SII-SWORD/CoKE huggingface dataset:
GINS complex, subunit Psf1 (GINS_Psf1)
Type: Family

DNA replication in eukaryotes results from a highly coordinated interaction between proteins, often as part of protein complexes, and the DNA template. One of the key early steps leading to DNA replication is formation of the prereplication complex, or pre-RC. The pre-RC is formed by the sequential binding of the origin recognition complex (ORC), Cdc6 and Cdt1 proteins, and the MCM complex. Activation of the pre-RC into the initiation complex (IC) is achieved via the action of S-phase kinases, eventually leading to the loading of the replication machinery.

Recently, a novel replication complex, GINS (for Go, Ichi, Nii, and San; five, one, two, and three in Japanese), has been identified . The precise function of GINS is not known. However, genetic and two-hybrid interactions indicate that it mediates the loading of the enzymatic replication machinery at a step after the action of the S-phase kinases . Furthermore, GINS may be a part of the replication machinery itself, since it is found associated with replicating DNA . Electron microscopy of GINS shows that it forms a ring-like structure , reminiscent of the structure of PCNA , the DNA polymerase delta replication clamp.This observation, coupled with the observed interactions for GINS, indicates that the complex may represent the replication clamp for DNA polymerase epsilon .

This family of proteins represents the PSF1 component (for partner of SLD five) of the GINS complex.
Mitochondrial import inner membrane translocase subunit Tim16 (Tim16)
Type: Family

This entry represents the mitochondrial import inner membrane translocase subunit Tim16 (also known as Pam16).
Nucleolar complex protein 2 (Noc2)
Type: Family

In Saccharomyces cerevisiae, Nucleolar complex protein 2 (Noc2) forms a nucleolar complex with Mak21 that binds to 90S and 66S pre-ribosomes. It also forms a nuclear complex with Noc3 that binds to 66S pre-ribosomes . Both complexes mediate intranuclear transport of ribosomal precursors .

In humans, Noc2 (also known as NIR) acts as an inhibitor of histone acetyltransferase activity; prevents acetylation of all core histones by the EP300/p300 histone acetyltransferase at p53/TP53-regulated target promoters in a histone deacetylases (HDAC)-independent manner. It also acts as a transcription corepressor of p53/TP53- and TP63-mediated transactivation of the p21/CDKN1A promoter. It is involved in the regulation of p53/TP53-dependent apoptosis .

Nucleolar complex-associated protein 2 (Noc2) from Arabidopsis thaliana appears to be involved in pre-ribosome export from the nucleus to the cytoplasm . Also from A.thaliana, Protein REBELOTE influences floral meristem (FM) determinacy in an AGAMOUS and SUPERMAN-dependent manner, thus contributing to the floral developmental homeostasis .
TMEM33/Pom33 family (TMEM33/Pom33)
Type: Family

This entry represents the TMEM33/Pom33 family. Budding yeast Pom33 is a transmembrane nucleoporin that contributes to proper distribution and/or efficient assembly of nuclear pores . Proteins in this entry also include Tts1 from fission yeasts , Kr-h2 (krueppel homologue 2) from flies and TMEM33 from vertebrates .

Tts1 is required for the correct positioning of the cellular division plane by delimiting the actomyosin ring assembly at the cell equator .

Kr-h2 is a member of the dosage-dependent hierarchy effective upon white gene expression .

TMEM33 regulates the tubular structure of endoplasmic reticulum by suppressing the membrane-shaping activity of reticulons . It was also demonstrated that TMEM33 regulates the unfolded protein response which is activated during endoplasmic reticulum stress .
PHF5-like (PHF5)
Type: Family

Phf5 is a member of a novel murine multigene family that is highly conserved during evolution and belongs to the superfamily of PHD-finger proteins. At least one example, from Mus musculus (mouse), may act as a chromatin-associated protein . The Schizosaccharomyces pombe (fission yeast) ini1 gene is essential, required for splicing . It is localised in the nucleus, but not detected in the nucleolus and can be complemented by human ini1 . The proteins of this family contain five CXXC motifs.
RnfH protein (RnfH)
Type: Family

The RnfH family is a member of the ubiquitin superfamily. Members of the RnfH family strongly co-occur in two distinct gene neighbourhood contexts. In one it is associated with a START domain protein, a membrane protein SmpA and the transfer mRNA binding protein SmpB. This association suggests a possible role in the SmpB-tmRNA-based tagging and degradation system of bacteria, which is interesting given that other members of the ubiquitin system are analogously involved in protein-tagging and degradation across eukaryotes and various prokaryotes. The second context in which the RnfH genes are present is in a membrane associated complex involved in transporting electrons for various reductive reactions such as nitrogen fixation .
TMEM14 family (TMEM14)
Type: Family

This entry includes a group of transmembrane proteins, including protein FATTY ACID EXPORT 1 (FAX1) from Arabidopsis and TMEM14 from animals. FAX1 mediates the export of free fatty acid from the plastids and is required for biogenesis of the outer pollen cell wall, in particular for the assembly of exine and pollen coat and for the release of ketone wax components . The Zebrafish TMEM14 is required for normal heme biosynthesis . The structure of human TMEM14 showed a three helical bundle .
Uncharacterised protein family UPF0137 (UPF0137)
Type: Family

This family of proteins mainly found in Chlamydiae includes a number of plasmid-encoded virulence proteins, such as Virulence plasmid protein pGP6-D from Chlamydia trachomatis, which seems to be required for growth within mammalian cells .
PAT complex subunit Asterix (ASTER)
Type: Family

This family represents Asterix proteins which are a component of the PAT complex, an endoplasmic reticulum (ER)-resident membrane multiprotein complex that facilitates multi-pass membrane proteins insertion into membranes . The PAT complex, formed by CCDC47 and Asterix proteins, acts as an intramembrane chaperone by directly interacting with nascent transmembrane domains (TMDs), releasing its substrates upon correct folding, and is needed for optimal biogenesis of multi-pass membrane proteins . WDR83OS/Asterix, (

) is the substrate-interacting subunit of the PAT complex, whereas CCDC47 is required to maintain the stability of WDR83OS/Asterix . WDR83OS/Asterix associates with the first transmembrane domain (TMD1) of the nascent chain, independently of the N-glycosylation of the chain and irrespective of the amino acid sequence and transmembrane topology of TMD1 . The PAT complex favors the binding to TMDs with exposed hydrophilic amino acids within the lipid bilayer and provides a membrane-embedded partially hydrophilic environment in which TMD1 binds . This entry also includes the ER membrane uncharacterised protein from Schizosaccharomyces pombe C18B11.08c.
Erg28 (Erg28)
Type: Family

This is a family of integral membrane proteins, which may contain four transmembrane helices. Members of this family are thought to be involved in sterol C-4 demethylation. In Saccharomyces cerevisiae (Baker's yeast) they may tether Erg26p (sterol dehydrogenase/decarboxylase) and Erg27p (3-ketoreductase) to the endoplasmic reticulum or may facilitate interaction between these proteins . The family contains a conserved arginine and histidine that may be functionally important.
Uncharacterised protein family UPF0146 (UPF0146)
Type: Family

This family consists of functionally uncharacterised proteins predominantly found in archaea, including

from Methanothermobacter thermautotrophicus, which shows an α/β structure.
Uncharacterised protein family UPF0147 (UPF0147)
Type: Family

This family represents a group of proteins predominantly found in archaea, including UPF0147 protein Ta0600 from Thermoplasma acidophilum

, which shows an all-α structure. Members of this entry are functionally uncharacterised.
Putative zinc- or iron-chelating domain containing protein (Puta_zinc/iron-chelating_dom)
Type: Family

This family of proteins contains 8 conserved cysteines. It has in the past been annotated as being one of the complex of proteins of the flagellar Fli complex. However this was due to a mis-annotation of the original Salmonella LT2 Genbank entry of 'fliB'. With all its conserved cysteines it is possibly a domain that chelates iron or zinc ions .
Protein with unknown function UPF0154 (UPF0154)
Type: Family

This entry includes a group of bacterial proteins that are functionally uncharacterised.
Uncharacterised protein family UPF0158 (UPF0158)
Type: Family

This is a small family of hypothetical bacterial proteins of unknown function.
Uncharacterised protein family UPF0164 (UPF0164)
Type: Family

This family of uncharacterised proteins were first identified in the proteome of Treponema pallidum where they are assumed to be secreted proteins because of the presence of putative signal peptides. Homologues are known from other spirochaetes, Elusimicrobia and other bacteria.
Uncharacterised protein family UPF0167 (UPF0167)
Type: Family

The proteins in this family are about 200 amino acids long and each contain 3 CXXC motifs.
Nitrogen permease regulator 3 (Npr3)
Type: Family

In budding yeasts, Npr3 forms a complex with NPR2. This complex heterodimer is responsible for inactivating TORC1, an evolutionarily conserved protein complex that controls cell size via nutritional input signals, specifically, in response to amino acid starvation . In fission yeast, Nitrogen permease regulator 3-like protein (part of GATOR complex) is dispensable for TORC1 regulation under amino acid starvation and thus, responds to nitrogen starvation .

In humans, Npr3 like protein, NPRL3, is part of the GATOR1 complex that functions as an inhibitor of the amino acid-sensing branch of the TORC1 pathway .
ER membrane protein complex subunit 8/9 (EMC8/9)
Type: Family

Saccharomyces cerevisiae ER membrane protein complex (EMC) comprises six subunits . Four and three additional subunits have been identified in mammals and Drosophila, respectively . EMC is required for protein folding in the endoplasmic reticulum (ER). It also facilitates lipid transfer from ER to mitochondria .

This family includes mammalian subunits EMC8 and EMC9, and Drosophila EMC8/9 homologue . EMC8 is also known as neighbour of COX4 (NOC4) .
Uncharacterised protein family UPF0175 (UPF0175)
Type: Family

This entry contains small proteins of unknown function.
Uncharacterised protein family UPF0179 (UPF0179)
Type: Family

The function of this family is unknown, however the proteins contain two cysteine clusters that may be iron sulphur redox centres.
Uncharacterised protein family UPF0180 (UPF0180)
Type: Family

The members of this family are small uncharacterised proteins.
Uncharacterised protein family UPF0181 (UPF0181)
Type: Family

This family contains small proteins of about 50 amino acids of unknown function. The family includes YoaH (

).
Uncharacterised protein family UPF0182 (UPF0182)
Type: Family

This family contains uncharacterised integral membrane proteins.
Phagosome assembly factor 1 (PHAF1)
Type: Family

PHAF1 and BCAS3 form a complex that affects the recruitment of several core autophagy proteins to the phagophore assembly site .
Bublin coiled-coil protein-like, eukaryota (BBLN_eukaryota)
Type: Family

This small family includes Bublin coiled-coil proteins (BBLNs) found in eukaryotes (also known UPF0184 proteins), including the human BBLN previously known as UPF0184 protein C9orf16 and other uncharacterised proteins. Their function is currently unknown.
Ubiquitin-fold modifier 1 (UFM1)
Type: Family

This entry represents Ufm1 (ubiquitin-fold modifier), which is a ubiquitin-like protein with structural similarities to ubiquitin . Ufm1 is one of a number of ubiquitin-like modifiers that conjugate to target proteins in cells through Uba5 (E1) and Ufc1 (E2). The Ufm1-system is conserved in metazoa and plants, suggesting it has a potential role in multicellular organisms . Human Ufm1 is synthesized as a precursor consisting of 85 amino-acid residues. Prior to activation by Uba5, the extra amino acids at the C-terminal region of Ufm1 are removed to expose Gly, which is necessary for conjugation to target molecule(s). C-terminal processing of Ufm1 requires two specific cysteine peptidases (

): UfSP1 and UfSP2; both peptidases are also able to release Ufm1 from Ufm1-conjugated cellular proteins. UfSP2 is present in most, if not all, of multi-cellular organisms including plant, nematode, fly, and mammal, whereas UfSP1 is not present in plants and nematodes .
Adenovirus DNA-binding, zinc-binding domain (Adenovirus_DNA-bd_zn-bd)
Type: Domain

The adenovirus early E2A DNA-binding protein (Ad DBP) is a multifunctional protein required, amongst other things, for DNA replication and transcription control. It binds to single- and double-stranded DNA, as well as to RNA, in a sequence-independent manner. This signature represents the zinc binding domain of the viral DNA- binding protein, which is active in DNA replication. The zinc atoms appear to be required for the stability of the protein fold rather than being involved in direct contacts with the DNA, the protein contains two zinc atoms in different, novel coordinations. Two copies of this domain are found at the C terminus of many members of the family .
Vacuolar protein sorting-associated protein 35 (Vps35)
Type: Family

This entry represents vacuolar protein sorting-associated protein 35 (Vps35) from eukaryotes.

Vps35 is a core component of the retromer complex which functions in the endosome-to-Golgi retrieval cargo transport pathway . Vps35 is part of the a cargo-selective complex trimer (CSC) of the retromer, which is composed of Vps26, Vps29 and Vps35 and is responsible for binding to and sorting protein cargo . Mutations in the Vps35 gene have been linked to Parkinson's disease . Structurally, VPS35 forms a horseshoe-shaped, right-handed, α-helical solenoid .
Factor of DNA methylation 1-5/IDN2 , domain XH (FDM1-5/IDN2_XH)
Type: Domain

The XH (rice gene X Homology) domain is found in a family of plant proteins including Oryza sativa (Rice)

and Arabidopsis FDM1-5/IDN2. These proteins usually contain an XS domain (

) that is also found in the PTGS protein SGS3. As the XS and XH domains are fused in most of these proteins, these two domains may interact. The XH domain is between 124 and 145 residues in length and contains a conserved glutamate residue that may be functionally important .

FDM1-5 and IDN2 are components of RNA-directed DNA methylation pathway (RdDM) .
XS domain (XS_domain)
Type: Domain

This XS (named after rice gene X and SGS3) domain is a single-stranded RNA-binding domain (RBD) and possesses a unique version of a RNA recognition motif (RRM) fold . It is conserved in a family of plant proteins including gene X and SGS3. Although its function is still unknown, the plant SGS3 proteins are thought to be involved in post-transcriptional gene silencing (PTGS) pathways . In addition, they contain a conserved aspartate residue that may be functionally important.
Zinc finger-XS domain (Znf-XS_domain)
Type: Domain

This domain is a putative nucleic acid binding zinc finger and is found at the N terminus of proteins that also contain an adjacent XS domain

and in some proteins a C-terminal XH domain

. Proteins containing this domain include protein SUPPRESSOR OF GENE SILENCING 3 (SGS3), which is required for post-transcriptional gene silencing and natural virus resistance .
CC chemokine receptor 10 (Chemokine_CCR10)
Type: Family

Chemokines (chemotactic cytokines) are a family of chemoattractant molecules. They attract leukocytes to areas of inflammation and lesions, and play a key role in leukocyte activation. Originally defined as host defense proteins, chemokines are now known to play a much broader biological role . They have a wide range of effects in many different cell types beyond the immune system, including, for example, various cells of the central nervous system , and endothelial cells, where they may act as either angiogenic or angiostatic factors .

The chemokine family is divided into four classes based on the number and spacing of their conserved cysteines: 2 Cys residues may be adjacent (the CC family); separated by an intervening residue (the CXC family); have only one of the first two Cys residues (C chemokines); or contain both cysteines, separated by three intervening residues (CX3C chemokines).

Chemokines exert their effects by binding to rhodopsin-like G protein-coupled receptors on the surface of cells. Following interaction with their specific chemokine ligands, chemokine receptors trigger a flux in intracellular calcium ions, which cause a cellular response, including the onset of chemotaxis. There are over fifty distinct chemokines and least 18 human chemokine receptors . Although the receptors bind only a single class of chemokines, they often bind several members of the same class with high affinity. Chemokine receptors are preferentially expressed on important functional subsets of dendritic cells, monocytes and lymphocytes, including Langerhans cells and T helper cells . Chemokines and their receptors can also be subclassified into homeostatic leukocyte homing molecules (CXCR4, CXCR5, CCR7, CCR9) versus inflammatory/inducible molecules (CXCR1, CXCR2, CXCR3, CCR1-6, CX3CR1).

CC chemokine receptors are a subfamily of the chemokine receptors that specifically bind and respond to cytokines of the CC chemokine family. There are currently ten members of the CC chemokine receptor subfamily, named CCR1 to 10. The receptors receptors are found in monocytes, lymphocytes, basophils and eosinophils.

This entry represents CC chemokine receptor 10 (CCR10), previously known as G protein-coupled receptor 2 (GPR2) . CCR10 is a receptor for CCL27 , and CCL28 . CCR10 is found in melanocytes , dermal fibroblasts, dermal micro-vascular endothelial cells and has also been detected in T-cells . It is involved in T cell-mediated skin inflammation, having been shown to recruit regulatory T cells to mucosal layers . The receptor may also play a role in directing metastasis .
Atypical chemokine receptor 4 (ACKR4)
Type: Family

Just like classical chemokine receptors, atypical chemokine receptors (ACKRs) are seven-transmembrane-helix (7TM) receptors that bind chemokines . However, they lack the canonical DRYLAIV motif necessary for GPCR coupling to G proteins and induction of classical signalling pathways. Instead, ACKRs internalise their chemokine ligands, which may subsequently affect chemokine availability. The ACKR family comprises five members: Duffy Antigen Receptor for Chemokines (DARC, ACKR1), D6 (ACKR2), CXCR7 (ACKR3), CCRL1 (ACKR4) and CCRL2 (ACKR5) .

Atypical chemokine receptor 4 (ACKR4/CCRL1/CCX-CKR) binds and scavenges the ligands of the chemokine receptors CCR7 and CCR9 (CCL19/CCL21 and CCL25, respectively) and targets them for subsequent lysosomal degradation . Apart from being a scavenger for chemokines, it may prevent CXCR3-induced chemotaxis by heteromerisation . ACKR4 appears to have a mayor role in normal thymus development and function .
Lysophosphatidic acid receptor EDG-7 (LPA_rcpt_EDG7)
Type: Family

G protein-coupled receptors (GPCRs) constitute a vast protein family that encompasses a wide range of functions, including various autocrine, paracrine and endocrine processes. They show considerable diversity at the sequence level, on the basis of which they can be separated into distinct groups . The term clan can be used to describe the GPCRs, as they embrace a group of families for which there are indications of evolutionary relationship, but between which there is no statistically significant similarity in sequence . The currently known clan members include rhodopsin-like GPCRs (Class A, GPCRA), secretin-like GPCRs (Class B, GPCRB), metabotropic glutamate receptor family (Class C, GPCRC), fungal mating pheromone receptors (Class D, GPCRD), cAMP receptors (Class E, GPCRE) and frizzled/smoothened (Class F, GPCRF) . GPCRs are major drug targets, and are consequently the subject of considerable research interest. It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice . Most GPCRs are identified on the basis of their DNA sequences, rather than the ligand they bind, those that are unmatched to known natural ligands are designated by as orphan GPCRs, or unclassified GPCRs .

The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices .

The G protein-coupled receptors EDG-2, EDG-4 and EDG-7 have now been identified as high affinity receptors for lysophosphatidic acid (LPA). EDG-7 is expressed at high levels in the testis, prostate, heart, pancreas and frontal cerebral cortex in humans and at lower levels in the intestine, lung and ovary. Binding of LPA to the receptor leads to increased cyclic AMP and calcium levels and activation of MAP kinases. It is believed that these effects are mediated by Gq and possibly Gi class proteins . EDG-7 does not appear to be able to couple to G1.