SII-SWORD/CoKE huggingface dataset:
5'-AMP-activated protein kinase catalytic subunit alpha-2, C-terminal (AMPKA2_C)
Type: Domain

AMPK, a serine/threonine protein kinase (STK), catalyzes the transfer of the gamma-phosphoryl group from ATP to S/T residues on protein substrates. It acts as a sensor for the energy status of the cell and is activated by cellular stresses that lead to ATP depletion such as hypoxia, heat shock, and glucose deprivation, among others. AMPK is a heterotrimer of three subunits: alpha, beta, and gamma . The alpha subunit is the catalytic subunit and it contains an N-terminal kinase domain, a putative autoinhibitory domain (AID) and a C-terminal region required for beta subunit binding. The beta scaffolding subunit mediates AMPK assembly by bridging alpha and gamma subunits. The C-terminal domain of the AMPK alpha 1 subunit interacts with the C-terminal region of the beta subunit to form a tight alpha-beta complex that is associated with the gamma subunit. The AMPK alpha subunit auto-inhibitory region interacts with the kinase domain; this inhibition is negated by the interaction with the AMPK gamma subunit .

AMPK has been implicated in a number of diseases related to energy metabolism including type 2 diabetes, obesity and cancer . AMPK is activated by rising AMP concentrations coupled with falling ATP concentrations. Activation of AMPK is also dependent on the phosphorylation of alpha subunit by upstream kinases such as LKB1 .

Vertebrates contain two isoforms of the alpha subunit, alpha1 and alpha2, which are encoded by different genes, PRKAA1 and PRKAA2, respectively, and show varying expression patterns. AMPKalpha2 shows cytoplasmic and nuclear localization, whereas AMPKalpha1 is localized only in the cytoplasm .
Zinc finger protein 800 (ZNF800)
Type: Family

This family includes Zinc finger protein 800 from human which contain C2H2-type zinc fingers. The function of ZNF800 is not clear.
Transcription elongation factor, mitochondrial (TEFM)
Type: Family

TEFM is a mitochondrial transcription elongation factor and an essential part of the mitochondrial transcription machinery . Homologues are found only in metazoa.
Protein inturned (INTU)
Type: Family

Protein inturned is a cilia and planar polarity effector, performing prominent ciliogenic functions during morphogenesis . It links NPHP4 to Daam1 to control the subapical actin network in multiciliated cells . Homologues are found only in metazoa.
Fetal and adult testis-expressed transcript protein (FATE1)
Type: Family

FATE1 is a member of the Miff protein family, whose members are involved in the control of mitochondrial and peroxisomal fission. It is localized in mitochondria associated ER membranes (MAM) and is implicated in the regulation of Ca2+ and drug-dependent apoptosis in cancer cells by modulating ER-mitochondria distance . Homologues are found only in chordates.
Serine/Threonine kinase LKB1, catalytic domain (LKB1_c)
Type: Domain

Serine/threonine kinases (STKs) catalyze the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. LKB1, also called STK11, was first identified as a tumour suppressor responsible for Peutz-Jeghers syndrome, a disorder that leads to an increased risk of spontaneous epithelial cancer. It serves as a master upstream kinase that activates AMP-activated protein kinase (AMPK) and most AMPK-like kinases. LKB1 and AMPK are part of an energy-sensing pathway that links cell energy to metabolism and cell growth . They play critical roles in the establishment and maintenance of cell polarity, cell proliferation, cytoskeletal organization, as well as T-cell metabolism, including T-cell development and function . Loss of LKB1 function in the liver results in hyperglycemia with increased gluconeogenic and lipogenic gene expression, indicating role as a mediator of glucose homeostasis . To be activated, LKB1 requires the adaptor proteins STe20-Related ADaptor (STRAD) and mouse protein 25 (MO25).
Malectin (MLEC)
Type: Family

Malectin is a membrane-anchored protein of the endoplasmic reticulum that recognises and binds Glc2-N-glycan. It carries a signal peptide from residues 1-26, a C-terminal transmembrane helix from residues 255-274, and a highly conserved central part of approximately 190 residues followed by an acidic, glutamate-rich region. Carbohydrate-binding is mediated by the four aromatic residues, Y67, Y89, Y116, and F117 and the aspartate at D186. NMR-based ligand-screening studies has shown binding of the protein to maltose and related oligosaccharides, on the basis of which the protein has been designated "malectin", and its endogenous ligand is found to be Glc2-high-mannose N-glycan .
PHAF1/Protein broad-minded (PHAF1/BROMI)
Type: Family

This entry includes protein broad-minded, which interacts with cell cycle-related kinase (CCRK) and together these proteins regulate ciliary membrane and axonemal growth ; and phagosome assembly factor 1 (PHAF1) and its homologues. PHAF1 and BCAS3 form a complex that affects the recruitment of several core autophagy proteins to the phagophore assembly site .
RNA-binding protein 18, RNA recognition motif (RBM18_RRM)
Type: Domain

This entry represents the RRM (RNA recognition motif) of RBM18, a putative RNA-binding protein containing a well-conserved RNA recognition motif (RRM), also termed RBD (RNA binding domain) or RNP (ribonucleoprotein domain). The biological role of RBM18 remains unclear .
Solute carrier family 25 member 46 (SLC25A46)
Type: Family

SLC25A46 is a modified solute transporter that has been recruited to the outer mitochondrial membrane and interacts with the inner membrane remodeling protein mitofilin (Fcj1) . It plays a role in mitochondrial dynamics and cristae maintenance . Mutations in the SLC25A46 gene cause optic atrophy spectrum disorder .
SAYSvFN domain-containing protein 1 (SAYSD1)
Type: Family

This entry represents the uncharacterised SAYSvFN domain-containing protein 1 and its homologues. The proteins contain a SAYSvFN domain.
Uncharacterized protein C19orf47-like (C19orf47-like)
Type: Family

The function of C19orf47 is not clear. Homologues are found only in metazoa.
Homeodomain-only protein (HOPX)
Type: Family

HOPX contains a homeobox-like domain but lacks certain conserved residues required for DNA binding. It is expressed in tumour cells and various normal tissues . It plays an essential role in the differentiation of various cells and could act as a tumour suppressor via the epigenetic regulation of SNAIL transcription .
ER membrane protein complex subunit 7 (EMC7)
Type: Family

ER membrane protein complex subunit 7 (EMC7) is a component of the endoplasmic reticulum membrane protein complex (EMC). This complex was first found to interact with the degradation of misfolded proteins by the ubiquitin- and proteasome-dependent process known as ER-associated degradation (ERAD) , thus suggesting a role in the biosynthesis of transmembrane proteins. More recently, it was shown that EMC acts as a conserved co- and post-translational insertase at the endoplasmic reticulum in an energy-independent manner . EMC7 has been misnamed C11orf3, but is more correctly named C15orf24 because the gene is actually on human chromosome 15.
E3 ubiquitin-protein ligase UBR1-like (UBR1-like)
Type: Family

This entry represents a group of E3 ubiquitin-protein ligases, including UBR1, UBR2 and UBR3. They are part of the N-end rule pathway . They recognize and bind to proteins bearing specific N-terminal residues, leading to their ubiquitination and subsequent degradation .

The UBR1 protein was shown to bind specifically to proteins bearing N-terminal residues that are destabilising according to the N-end rule, but not to otherwise identical proteins bearing stabilising N-terminal residues . UBR1 contains an N-terminal conserved region (the UBR-type zinc finger) which is also found in various proteins implicated in N-degron recognition .
CREB3 regulatory factor (CREBRF)
Type: Family

CREBRF, also known as LRF, recruits CREB3 (also known as Luman) into nuclear foci and represses CREB3-mediated activation of UPRE (unfolded protein response element)-containing promoters . CREB3 is implicated in herpes simplex virus-1 (HSV-1) latency/reactivation and the unfolded protein response (UPR) pathway . Homologues are found predominantly in metazoa.
Protein Abitram (Abitram)
Type: Family

This enty includes Abitram proteins. Abitram (also known as Simiate) functions in transcription regulation . Furthermore, it associates with both G- and F-Actin and affects actin polymerization and actin turnover, influencing filopodia dynamics and arborization of neurons .
Pre-mRNA-splicing factor Cwc2/Slt11 (Cwc2/Slt11)
Type: Family

This entry contains proteins involved in the first step of pre-mRNA splicing to remove introns. Splicing is performed by the spliceosome, which is a complex of snRNAs U1, U2, U4, U5, and U6 and proteins such as pre-mRNA-processing factor 19 (Prp19). The yeast protein Cwc2 contains motifs known to bind RNA, a zinc finger and an RNA recognition motif. Because mutations in the gene are lethal and lead to accumulation of pre-mRNA, and reduced levels of U1, U4, U5 and U6 snRNAs and U4/U6 snRNA complex levels, Cwc2 has been proposed to link the Prp19 complex to the spliceosome during pre-mRNA splicing . Because Cwc2 is at the spliceosome catalytic centre, it induces an active conformation of the spliceosome's catalytic RNA elements . Cwc2 is a component of the CWC complex . The human homologue, known as RBM22 , also translocates the protein SLU7 from the nucleus to the cytoplasm or vice versa in the case of the calcium-binding protein PDCD6 .

Also included in this entry is the pre-mRNA-splicing factor Slt11 (also known as Ecm2) .
Protein parting dancers (PTD)
Type: Family

This family of plant proteins includes Arabidopsis parting dancers (PTD), a protein that is required for chromosome segregation during meiosis . It is involved in type I crossover formation .
Chondroitin sulfate ABC lyase (Chondroitin_ABC_lyase)
Type: Family

Chondroitin sulfate ABC lyases (E.C. 4.2.2.4) are broad-specificity glycosaminoglycan-degrading enzymes. Their preferred substrates are chondroitin sulfate and dermatan sulfate, which are broken down to short oligosaccharides . Two distinct chondroitinase ABC lyases have been identified in Proteus vulgaris; chondroitinase ABC lyase I is an endoeliminase (endolyase) releasing tetrasaccharides and disaccharides, whereas chondroitinase ABC lyase II is an exoeliminase (exolyase) releasing only disaccharides . Chondroitinases have been employed in attempts to promote functional locomotor recovery following trauma to the central nervous system .
Mitochondrial import inner membrane translocase subunit TIM22 (TIM22)
Type: Family

The membrane-embedded multi-protein complexes of mitochondria mediate the transport of nuclear-encoded proteins across and into the outer or inner mitochondrial membranes . Two translocases of the inner mitochondrial membrane (TIM22 and TIM23 complexes) mediate protein transport at the inner membrane.

The TIM22 complex (a twin-pore carrier translocase) catalyses the insertion of multi-spanning proteins that have internal targeting signals into the inner membrane. The TIM22 complex mediates the membrane insertion of multi-spanning inner-membrane proteins that have internal targeting signals, and it uses the membrane potential as an external driving force . The Tim22 subunit of the mitochondrial import inner membrane translocase is included in this family. Tim22 forms a hydrophilic, high-conductance channel with distinct opening states and pore diameters, that is voltage-activated and specifically responds to an internal targeting signal .
Osteocalcin (Osteocalcin)
Type: Family

Bone gamma-carboxyglutamic acid protein (BGP), also known as osteocalcin, is a calcium-binding bone matrix protein that contains the vitamin-K-dependent amino acid, gamma-carboxyglutamic acid. It is a noncollagen proteins made in osteoblasts and odontoblasts and has been linked to bone formation. It may also act as a hormone to affect insulin sensitivity and energy expenditure; however, only the undercarboxylated form of osteocalcin is active .
Nonsense-mediated mRNA decay factor SMG9 (SMG9)
Type: Family

Nonsense-mediated mRNA decay (NMD) is a surveillance mechanism that detects and degrades mRNAs containing premature translation termination codons. Protein SMG9 is a component of the SMG1C protein kinase complex (along with SMG1 and SMG8) which is recruited to stalled ribosomes. SMG8 and SMG9 suppress SMG1 kinase activity in the isolated SMG1 complex .
Protein Lag2 (Lag2)
Type: Family

Lag2 from Caenorhabditis elegans is a putative intercellular signal for lin-12 and GLP-1 receptors . It is involved in the mediation of Notch signaling. This entry also includes Dsl-1 that works redundantly with Lag-2, Apx-1 and Osm-11 . Homologues are mainly found in nematodes from the order Rhabditida.
PDZ domain-containing protein 9 (PDZD9)
Type: Family

The function of PDZD9 is not clear. Homologues, each of which contains a PDZ domain, are found only in chordates.
Omega-hydroxyceramide transacylase PNPLA1 (PNPLA1)
Type: Family

Members of this family share a patatin domain, initially discovered in potato tubers, and are known as patatin-like phospholipase domain containing proteins (PNPLA). They serve critical roles in diverse aspects of lipid metabolism and signaling. Some PNPLA1 proteins do not have the lipase consensus sequence Gly-X-Ser-X-Gly which is essential for hydrolase activity. This entry includes PNPLA1 from Homo sapiens and Gallus gallus. It is expressed in various human tissues in low mRNA levels .

In humans PNPLA1 has a role in the formation of the epidermal lipid barrier; mutations in this gene are associated with the skin disorder known as ichthyosis . PNPLA1 acts as an omega-hydroxyceramide transacylase involved in the synthesis of omega-O-acylceramides (esterified omega-hydroxyacyl-sphingosine; EOS), which are extremely hydrophobic lipids involved in skin barrier formation . It catalyzes the last step of the synthesis of omega-O-acylceramides by transferring linoleic acid from triglycerides to an omega-hydroxyceramid .
Endosome/lysosome-associated apoptosis and autophagy regulator family member 1/2 (Elapor1/2)
Type: Family

This entry represents mammal endosome/lysosome-associated apoptosis and autophagy regulator family members 1/2 (Elapor1/2) and similar sequences predominantly found in vertebrates.

Human Elapor1, also known as EIG121 and KIAA1324, is a type I transmembrane protein induced by estrogen. It is associated with the endosome-lysosome compartments and may play an important role in autophagy and cell proliferation .

Mouse Elapor2 (Eig121l) functions as a regulator of the BMP signalling pathway and may be involved in epidermal differentiation .
Ribonucleases P/MRP protein subunit Pop1 (Pop1)
Type: Family

Pop1 is a component of ribonuclease P, a ribonucleoprotein enzyme that cleaves precursor tRNA transcripts to give mature 5' ends. It is also a component of RNase MRP .
Coiled-coil domain-containing protein 66 (CCD66)
Type: Family

CCDC66 localizes to the centrosome and the centriolar satellites . It interacts with CEP290 and functions in cilium formation and trafficking. It has also been shown to bind to microtubules in vitro and in vivo . Mutations of the CCD66 gene in dogs cause progressive retinal atrophy . Homologues are found only in metazoa.
Sterile alpha and TIR motif-containing protein 1 (SARM1)
Type: Family

SARM1 (sterile alpha and TIR motif-containing protein 1) is a TIR (Toll-interleukin 1 receptor) adaptor that downregulates Toll-like receptor signalling . It plays a role in innate immunity . It is also an essential mediator of axon degeneration know as Wallerian degeneration . A specific motif in its TIR domain is responsible for NAD+ loss and injury-induced SARM1 activation .
1-acylglycerol-3-phosphate O-acyltransferase PNPLA3 (Pat_PNPLA3)
Type: Family

This family represents PNPLA3 (patatin-like phospholipase domain-containing protein 3) from mammals, also known as ADPN (adiponutrin) or iPLA2-epsilon (calcium-independent phospholipase A2). PNPLA3 is a triacylglycerol lipase that mediates triacylglycerol hydrolysis in adipocytes and is an indicator of the nutritional state. Human adiponutrins are bound to the cell membrane of adipocytes and show transacylase, TG hydrolase, and PLA2 activity . In murine models, PNPLA3 was found to be involved in the hepatic metabolism of triglycerides and in the regulation of systemic glucose homeostasis .
Strawberry notch, AAA domain (SNO_AAA)
Type: Domain

This entry represents the AAA domain found in Strawberry notch protein.

Strawberry notch proteins carry DExD/H-box groups and helicase C-terminal domains. These proteins promote the expression of diverse targets, potentially through interactions with transcriptional activator or repressor complexes . Strawberry notch was first identified in Drosophila where functions downstream of Notch and regulates gene expression during development .
CTD phosphatase Fcp1 (Fcp1)
Type: Family

This entry represents Fcp1 and its homologues, including CTDP1 from humans and CPL1/2/3/4/5 from Arabidopsis. They are carboxy-terminal domain (CTD) phosphatases. CPL1 has been shown to interact with two NMD (nonsense-mediated decay) factors, eIF4AIII and UPF3, and is involved in the dephosphorylation of eIF4AIII . CPL4 functions as a pol II CTD phosphatase and has been shown to dephosphorylate both Ser2- and Ser5-PO(4) of CTD in vitro . Budding yeast Fcp1 has been shown to dephosphorylate RNA polymerase (RNAP) II subunit, and this interaction is modulated by the Pin1 protein .
Tetratricopeptide repeat protein 14 (TTC14)
Type: Family

The function of TTC14 is not clear. Homologues contain tetratricopeptide repeats and are found in eukaryotes.
Nopp140-like (Nopp140-like)
Type: Family

This entry includes mammalian NOLC1 (also known as Nopp140) and its orthologue dao-5 from C.elegans. They are nucleolar proteins that contain a central domain consisting of ten repeats of acidic serine clusters alternating with lysine-, alanine- and proline-rich basic stretches . Human NOLC1 interacts with casein kinase 2 (CK2), RNA polymerase I, p80 coilin , NAP57, and both major classes (box H/ACA and box C/D) of snoRNPs . It acts as a regulator of RNA polymerase I by connecting RNA polymerase I with enzymes responsible for ribosomal processing and modification .

Mutations of the Dao-5 gene alters rDNA transcription and increases germ cell apoptosis in C. elegans . It binds to RNA polymerase I and rDNA and is required for efficient RNA polymerase I-mediated rDNA transcription. It also plays a role in the modulation of nucleolus size .
Glycogen synthase kinase 3, catalytic domain (STKc_GSK3)
Type: Domain

Glycogen synthase kinase 3 (GSK3) is a mutifunctional kinase involved in many cellular processes including cell division, proliferation, differentiation, adhesion, and apoptosis. In plants, GSK3 plays a role in the response to osmotic stress . In Caenorhabditis elegans, it plays a role in regulating normal oocyte-to-embryo transition and response to oxidative stress . In Chlamydomonas reinhardtii, GSK3 regulates flagellar length and assembly .

Mammals have two isoforms of GSK3, GSK3alpha and GSK3beta, which show both distinct and redundant functions. The two isoforms differ mainly in their N-termini . They are both involved in axon formation and in Wnt signaling . They play distinct roles in cardiogenesis, with GSKalpha being essential in cardiomyocyte survival, and GSKbeta regulating heart positioning and left-right symmetry . GSK3beta was first identified as a regulator of glycogen synthesis, but has since been determined to play other roles. It regulates the degradation of beta-catenin and IkB. Beta-catenin is the main effector of Wnt, which is involved in normal haematopoiesis and stem cell function. IkB is a central inhibitor of NF-kB, which is critical in maintaining leukemic cell growth. GSK3beta is enriched in the brain and is involved in regulating neuronal signaling pathways. It is implicated in the pathogenesis of many diseases including Type II diabetes, obesity, mood disorders, Alzheimer's disease, osteoporosis, and some types of cancer, among others .
Small ribosomal subunit protein uS17m, metazoa (Ribosomal_uS17m_metazoa)
Type: Family

This entry represents the small ribosomal subunit protein uS17m (also known as 28S ribosomal protein S17) from metazoans . The mammalian mitochondrial ribosome (mitoribosome), consists of small (28S) and large (39S) subunits, is responsible for the synthesis of 13 proteins of the inner mitochondrial membrane. The 28S small subunit, contains a 12S rRNA (950 nucleotides) and 29 proteins, is much more elongated than its bacterial 30S counterpart .
Ankyrin repeat domain-containing protein 40 (ANKRD40)
Type: Family

The function of ANKRD40 is not clear.
ATP synthase assembly factor Fmc1, mitochondrial (Fmc1)
Type: Family

Fmc1 is a mitochondrial protein required for the assembly of the mitochondrial F1-F0 complex at high temperature . Homologues are from fungi.
Mrs1/Cce1 (Mrs1/Cce1)
Type: Family

This entry includes Mrs1 and its paralogue, Cce1 from fungi. They are mitochondrial proteins. Mrs1 is required for splicing of two mitochondrial group I introns (BI3 in COB and AI5beta in COX1) . Cce1 is an endonuclease that cleaves Holliday junctions formed during recombination of mitochondrial DNA .
Srl3/Whi5 (Srl3/Whi5)
Type: Family

This entry includes Whi5 and its paralogue, Srl3 (also known as Whi7) . Each contains a GTB (G1/S transcription factor binding) motif. Whi5 is a transcriptional repressor that negatively regulates G1-specific, SBF- and MBF-dependent transcription . Whi7 is a cell cycle regulated protein that acts as a depressor of the Start transcriptional program .
FAM91 (FAM91)
Type: Family

The function of FAM91 is not clear. Homologues are found in metazoa and plants, but not fungi.
Ectodysplasin-A receptor-associated adapter protein (EDARADD)
Type: Family

EDARADD is a death domain-containing adaptor molecule for ectodysplasin-A receptor . Mutations of the EDARADD gene has been linked to hypohidrotic ectodermal dysplasia (HED), a rare disorder characterised by deficient development of structures derived from the ectoderm including hair, nails, eccrine glands, and teeth . Homologues are known only from chordates.
PAK4-inhibitor inka (Inka)
Type: Family

This entry includes INKA1 and INKA2. They are inhibitors of PAK4, a metazoan-specific kinase acting downstream of Cdc42 . Danio rerio (Zebrafish) Inka1 is required for the proper migration of neural crest cells during embryonic development . Homologues are known only from chordates and contain a FAM212 domain.
Magnesium transporter MRS2-like (MRS2-like)
Type: Family

This functionally diverse eukaryotic family includes the inner mitochondrial membrane Mg2+ transporters Mfm1p/Lpe10p and Mrs2p from Saccharomyces cerevisiae; and human MRS2/MRS2L . It also includes a family of Arabidopsis thaliana proteins (AtMGTs) some of which are localized to distinct tissues, and not all of which can transport Mg2+ .
NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 11 (NDUFA11)
Type: Family

Subunit 11 of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) is an accessory subunit. It is thought not to be involved in catalysis .
MORF/ORRM1/DAG-like (MORF/ORRM1/DAG-like)
Type: Family

This entry represents a group of plant proteins, including multiple organellar RNA editing factor 1-9 (MORF1-9) and ORRM1 from Arabidopsis, and DAG protein from Antirrhinum majus. DAG shares protein sequence similarity with MORFs and the N terminus of ORRM1. However, ORRM1 also contains a C-terminal RNA recognition motif (RRM), which is absent in DAG and MORFs. They are involvled in C-to-U RNA editing (deamination of cytidine to uridine), an essential step of RNA maturation in chloroplasts and mitochondria of land plants from bryophytes to angiosperms . They interact selectively with diverse PPR (PLS-class of pentatricopeptide repeat) proteins, and these interactions are important for their RNA editing function. MORFs are required for RNA editing in mitochondria and plastids .