SII-SWORD/CoKE huggingface dataset:
Nkap domain containing 1 (Nkap_D1)
Type: Family

NF-kappa-B-activating protein (Nkap) is a highly conserved protein which functions as a transcriptional repressor on Notch target genes. It is required for T cell development and acquisition of functional competency . It also plays a role in RNA splicing and processing involved in transcriptional repression, maintenance and survival of adult haematopoietic stem cells.

Nkap is divided into three domains, an N-terminal domain containing RS repeats, a highly basic middle domain and the C-terminal domain (

) .

This entry represents uncharacterised proteins that contain Nkap domain 1.
IQ domain-containing protein K (IQCK)
Type: Family

The function of IQ domain-containing protein K is not clear.
Esterase FrsA (FrsA)
Type: Family

Fermentation-respiration switch protein (FrsA) is an esterase containing the α/β-hydrolase fold. . In Vibrio vulnificus, FrsA catalyses the hydrolysis of p-nitrophenyl alkanoate esters to produce p-nitrophenol and pNPA (C2) .
Protein BRANCHLESS TRICHOME-like (BLT-like)
Type: Family

This entry includes protein BRANCHLESS TRICHOME (BLT, At1g64690) and At5g41620 from Arabidopsis. BLT is a regulator of trichome branching. It interacts with STICHEL, another key regulator of trichome branching . The function of At5g41620 is not clear.
NusG-like (NusG-like)
Type: Family

Bacterial transcription antitermination protein, NusG, is a component of the transcription complex and interacts with the termination factor Rho and RNA polymerase . NusG is a bacterial transcriptional elongation factor involved in transcription termination and antitermination .

RfaH is a transcription antitermination protein that enhances distal genes transcription elongation in a specialized subset of operons that encode extracytoplasmic components . It is most closely related to the transcriptional termination/antitermination protein NusG and contains the KOW motif . This protein appears to be limited to the proteobacteria.

RfaH is recruited into a multi-component RNA polymerase complex by the ops element, which is a short conserved DNA sequence located downstream of the main promoter of these operons. Once bound, RfaH suppresses pausing and inhibits Rho-dependent and intrinsic termination at a subset of sites. Termination signals are bypassed, which allows complete synthesis of long RNA chains. Enhances expression of several operons involved in synthesis of lipopolysaccharides, exopolysaccharides, hemolysin, and sex factor. Also negatively controls expression and surface presentation of AG43 and possibly another AG43-independent factor that mediates cell-cell interactions and biofilm formation .

This entry includes NusG and its paralogue RfaH .
Membrane-bound lytic murein transglycosylase B-like (MltB-like)
Type: Family

Bacterial lytic transglycosylases degrade murein via cleavage of the beta-1,4-glycosidic bond between N-acetylmuramic acid and N-acetylglucosamine, with the concomitant formation of a 1,6-anhydrobond in the muramic acid residue. There are both soluble (Slt enzymes) and membrane-bound (Mlt enzymes) lytic transglycosylases that differ in size, sequence, activity, specificity and location. The multi-domain structure of the 70 Kd soluble lytic transglycosylase Slt70 is known . Slt70 has 3 distinct domains, each rich in α helices: an N-terminal superhelical U-shaped domain, a superhelical linker domain (L-domain,

), and a C-terminal catalytic domain (

). Both the U-and L-domain share a similar superhelical structure. These two domains are connected, and together form a closed ring with a large central hole; the catalytic domain is packed on top of, and interacts with, this ring. The catalytic domain has a lysosome-like fold.

This entry includes membrane-bound lytic murein transglycosylase B (mltB, also known as Slt35) from E. coli. MltB is a murein-degrading enzyme that catalyses the cleavage of the glycosidic bonds between N-acetylmuramic acid and N-acetylglucosamine residues in peptidoglycan . This entry also includes uncharacterised proteins that contain the SLT domain 2.
Lipoprotein YscJ/Flagellar M-ring protein (YscJ/FliF)
Type: Family

This entry includes flagellar M-ring protein (FliF) and Yop proteins translocation lipoprotein J (YscJ). They share a low level of similarity, presumably due to evolution of the type III secretion system from the flagellar biosynthetic pathway.

FliF is the major protein
of the M-ring in bacterial flagellar basal body .
The basal body consists of four rings (L,P,S and M) surrounding the
flagellar rod, which is believed to transmit motor rotation to the filament
.
The M ring is integral to the inner membrane of the cell, and may be
connected to the rod via the S (supramembrane) ring, which lies just distal
to it. The L and P rings reside in the outer membrane and periplasmic space,
respectively.
FliF lacks a signal peptide and is predicted to have considerable
α-helical structure, including an N-terminal sequence that is likely
to be membrane-spanning . Overall, however, FliF has a relatively
hydrophilic sequence, with a high charge density, especially towards its
C terminus .

The type III secretion system is of great interest as it is used to transport virulence factors from the pathogen directly into the host cell and is only triggered when the bacterium comes into close contact with the host. The protein subunits of the system are very similar to those of bacterial flagellar biosynthesis . However, while the latter forms a ring structure to allow secretion of flagellin and is an integral part of the flagellum itself, type III subunits in the outer membrane translocate secreted proteins through a channel-like structure.

One of the outer membrane protein subunit families, termed "K" here for nomenclature purposes, aids in the structural assembly of the invasion complex . It is also described as a lipoprotein. These lipoproteins include the PrgK and SsaJ from Salmonella, MxiJ from Shigella, YscJ from Yersinia, and from the plant enteropathogens NolT (Rhizobium) and HrcJ (Erwinia).
High-affinity branched-chain amino acid transport system permease protein LivM-like (LivM-like)
Type: Family

This entry includes transmembrane subunit (TM) of Escherichia coli LivM, Pseudomonas aeruginosa BraE, and related proteins. LivM is one of two TMs of the E. coli LIV-1/LS transporter, a Periplasmic Binding Protein (PBP)-dependent ATP-Binding Cassette (ABC) transporter involved in the uptake of branched-chain amino acids (AAs). These types of transporters generally bind type 1 PBPs. PBP-dependent ABC transporters consist of a PBP, two TMs, and two cytoplasmic ABCs, and are mainly involved in importing solutes from the environment. The solute is captured by the PBP, which delivers it to a gated translocation pathway formed by the two TMs. The two ABCs bind and hydrolyze ATP and drive the transport reaction .
ABC transporter membrane protein permease protein ArtM/GltK/GlnP/TcyL/YhdX-like (ArtM/GltK/GlnP/TcyL/YhdX-like)
Type: Family

This entry represents the membrane component of a group of amino acid transport systems, including arginine ABC transporter permease protein ArtM , glutamine transport system permease protein GlnP, glutamate/aspartate import permease protein GltJ/GltK , L-cystine transport system permease protein TcyL , and uncharacterised proteins such as YhdX and YhdY.

ABC transporters are minimally constituted of two conserved regions: a highly conserved ATP binding cassette (ABC) and a less conserved transmembrane domain (TMD). These regions can be found on the same protein (mostly in eukaryotes and bacterial exporters) or on two different ones (mostly bacterial importers) . In importers, the TMD displays a distinctive signature, the EAA motif, a 20 amino acid conserved sequence located about 100 residues from the C terminus. The motif is hydrophilic and has been found to reside in a cytoplasmic loop located between the penultimate and the antepenultimate transmembrane segment in all proteins with a known topology . It appears to play an important role in ensuring the correct assembly of the prokaryotic ABC transport complex and constituting an interaction site with the so-called helical domain of the ABC module .
Junction-associated protein Tjap1/BEGAIN (Tjap1/BEGAIN)
Type: Family

This entry includes brain-enriched guanylate kinase-associated protein (BEGAIN) and tight junction-associated protein 1 (Tjap1).

Brain-enriched guanylate kinase-associated protein (BEGAIN) interacts with postsynaptic density protein PSD-95/SAP90 and may be involved in the organization of the components of synaptic junctions .

Tight junction-associated protein 1 (also known as Pilt) is a family of eukaryotic tight junction-proteins . Pilt is a component of TJs (Tight junctions) rather than AJs (Adhesin junctions). TJs function as a barrier preventing solutes and water from passing freely through the paracellular pathway. TJs consist of transmembrane proteins (claudin, occludin, and JAM) plus many peripheral membrane proteins and cell polarity molecules. Pilt is a novel peripheral membrane protein which is incorporated into TJs after TJ strands are formed, thereby the name Pilt for 'protein incorporated later into TJs'. Pilt binds to the guanylate-kinase region of hDlg/SAP97 (disk large homologue/synapse-associated protein 97) .
PGC-1 and ERR-induced regulator in muscle protein 1 (Perm1)
Type: Family

Peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1 alpha (PGC-1 alpha) and PGC-1 beta are two members of the PGC-1 family and important regulators of mitochondrial metabolism. They are expressed at high levels in heart and skeletal muscle and can induce mitochondrial biogenesis and oxidative capacity. PGC-1 alpha and PGC-1 beta regulate DNA-binding transcription factors, such as estrogen-related receptors (ERRS). ERR beta and ERR gamma are orphan nuclear receptors that act both downstream and parallel to PGC-1 coactivators to control the expression of a broad set of genes important for energy homeostasis.

PGC-1/ERR-induced regulator in muscle 1 (Perm1) is a downstream effector of PGC-1 and ERRs , regulating muscle-specific pathways important for energy metabolism and contractile function. Perm1 does not function as a classical coactivator, but has been suggested to act by regulating signalling pathways in a tissue-selective manner to enable PGC-1/ERRs to induce specific sets of genes. It has been shown that Perm1 is also required for the efficient expression of the glucose transporter Glut4, thus, it may affect glucose uptake, and of the mitochondrial creatine kinase Ckmt2 .
FYN-binding protein 1/2-like (FYB1/2-like)
Type: Family

This entry includes FYN-binding protein 1 and 2 (FYB1, FYB2) and PML-RARA-regulated adapter molecule 1 (PRAM1). Most of the proteins in this entry contain an altered SH3 domain fold.

FYN-binding protein 1 (FYB1), also known as ADAP or SLAP, is an adapter protein in beta 1 integrin signalling and T lymphocyte migration . It has been found to co-localise with F-actin in membrane ruffles, adhesion plaques/podosomes and phagocytic cups . In activated T cells, Fyb/SLAP associates with Ena/VASP family proteins and may link T cell signalling to the actin cytoskeleton remodelling . FYB1 also interacts with mammalian actin binding protein 1 (mAbp1) that affects F-actin dynamics .

FYN-binding protein 2 (FYB2, also known as ARAP) is a adaptor protein required for TCR signaling and integrin-mediated adhesion .

PRAM1 is an intracellular adaptor molecule that is upregulated during the induced granulocytic differentiation of promyelocytic leukemic cells and during normal human myelopoiesis .
Protein TESPA1-like (TESPA1-like)
Type: Family

This entry includes TESPA1, ITPRID1 (also known CCDC129) and ITPRID2 (also known as SSFA2).

SSFA2, also known as Ki-ras-induced actin-interacting protein (KRAP), interacts with inositol 1,4,5-trisphosphate receptor (IP3R, also known as ITPR) . SSFA2 was first localised as a membrane-bound form with extracellular regions suggesting it might be involved in the regulation of filamentous actin and signals from the outside of the cells . It has now been shown to be critical for the proper subcellular localisation and function of IP3R. Inositol 1,4,5-trisphosphate receptor functions as the Ca2+ release channel on specialised endoplasmic reticulum membranes, so the subcellular localisation of IP3R is crucial for its proper function .

TESPA1 (Thymocyte-expressed positive selection-associated protein 1) is required for the development and maturation of T-cells, its function being essential for the late stages of thymocyte development. It plays a role in T-cell antigen receptor (TCR)-mediated activation of the ERK and NFAT signaling pathways, possibly by serving as a scaffolding protein that promotes the assembly of the LAT signalosome in thymocytes . TESPA1 shows sequence homology to SSFA2 and physically associates with IP3R in T and B lymphocytes .

The function of ITPRID1 is not clear.
TMEPAI family (TMEPAI/LRAD4)
Type: Family

This entry includes TMEPAI and LRAD4 (C18ORF1). They contain two PY motifs and one Smad-interacting motif (SIM) domain. They are both known to inhibit transforming growth factor-beta (TGF-beta) signalling via its competition for binding of receptor-regulated Smad with Smad anchor for receptor activation .

TMEPAI was originally identified as a highly androgen-induced gene by serial analysis of gene expression in androgen-treated LNCaP prostate cancer (CaP) cells
. It is a type I transmembrane protein that has an N-erminal extracellular and a single transmembrane domains. TMEPAI contains two PY motifs that can be targetedby the WW domain. It is involved in a negative feedback loop to control the duration and intensity of TGF-beta signaling, which regulates growth suppression, apoptosis induction, extracellular matrix production, and differentiation . It is also involved in androgen receptor signalling, phosphatase and tensin homologue deleted on chromosome 10 signalling, and formation of autophagosomes in addition to degradation of TbetaRI (TGF-beta type I receptor) through lysosomes . TMEPAI has been linked to cancers .

Low-density lipoprotein receptor class A domain-containing protein 4 (LRAD4) is a negative regulator of TGF-beta signaling. TMEPAI might help LRAD4 to inhibit TGF-beta signaling in a coordinated manner when cells are stimulated with high levels of TGF-beta . LRAD4 is elevated in hepatic cancers and tumour tissues .
Neurabin-like family (Neurabin-like)
Type: Family

This entry includes the SAM domains-containing proteins such as Neurabin-1/Neurabin-2 and SAMD14 (Sterile alpha motif domain-containing protein 14). Most of them are multidomain proteins and in addition to SAM domain they contain other protein-binding domains such as PDZ and actin-binding domains. Members of this family participate in signal transduction. Neurabin-1 is involved in the regulation of Ca(2+) signaling intensity in alpha-adrenergic receptors . It forms a functional pair of opposing regulators with neurabin-2. Neurabins are expressed almost exclusively in neuronal cells. They are known to interact with protein phosphatase 1 and inhibit its activity . They also can bind actin filaments .

The function of SAMD14 is not clear.
CCDC120/INAVA (CCDC120/INAVA)
Type: Family

This entry includes INAVA and CCDC120.

Coil-coiled domain-containing protein 120 (CCDC120) was first identified as a centrosome protein . Later, it was found to interact with cytohesin-2 to regulate vesicular trafficking and neurite growth . It is part of the centriole subdistal appendages (SDAs) that anchor microtubules in interphase cells .

Innate immunity activator protein (INAVA) is required for optimal MAPK and NF-kappaB activation, cytokine secretion, and intracellular bacterial clearance. Genetic variations in INAVA are associated with an increased risk of inflammatory bowel disease . Homologues are known from chordates.
Pleckstrin homology domain-containing family O member 1/2 (PKHO1/2)
Type: Family

This entry includes PKHO1and PKHO2. They both contain a single PH domain.

Pleckstrin homology domain-containing family O member 1 (PKHO1), also known as CKIP-1, plays a role in the regulation of the actin cytoskeleton through its interactions with actin capping protein (CP) . CKIP-1 can interact with Akt, down-regulates the PI3K/Akt signaling and suppresses tumour growth . CKIP-1 can also interacts and recruits protein kinase CK2 to the plasma membrane . Moreover, it may play a role in phosphatidylinositol 3-kinase (PI3-K)-regulated muscle differentiation .

The function of PKHO2 is not clear.
PHD finger protein 20-like (PHF20-like)
Type: Family

This entry includes PHF20 and PHF20L1 proteins.

PHD finger protein 20 (PHF20) binds dimethyl lysine residues via its Tudor domain . It is a component of the MLL1, MOF histone acetyltransferase and NSL protein complexes .

PHF20L1 binds to monomethylated lysine 142 on DNA (cytosine-5) methyltransferase 1 (DNMT1). It has been shown to antagonize DNMT1 proteasomal degradation .
Coiled-coil domain-containing protein 89-like (CCDC89-like)
Type: Family

This entry represents coiled-coil domain-containing protein 89 (CCDC89) and tumor suppressor candidate gene 1 protein (TUSC1).

Hairy-related transcription factor (HRT), also known as Bc8, is a transcriptional repressor and has been identified as effector of the Notch signalling pathway. HRT proteins contain a conserved amino acid domain, denoted either as the Orange domain or as helix III/IV located at the C-terminal after the bHLH domain that is characteristic of all HES/E(spl)-related proteins, also referred to as bHLH-Orange (bHLH-O) proteins.

Coiled-coil domain-containing protein 89 (CCDC89), also known as Bc8 orange-interacting protein (BOIP), interacts with the orange domain of HRT1. BOIP binds to the orange domain of HRT1/Hey1 and is predominantly expressed at a specific stage in spermatogenesis. BOIP may play a role in the maturation process from haploid round spermatids to spermatozoa, possibly as a tissue-specific regulator of HRT1/Hey1 activity .

Tumor suppressor candidate 1 (TUSC1) has been identified as a potential tumor suppressor in human cancers and could be a novel therapeutic target for glioblastoma .
Myocardin-like (Myocardin-like)
Type: Family

Myocardin (Myocd) is a coactivator of serum response factor (SRF), which is a key regulator of the expression of smooth and cardiac muscle genes. Myocardin plays a crucial role in cardiogenesis and differentiation of the smooth muscle cell lineage (myogenesis) . It contains the RPEL repeats, which are monomeric globular actin (G-actin) binding elements. However, it binds to actin-related protein 5 (Arp5) instead of conventional actin, resulting in a significant suppression of Myocd activity .

Myocardin-related transcription factor A (MRTFA, also known MKL1) is an actin-binding transcriptional coactivator whose localisation is regulated by its interaction with monomeric actin (G-actin) . Its N-terminal domain consists of three tandem RPEL repeats, where the G-actin binding site and the nuclear localisation signal can be found . In the nucleus MAL associates with SRF (serum response factor) and activates transcription of SRF:MAL-dependent target genes . It has been implicated in human diseases, such as acute megakaryocytic leukemia and other cancers .

MKL2 binds to and activates SRF (serum response factor) similar to myocardin and MKL1 .

This entry includes Myocardin and MKL/myocardin-like protein 1/2 (MKL1/2).
Plant bZIP transcription factors (BZIP46-like)
Type: Family

This family is composed of a group of plant bZIP transcription factors with similarity to OsbZIP46, which regulates abscisic acid (ABA) signalling-mediated drought tolerance in rice . Plant bZIPs are involved in developmental and physiological processes in response to stimuli/stresses such as light, hormones, and temperature changes. bZIP factors act in networks of homo and heterodimers in the regulation of a diverse set of cellular processes .

This entry also includes ABI5 from Arabidopsis. ABI5 is a transcription factor that participates in ABA-regulated gene expression during seed development and subsequent vegetative stage by acting as the major mediator of ABA repression of growth . It is also involved in the sugar signalling response in plants .
Slm1, PH domain (Slm1_PH)
Type: Domain

Slm1 is a component of the target of rapamycin complex 2 (TORC2) signaling pathway. It plays a role in the regulation of actin organization and is a target of sphingolipid signaling during the heat shock response . Slm1 contains a single PH domain that binds PtdIns(4,5)P2, PtdIns(4)P, and dihydrosphingosine 1-phosphate (DHS-1P). Slm1 possesses two binding sites for anionic lipids. The non-canonical binding site of the PH domain of Slm1 is used for ligand binding, and it is proposed that beta-spectrin, Tiam1 and ArhGAP9 also have this type of phosphoinositide binding site .

PH domains have diverse functions, but in general are involved in targeting proteins to the appropriate cellular location or in the interaction with a binding partner . They share little sequence conservation, but all have a common fold, which is electrostatically polarised. Less than 10% of PH domains bind phosphoinositide phosphates (PIPs) with high affinity and specificity . PH domains are distinguished from other PIP-binding domains by their specific high-affinity binding to PIPs with two vicinal phosphate groups: PtdIns(3,4)P2, PtdIns(4,5)P2 or PtdIns(3,4,5)P3 which results in targeting some PH domain proteins to the plasma membrane . A few display strong specificity in lipid binding. Any specificity is usually determined by loop regions or insertions in the N terminus of the domain, which are not conserved across all PH domains. PH domains are found in cellular signalling proteins such as serine/threonine kinase, tyrosine kinases, regulators of G-proteins, endocytotic GTPases, adaptors, as well as cytoskeletal associated molecules and in lipid associated enzymes .
NPH3/RPT2-like family (NPH3/RPT2-like)
Type: Family

The NRL (for NPH3/RPT2-Like) family is formed by signaling molecules specific
to higher plants. Several regions of sequence and predicted structural
conservation define members of the NRL family, with three domains being most
notable: an N-terminal BTB domain, a centrally located NPH3
domain, and a C-terminal coiled coil domain. The function of the NPH3 domain
is not yet known .

Root phototropism protein 3 (RPT3), also known as nonphototropic hypocotyl 3 (NPH3), and root phototropism 2 (RPT2) represent the founding members of a novel plant-specific family . Three domains define the members of this family: an N-terminal BTB (broad complex, tramtrack, bric a brac) domain (

), a centrally located NPH3 domain (

), and a C-terminal coiled-coil domain.

NPH3 assembles with CUL3 to form a E3 complex that ubiquitinates phototropin 1 (phot1) and modulates phototropic responsiveness . NPH3 is necessary for root and hypocotyl phototropisms, but not for the regulation of stomata opening or chloroplast relocation . Coleoptile phototropism protein 1 (CPT1) is a rice orthologue of Arabidopsis NPH3 also required for phototropism . This entry also includes DOT3 (AT5G10250) that is involved in shoot and primary root growth; DOT3 mutants produce an aberrant parallel venation pattern in juvenile leaves . Also included is SR1IP1 that acts as a positive regulator of plant defense by removing the defense suppressor CAMTA3/SR1 by acting as a substrate adapter that recruits CAMTA3/SR1 for ubiquitination and degradation during pathogen infection .