperone) family of proteins is found in bacteria, archaea and eukaryotes. Proteins in this family are typically between 247 and 307 amino acids in length. Its C-terminal segment containing the potential proteasome-activating HbYX motif. These proteins function as a chaperone for the 26S proteasome, which is about 2000 kilodaltons (kDa) in molecular mass and contains one 20S core particle structure and two 19S regulatory caps. The 26S proteasome mediates ubiquitin-dependent proteolysis in eukaryotic cells. A number of studies including very recent ones have revealed that assembly of its 20S catalytic core particle is an ordered process that involves several conserved proteasome assembly chaperones (PACs). Two heterodimeric chaperones, PAC1-PAC2 and PAC3-PAC4, promote the assembly of rings composed of seven alpha subunits .
Protein of unknown function DUF2046 (DUF2046)
Type: Family

This is the conserved N-terminal 350 residues of a family of proteins of unknown function possibly containing a coiled-coil domain.
DDRGK domain containing protein (DDRGK_dom-contain)
Type: Family

This is a family of proteins that contain a highly conserved DDRGK motif. In humans, DDRGK domain-containing protein 1 is a substrate adapter for ufmylation, the covalent attachment of the ubiquitin-like modifier UFM1 to substrate proteins, which plays a key role in reticulophagy (also called ER-phagy) . It is also involved in cartilage development through SOX9, inhibiting the ubiquitin-mediated proteasomal degradation of this transcriptional regulator .
Arb2-like domain (Arb2-like_domain)
Type: Domain

This entry represents the C-terminal non-catalytic domain of Clr3 (Cryptic loci regulator 3, also known as histone deacetylase clr3) (

) from S. pombe and its orthologue HDA1 from S. cerevisiae. Structure analysis reveals that this domain is related to Arb2 domain from S. pombe (not included in this entry), which has clear homology to α/β-hydrolases but it lacks the catalytic triad of these enzymes. Functional studies show that the Arb2-like domain of members in this entry is necessary for centromeric heterochromatin silencing suggesting a model where the Arb2 domain, through residues N562 and Y563, acts as an anchor that connects the HDAC activity of Clr3 to the SHREC complex. SHREC (Snf2/Hdac Repressive) complex in fission yeast drives transcriptional gene silencing in heterochromatin . Studies in HDA1 described that two Arb2-like domains form a compact homo-dimer via the arm elements, and assemble as an inverse 'V' shape and that the domain possesses histone binding ability .
CLEC16A/TT9, N-terminal (CLEC16A/TT9_N)
Type: Domain

CLEC16A (C-Type Lectin Domain Containing 16A) has an inhibitory role in autophagy, probably by activating the mTOR pathway . It also has a role in beta-cells as a regulator of mitophagy .

GFS9/TT9 (TRANSPARENT TESTA 9) is a protein from Arabidopsis required for vacuolar development through membrane fusion at vacuoles. It contributes to intracellular membrane trafficking and flavonoid accumulation .

This entry represents a domain found at the N terminus of CLEC16A and GFS9/TT9.
Ataxin-10 domain (Ataxin-10_domain)
Type: Domain

This is the conserved C-terminal 100 residues of Ataxin-10. Ataxin-10 belongs to the family of armadillo repeat proteins and in solution it tends to form homotrimeric complexes, which associate via a tip-to-tip association in a horseshoe-shaped contact with the concave sides of the molecules facing each other. This domain may represent the homo-association site since that is located near the C terminus of Ataxin-10. The protein does not contain a signal sequence for secretion or any subcellular compartment confirming its cytoplasmic localisation, specifically to the olivocerebellar region .
CCDC93, coiled-coil domain (CCDC93_CC)
Type: Domain

This entry represents the coiled-coil domain found in CCDC93.

Human CCDC93 is part of the COMMD/CCDC22/CCDC93 (CCC) complex that interacts with the multisubunit WASH complex, which is required for endosomal deposition of F-actin and cargo trafficking in conjunction with the retromer . The CCC complex controls Notch activation by modulating its intracellular trafficking .
Exocyst complex component Sec3, coiled-coil (Sec3_CC)
Type: Domain

This entry represents the C-terminal domain of Sec3 (also known as ExoC1), a component of the exocyst complex (composed of Exoc1, Exoc2, Exoc3, Exoc4, Exoc5, Exoc6, Exoc7 and Exoc8) which mediates the tethering of post-Golgi secretory vesicles to the plasma membrane and promotes the assembly of the SNARE complex for membrane fusion. The exocyst is also involved in other cell processes such as cell polarisation, primary ciliogenesis, cytokinesis, and tumorigenesis and metastasis . This complex has an elongated shape consisting of packed long rods, a structure that is shared among the Complex Associated with Tethering Containing Helical Rods (CATCHRs) proteins from related complexes such as Conserved Oligomeric Golgi complex (COG) and Golgi-Associated Retrograde Protein complex (GARP) . Subunits of these complexes, apart of helical bundles, they usually have a coiled-coil (CC) region at the N-terminal. Sec3 is described as a membrane-anchoring component which serves as a spatial landmark in the plasma membrane for incoming secretory vesicles. Sec3 binds to the C-terminal cytoplasmic domain of GLYT1 (glycine transporter protein 1). Sec3 is recruited to the sites of polarised membrane growth through its interaction with Rho1p, a small GTP-binding protein .
Fanconi anemia complex, subunit FancL, WD-repeat containing domain (FancL_WD-rpt_cont_dom)
Type: Domain

This entry represents a region of approximately 100 residues containing three WD repeats and six cysteine residues- possibly as three cysteine-bridges associated with FancL.

FancL is the ubiquitin ligase protein that mediates ubiquitination of FancD2, a key step in the DNA damage pathway . FancL belongs to the multisubunit Fanconi anemia (FA) complex, which is composed of subunits: FancA, FancB, FancC, FancE, FancF, FancG, FancL/PHF9 and FancM. The WD repeats are required for interaction of FancL with other subunits of the FA complex .

In humans defects in FancL are a cause of Fanconi anemia (FA) , and the FA complex is not found in FA patients. FA is a genetically heterogeneous, autosomal recessive disorder characterised by progressive pancytopenia, a diverse assortment of congenital malformations, and a predisposition to the development of malignancies. At the cellular level it is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage), and defective DNA repair.
THO complex, subunit 5 (THO_Thoc5)
Type: Family

This entry represents Thoc5 which is one of the subunits of the THO complex, which additionally contains: HPR1, Thoc2, Thoc6 and Thoc7. The evolutionarily conserved multisubunit THO complex, which is recruited to actively transcribed genes is required for the efficient expression of genes that have internal tandem repeats. It is suggested that the THO complex functions to rectify aberrant structures that arise during transcription and is required for cell proliferation and for proper export of heat-shock mRNAs under heat stress .

This entry also identifies the crucial 144 N-terminal residues of the FMIP protein, which is essential for the binding of the protein to the cytoplasmic domain of activated Fms-molecules in M-CSF induced haematopoietic differentiation of macrophages. The C terminus contains a putative nuclear localisation sequence and a leucine zipper which suggest further, as yet unknown, nuclear functions. The level of FMIP expression might form a threshold that determines whether cells differentiate into macrophages or into granulocytes .
Transmembrane protein 147 (TMEM147)
Type: Family

TMEM147 is a component of the Nicalin-NOMO protein complex, which catalyzes the proteolytic cleavage of the transmembrane domain of various proteins including the beta-amyloid precursor protein and Notch . It is a component of the multi-pass translocon (MPT) complex that mediates insertion of multi-pass membrane proteins into the lipid bilayer of membranes .