SII-SWORD/CoKE huggingface dataset:
Rho GTPase-activating protein 11 (ARHGAP11A/B)
Type: Family

This entry includes ARHGAP11A and ARHGAP11B from humans. ARHGAP11B gene arose from partial duplication of ARHGAP11A (which encodes a Rho guanosine triphosphatase-activating protein) on the human lineage after separation from the chimpanzee lineage . A lack of 55 nucleotides in ARHGAP11B mRNA leads to loss of RhoGAP activity by GAP domain truncation and addition of a human-specific C-terminal amino acid sequence . ARHGAP11B promotes basal progenitor amplification and is implicated in neocortex expansion .
DAPK3, catalytic domain (DAPK3_STKc)
Type: Domain

This entry represents the catalytic domain of DAPK3, which is a member of the Ca(2+)/calmodulin-regulated family of serine/threonine protein kinases .

STKs (serine/threonine kinases) catalyse the transfer of the gamma-phosphoryl group from ATP to serine/threonine residues on protein substrates. DAPKs mediate cell death and act as tumour suppressors. They are necessary to induce cell death and their overexpression leads to death-associated changes including membrane blebbing, cell rounding, and formation of autophagic vesicles .
Kelch repeat and BTB domain-containing protein 4 (KBTBD4)
Type: Family

The function of Kelch repeat and BTB domain-containing protein 4 (KBTBD4) is not clear. It belongs to a large family of cullin-RING ubiquitin ligase adaptors that facilitate the ubiquitination of target substrates.
Heavy metal-associated isoprenylated plant protein 47/16 (HIPP47/16)
Type: Family

This entry includes HIPP47 (At3g20180) and HIPP16 (At3g07600) from Arabidopsis . They contain an apparent HMA-like domain similarly to HIPP01/3/5/6 (

) but lack the core conserved Cys-X-X-Cys motif .
Cystatin-F (Cystatin-F)
Type: Family

Cystatin-F is a cysteine peptidase inhibitor that is targeted to endosomal/lysosomal compartments. It is synthesized as an inactive disulfide-linked dimer which is then converted to an active monomer by proteolytic cleavage of 15 N-terminal residues. It has been shown to regulate the cytotoxicity of natural killer (NK) cells and T cells .
Vesicle-associated membrane protein 4 (VAMP4)
Type: Family

Vesicle-associated membrane protein 4 (VAMP4) is required to maintain the ribbon structure of the Golgi apparatus . It is essential for activity-dependent bulk endocytosis (ADBE) .
G-protein-signaling modulator 3 (GPSM3)
Type: Family

G-protein-signaling modulator 3 (GPSM3), also known as AGS4 or G18, contains three tandem GoLoco motifs and a LSL motif that interacts with monomeric Gbeta subunits . It interacts with Galpha and Gbeta subunits of heterotrimeric G proteins to regulate downstream intracellular signals initiated by G protein coupled receptors (GPCRs) and has been linked to immune-mediated diseases .
BTB/POZ domain-containing protein 18 (BTBD18)
Type: Family

BTB/POZ domain-containing protein 18 (BTBD18) is a pachytene nuclear protein that regulates transcription activation through RNA polymerase II elongation at a subset of genomic piRNA loci .
C-type lectin domain family 12 member A/B (CLEC12A/B)
Type: Family

C-type lectin domain family 12 member B (CLEC12B) is a lectin C-type inhibitory receptor that plays a role in myeloid cell function . CLEC12A (also known as MICL or DCAL-2) is expressed in monocytes, macrophages, and dendritic-cells (DCs). It serves as a functional receptor on DCs and can internalize and collaborate with TLR or CD40 signaling and regulate immune responses .
Homeobox protein MIXL1 (MIXL1)
Type: Family

This entry represents human Homeobox protein MIXL1 and similar sequences mainly found in vertebrates. MIXL1 is a homeobox transcription factor essential for the patterning of axial mesendodermal structures during early embryogenesis . It interacts with the T-box protein Brachyury and related members of the T-box family of transcription factors; this interaction negatively regulates MIXL1 transcriptional activity . In mice, enforced expression of MIXL1 results in transplantable AML (acute myeloid leukaemia), suggesting a leukaemogenic potential for MIXL1 .
Pleckstrin homology domain-containing family G member 6 (PLEKHG6)
Type: Family

Pleckstrin homology domain-containing family G member 6 (PLEKHG6), also known as MyoGEF, is a guanine nucleotide exchange factor required for cytokinesis . It interacts with ezrin; this interaction promotes RhoG-dependent apical cytoskeleton rearrangements in epithelial cells .
Retrotransposon Gag-like protein 9 (RTL9)
Type: Family

Retrotransposon Gag-like protein 9 (RTL9) is a member of the neofunctionalized Ty3/gypsy retrotransposon family. They have lost essential structural features necessary for autonomous retrotransposition before divergence between mouse and human .
Izumo sperm-egg fusion protein 2 (IZUMO2)
Type: Family

This entry represents Izumo sperm-egg fusion protein 2 (IZUMO2), a member of the IZUMO family.

IZUMO is a protein with a single immunoglobulin (Ig) domain. Its expression has been found to be testis-specific . IZUMO is not detectable on the surface of fresh sperm, but becomes exposed after an exocytotic process, the acrosome reaction, has occurred. It is thought to bind to putative Izumo receptors on the oocyte. Studies have shown that knock-out mice (Izumo-/- males) were sterile despite normal mating behaviour and ejaculation, indicating the importance of the protein in fertilisation . IZUMO is a typical type I membrane glycoprotein with one immunoglobulin-like domain and a putative N-glycoside link motif (Asn 204) . It contains cysteine residues thought to form a disulphide bridge, and a conserved GCL sequence motif.
Cystatin-like 1 (CSTL1)
Type: Family

The function of Cystatin-like 1 (CSTL1) is not clear.
Cystatin-11 (CST11)
Type: Family

Cystatin-11 (CST11) is a member of the CST type 2 family of cysteine protease inhibitors. It may have antimicrobial activity .
Ataxin-7-like protein 3B (ATXN7L3B)
Type: Family

Ataxin-7-like protein 3B (ATXN7L3B) interacts with ENY2, a SAGA component. It regulates histone H2Bub1 levels and SAGA deubiquitinase activity through competition for ENY2 binding . It has been linked to neurodegenerative disease .
B(0)AT2, solute-binding domain (B(0)AT2)
Type: Domain

B(0)AT2 (also called SBAT1, v7-3, NTT7-3) is a high-affinity Na(+)-dependent transporter for large neutral amino acids, including leucine, isoleucine, valine, proline and methionine . Human SBAT1 is encoded by the SLC6A15 gene, a susceptibility gene for major depression. SBAT1 is expressed in brain, and may have a role in transporting neurotransmitter precursors into neurons. B(0)AT2 belongs to the solute carrier 6 (SLC6) transporter family .
tRNA-specific adenosine deaminase 1 (Tad1)
Type: Family

Tad1 is a yeast tRNA-specific adenosine deaminase that deaminates adenosine-37 to inosine in tRNA-Ala .
Nuclear hormone receptor family member nhr-150 (Nhr-150)
Type: Family

This entry includes Nuclear hormone receptor family member Nhr-150 from C. elegans. It is an orphan nuclear receptor. Its function is not clear.
Trichohyalin-like protein 1 (TCHHL1)
Type: Family

Trichohyalin-like protein 1 (TCHHL1) is a member of the fused-type S100 protein family. It contains an N-terminal E-hand domain, one trans-membrane domain and a nuclear localization signal. Its function is not clear. It is expressed in the basal layer of the normal epidermis and may be associated with the proliferation of keratinocytes .

The fused-type S100 protein family is a group of calcium binding S100-related proteins. The 'fused' gene family includes multifunctional epidermal differentiation proteins - profilaggrin, trichohyalin, repetin , hornerin, and cornulin; functionally these proteins are associated with keratin intermediate filaments and partially crosslinked to the cell envelope. These 'fused' gene proteins contain N-terminal sequence with two Ca-binding EF-hands motif, which may be associated with calcium signalling in epidermal cells and autoprocessing in a calcium-dependent manner. In contrast to S100 proteins, 'fused' gene family proteins contain an extraordinary high number of almost perfect peptide repeats with regular array of polar and charged residues similar to many known cell envelope proteins .
Phosphatidylinositol transfer protein Sfh5 (Sfh5)
Type: Family

In budding yeasts, Phosphatidylinositol transfer proteins (PITPs) are defined by their ability to transfer phosphatidylinositol (PtdIns) or phosphatidylcholine (PtdCho) monomers between membrane bilayers in vitro. The major PITP is encoded by SEC14. However, four other yeast SFH (Sec Fourteen Homologue) proteins designated Sfh2, Sfh3, Sfh4, and Sfh5, have been identified .

This entry represents Sfh5 from fungi, a non-classical PITP. It has PtdIns transfer activity in vitro and may function in regulation of post-Golgi membrane trafficking events . It is also involved in the organization of the actin cytoskeleton . Sfh5 is a novel heme-binding protein with an unusual heme-binding arrangement that involves co-axial tyrosine/histidine coordination strategy and a complex electronic structure which penta-coordinates high spin Fe3. It is conserved across Fungi and may play a role organic oxidant-induced stress responses, being the founding member of a new class of hemoproteins .
RUN and FYVE domain-containing protein 4 (RUFY4)
Type: Family

RUFY4 contains an N-terminal RUN domain and a C-terminal FYVE domain. It is a positive molecular regulator of macroautophagy in primary dendritic cells (DCs) .
Heat shock protein beta-9 (HSPB9)
Type: Family

Heat shock protein beta-9 (HspB9) is specifically expressed in testis, notably in the spermatogenic cells from late pachytene spermatocyte stage till elongate spermatid stage . Its function is not clear.
Kelch domain-containing protein 9 (KLDC9)
Type: Family

The function of Kelch domain-containing protein 9 (KLDC9) is not clear.
Laforin (Laforin)
Type: Family

Laforin (encoded by the EPM2A gene) is a protein phosphatase and one of the two proteins (the other one is malin, a E3-ubiquitin ligase) that is defective in Lafora disease (LD), a progressive form of inherited epilepsy associated with widespread neurodegeneration and the formation of polyglucosan bodies in the neurons . Laforin and malin form a functional complex, in which laforin could recognize and recruit putative substrates to be ubiquitinated by malin for degradation. The Laforin-malin complex regulates glycogen synthesis through targeting R5/PTG (Protein Targeting to Glycogen) for inactivation, most probably by proteolysis. Moreover, the Laforin-Malin complex is also involved in different pathways, such as intracellular protein degradation, oxidative stress, and the endoplasmic reticulum unfolded protein response . It contains a carbohydrate binding module (CBM) at the N terminus and a dual specificity phosphatase domain (DSP) at the C terminus. The structure of Laforin has been revealed .
Kunitz-type protease inhibitor 4 (SPINT4)
Type: Family

Kunitz-type protease inhibitor 4 (SPINT4) is a secreted protein composed of a single Kunitz domain and is relatively specific for the epididymis .
Collectrin (Collectrin)
Type: Family

Collectrin is a putative glycoprotein that shares homology with the C-terminal of angiotensin-converting enzyme-related carboxypeptidase (ACE2), but lacks the dipeptidyl carboxypeptidase catalytic domains. It is a target of HNF-1 in pancreatic beta cells and can increase exocytosis by interaction with snapin and facilitated SNARE complex formation .
LBH domain containing protein (LBH_dom_prot)
Type: Family

This entry represents LBH domain containing proteins, including protein LBH, LBHD1 and LBHD2.

LBH (limb-bud and heart) protein may act as a transcriptional activator in mitogen-activated protein kinase signalling pathway to mediate cellular functions. It has been shown to regulate cardiac gene expression by modulating the combinatorial activities of key cardiac transcription factors, as well as their individual functions in cardiogenesis in mice .
Carboxymethylenebutenolidase homolog (CMBL)
Type: Family

Carboxymethylenebutenolidase (CMBL) is a human homologue of Pseudomonas dienelactone hydrolase involved in the bacterial halocatechol degradation pathway. It is a cysteine hydrolase that can convert the prodrug olmesartan medoxomil into its pharmacologically active metabolite olmerstatan, an angiotensin receptor blocker, in liver and intestine .

This entry also includes uncharacterised DLH domain-containing proteins from plants.
FHL5, second LIM domain (FHL5_LIM2)
Type: Domain

This entry represents the second LIM domain of Four and a half LIM domains protein 5 (FHL5, also known as ACT), which belongs to the CREB/CREM family of transcription factors. FHL5 is highly expressed in male germ cells and is required for post-meiotic gene expression. It associates with CREM and confers a powerful transcriptional activation function . Activation by CREB has known to occur upon phosphorylation at an essential regulatory site and the subsequent interaction with the ubiquitous coactivator CREB-binding protein (CBP). However, the activation by FHL5 is independent of phosphorylation and CBP association. It represents a new route for transcriptional activation by CREM and CREB .

LIM domains are 50-60 amino acids in size and share two characteristic zinc finger motifs. The two zinc fingers contain eight conserved residues, mostly cysteines and histidines, which coordinately bind to two zinc atoms. LIM domains function as adaptors or scaffolds to support the assembly of multimeric protein complexes .
T-cell immunoglobulin and ITIM domain receptor (TIGIT)
Type: Family

T-cell immunoglobulin and ITIM domain receptor (TIGIT) is a surface protein and an inhibitory receptor that suppresses T cell activation by promoting the generation of mature immunoregulatory dendritic cells . It contains an immunoglobulin tail tyrosine (ITT)-like phosphorylation motif and an ITIM (immunoreceptor tyrosine-based inhibition motif) in its cytoplasmic tail. The identified ligands of TIGIT include the poliovirus receptor (PVR or CD155) and PVRL2 (Nectin2 or CD112). The TIGIT/PVR signaling has been shown to suppresses granule polarization and NK cell cytotoxicity .
KBTBD4, BTB/POZ domain (KBTBD4_BTB_POZ)
Type: Domain

This entry represents the BTB/POZ domain found in KBTBD4.

The function of Kelch repeat and BTB domain-containing protein 4 (KBTBD4) is not clear. It belongs to a large family of cullin-RING ubiquitin ligase adaptors that facilitate the ubiquitination of target substrates.
KBTBD4, BACK domain (KBTBD4_BACK)
Type: Domain

This entry represents the BACK domain found in KBTBD4.

The function of Kelch repeat and BTB domain-containing protein 4 (KBTBD4) is not clear. It belongs to a large family of cullin-RING ubiquitin ligase adaptors that facilitate the ubiquitination of target substrates.
ADP-ribosylation factor-like protein 10 (ARL10)
Type: Family

The function of ADP-ribosylation factor-like protein 10 (ARL10) is not clear. It belongs to the Arf family of small GTPases that contains a unique structural device, known as "interswitch toggle" .
Spermatogenic leucine zipper protein 1 (Spz1)
Type: Family

Spermatogenic leucine zipper protein 1 (Spz1) is a basic helix-loop-helix-leucine zipper (bHLH-Zip) transcription factor expressed specifically in the testis and epididymis of adult mice. It plays an important regulatory role during spermatogenesis . It also mediates mitogen-activated protein kinase cell proliferation, transformation, and tumorigenesis . TIP60-dependent acetylation of the SPZ1-TWIST complex has been shown to activate VEGF (vascular endothelial growth factor) expression, which regulates tumour metastasis and promotes several physiological and pathological events including angiogenesis, vascular hyperpermeability, cancer metastasis, and cancer stem cell transition .
Ubiquitin D (Ubiquitin_D)
Type: Family

Ubiquitin D (also known as FAT10) contains two ubiquitin-like β-grasp folds at N and C termini. The C-terminal domain interacts with proteasome subunit RPN10 while the N-terminal domain is associated with the adaptor protein NUB1L, which accelerates FAT10 degradation . FAT10 is a TNF-alpha-inducible ubiquitin-like protein that mediates proteasomal degradation in a ubiquitin-independent manner . It has been implicated in multiple biological activities, including antigen processing, antimicrobial defense, apoptosis, and oncogenesis .
NUDT18, NUDIX hydrolase domain (NUDT18_NUDIX)
Type: Domain

This entry represents the NUDIX domain found in NUDT18, an 8-oxo-dGDP phosphatase that mediates the hydrolysis of oxidized nucleoside diphosphate derivatives .

In general, Nudix hydrolases catalyse the hydrolysis of nucleoside diphosphates linked to other moieties, X, and contain the sequence motif or Nudix box, GX(5)EX(7)REUXEEXGU .
Late embryogenesis abundant protein, SMP subgroup (LEA_SMP)
Type: Family

LEA (late embryogenesis abundant) proteins were first identified in land plants. Plant LEA proteins have been found to accumulate to high levels during the last stage of seed formation (when a natural desiccation of the seed tissues takes place) and during periods of water deficit in vegetative organs. Later, LEA homologues have also been found in various species . They have been classified into several subgroups in Pfam and according to Bray and Dure .
Insulinoma-associated protein 1/2 (INSM1/2)
Type: Family

Insulinoma-associated protein 1 (INSM1) is a zinc-finger transcription factor exclusively expressed in the foetal pancreas and nervous system, and in tumours of neuroendocrine origin. It can recruits cyclin D1 and HDACs, which confer transcriptional repressor activity . It is involved in endocrine and neuronal cell differentiation . In pancreas, it is activated by the islet-specific endocrine factor neurogenin 3, and subsequently regulates downstream target genes NeuroD1 and insulin during beta-cell maturation .

Transcription factor egl-46 is the C. elegans orthologue from human INSM2, which is involved in neuron differentiation .
RING finger protein 222 (RNF222)
Type: Family

The function of RING finger protein 222 (RNF222) is not clear.
Junctional adhesion molecule C (JAM-C)
Type: Family

JAM-C (also known as JAM3) is an adhesion molecule expressed by endothelial cells (ECs) that plays a role in tight junction formation, leukocyte adhesion, and transendothelial migration . Platelet JAM-C has been find to bind neutrophil integrin alphaMbeta2 (Mac-1/CD11b/CD18) to help neutrophils to transmigrate through endothelium . Mutations in the JAM-C gene cause haemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts .

Junctional Adhesion Molecules (JAMs), including JAM-A/B/C, are a subset of the immunoglobulin superfamily, which have two extracellular immunoglobulin-like domains, a cytoplasmic tail and a PDZ-domain-binding motif . They can form homodimers at the surface of one cell and between two neighbouring cells and heterodimers can also occur between JAM-B and JAM-C. They can also interact with human leukocyte integrins .
Chaperone protein AtJ6-like (AtJ6-like)
Type: Family

Plant AtJ6-like proteins are related to Escherichia coli DnaJ. Arabidopsis AtJ6 contains an N-terminal J-domain, but which lacks the G/F, and C-rich domains characteristic of DnaJ. Their function is not clear.
von Willebrand factor C domain-containing protein 2-like (VWC2/VWC2L)
Type: Family

This entry includes VWC2 (also known as Brorin) and VWC2L proteins. Brorin is a secreted BMP antagonist that promotes neurogenesis in mouse neural precursor cells . VWC2L may also play roles in neural development and functions .
RING finger protein 11, RING-H2 finger (RNF11_RING-H2)
Type: Domain

RING finger protein 11 (RNF11) is an E3 ubiquitin-protein ligase that acts both as an adaptor and a modulator of itch-mediated control of ubiquitination events underlying membrane traffic. It is the downstream of an enzymatic cascade for the ubiquitination of specific substrates. It is also a molecular adaptor of homologous to E6-associated protein C terminus (HECT)-type ligases . RNF11 has been implicated in the regulation of several signaling pathways. It enhances the transforming growth factor receptor (TGFR) signaling by both abrogating Smurf2-mediated receptor ubiquitination and by promoting the Smurf2-mediated degradation of AMSH (associated molecule with the SH3 domain of STAM), a de-ubiquitinating enzyme that enhances transforming growth factor-beta (TGF-beta) signalling and epidermal growth factor receptor (EGFR) endosomal recycling
. It also acts directly on Smad4 to enhance Smad4 function, and plays a role in prolonged TGF-beta signalling . Moreover, RNF11 functions as a critical component of the A20 ubiquitin-editing protein complex that negatively regulates tumor necrosis factor (TNF)-mediated nuclear factor (NF)-kappaB activation . It also interacts with Smad anchor for receptor activation (SARA) and the endosomal sorting complex required for transport (ESCRT)-0 complex, thus participating in the regulation of lysosomal degradation of EGFR . Furthermore, RNF11 acts as a novel GGA cargo actively participating in regulating the ubiquitination of the GGA protein family . In addition, RNF11 functions together with TAX1BP1 to target TANK-binding kinase 1 (TBK1)/IkappaB kinase IKKi, and further restricts antiviral signaling and type I interferon (IFN)-beta production .
Homeobox protein GBX-1/2 (GBX-1/2)
Type: Family

GBX-1 and GBX-2 are homeobox proteins. The role of the mouse GBX-2 in defining the mid/hindbrain organiser has been studied extensively, but little is known about GBX-1. GBX-1 is expressed first during gastrulation and later in a dynamic pattern in the central nervous system .

Homeobox protein unplugged (unpg) from Drosophila plays a regulatory role in neural branching of the tracheae . Like vertebrate orthologue Gbx2, unplugged may also have a role in brain development. Studies indicate that Drosophila brain displays developmental genetic features similar to those observed for the midbrain/hindbrain boundary region in vertebrates .

The homeobox domain (homeodomain) is a 60-residue motif first identified in a number of Drosophila homeotic and segmentation proteins, but now known to be well-conserved in many other animals, including vertebrates . Proteins containing homeobox domains are likely to play an important role in development - most are known to be sequence-specific DNA-binding transcription factors. The domain binds DNA through a helix-turn-helix (HTH) structure.
Extracellular tyrosine-protein kinase PKDCC (PKDCC)
Type: Family

PKDCC (also known as vertebrate lonesome kinase, VLK) is a secreted tyrosine kinase that mediates phosphorylation of extracellular proteins and endogenous proteins in the secretory pathway, which is essential for patterning at organogenesis stages . It contains an N-terminal signal sequence and a divergent C-terminal catalytic protein kinase-like domain that replaces the canonical kinase 'DFG' and 'HRD' motifs with alternate, yet functional residues . It has been shown to interact with Gli3 to regulate chondrocyte differentiation during mouse long bone development .

In Xenopus, there are two members of the PKDCC family, Pkdcc1 and Pkdcc2. They are involved in the regulation of JNK dependent Wnt/PCP signaling pathway .
Chaperonin-containing T-complex member BBS12 (BBS12)
Type: Family

Bardet-Biedl syndrome (BBS) is a rare genetic disorder belonging to the group of ciliopathies, which encompasses several diseases that are caused by defects in cilia structure and/or function, especially affecting the primary cilium. Mutations of the BBS12 gene accounts for approximately 5% of all BBS cases . BBS12 is part of the BBS/CCT complex and is required or BBSome assembly . BBSome plays a key role in mediating molecular/vesicular transport in and out of the primary cilium, and also in intraciliary trafficking as part of the intraflagellar transport machinery .
Sushi domain-containing protein 4 (SUSD4)
Type: Family

Sushi domain-containing protein 4 (SUSD4) contains several Sushi or complement control protein domains . It functions as a complement inhibitor and a tumour suppressor .