SII-SWORD/CoKE huggingface dataset:
DNA topoisomerase, type IA, DNA-binding domain (Topo_IA_DNA-bd_dom)
Type: Domain

DNA topoisomerases regulate the number of topological links between two DNA strands (i.e. change the number of superhelical turns) by catalysing transient single-or double-strand breaks, crossing the strands through one another, then resealing the breaks . These enzymes have several functions: to remove DNA supercoils during transcription and DNA replication; for strand breakage during recombination; for chromosome condensation; and to disentangle intertwined DNA during mitosis . DNA topoisomerases are divided into two classes: type I enzymes (

; topoisomerases I, III and V) break single-strand DNA, and type II enzymes (

; topoisomerases II, IV and VI) break double-strand DNA .

Type I topoisomerases are ATP-independent enzymes (except for reverse gyrase), and can be subdivided according to their structure and reaction mechanisms: type IA (Topo IA; bacterial and archaeal topoisomerase I, topoisomerase III and reverse gyrase) and type IB (Topo IB; eukaryotic topoisomerase I and topoisomerase V). These enzymes are primarily responsible for relaxing positively and/or negatively supercoiled DNA, except for reverse gyrase, which can introduce positive supercoils into DNA. This function is vital for the processes of replication, transcription, and recombination. Unlike Topo IA enzymes, Topo IB enzymes do not require a single-stranded region of DNA or metal ions for their function. The type IB family of DNA topoisomerases includes eukaryotic nuclear topoisomerase I, topoisomerases of poxviruses, and bacterial versions of Topo IB . They belong to the superfamily of DNA breaking-rejoining enzymes, which share the same fold in their C-terminal catalytic domain and the overall reaction mechanism with tyrosine recombinases . The C-terminal catalytic domain in topoisomerases is linked to a divergent N-terminal domain that shows no sequence or structure similarity to the N-terminal domains of tyrosine recombinases .

This entry describes the DNA-binding domain (domain 3) found in type IA topoisomerases. The structures of bacterial topoisomerases I and III have been shown to consist of four domains that together form a toroidal structure with a central hole large enough to accommodate single- and double-stranded DNA. The N-terminal Toprim domain together with domain 3 (β-barrel) forms the active site of the enzyme, while domains 2 and 4 (both winged-helix-like) form a single-strand DNA-binding groove . All topoisomerases cleave DNA by forming a transient phosphotyrosine bond; in type IA topoisomerases, the active site tyrosine is in domain 3 .
U2A'/phosphoprotein 32 family A, C-terminal (U2A'_phosphoprotein32A_C)
Type: Domain

This motif occurs C-terminal to leucine-rich repeats in "sds22-like" and "typical" LRR-containing proteins. Examples from the metazoa are described as either "Acidic leucine-rich nuclear phosphoprotein 32 family member A" or have been characterised as U2A', the protein that interacts with U2B'' facilitating the interaction with U2 snRNA. U2A' is required for the spliceosome assembly and the efficient addition of U2 snRNP onto the pre-mRNA . The crystal structure of the spliceosomal U2B"-U2A' protein complex bound to a fragment of U2 small nuclear RNA has been described .
Matrin/U1-C-like, C2H2-type zinc finger (Matrin/U1-like-C_Znf_C2H2)
Type: Domain

Zinc finger (Znf) domains are relatively small protein motifs which contain multiple finger-like protrusions that make tandem contacts with their target molecule. Some of these domains bind zinc, but many do not; instead binding other metals such as iron, or no metal at all. For example, some family members form salt bridges to stabilise the finger-like folds. They were first identified as a DNA-binding motif in transcription factor TFIIIA from Xenopus laevis (African clawed frog), however they are now recognised to bind DNA, RNA, protein and/or lipid substrates . Their binding properties depend on the amino acid sequence of the finger domains and of the linker between fingers, as well as on the higher-order structures and the number of fingers. Znf domains are often found in clusters, where fingers can have different binding specificities. There are many superfamilies of Znf motifs, varying in both sequence and structure. They display considerable versatility in binding modes, even between members of the same class (e.g. some bind DNA, others protein), suggesting that Znf motifs are stable scaffolds that have evolved specialised functions. For example, Znf-containing proteins function in gene transcription, translation, mRNA trafficking, cytoskeleton organisation, epithelial development, cell adhesion, protein folding, chromatin remodelling and zinc sensing, to name but a few . Zinc-binding motifs are stable structures, and they rarely undergo conformational changes upon binding their target.

C2H2-type (classical) zinc fingers (Znf) were the first class to be characterised. They contain a short β-hairpin and an α-helix (β/β/α structure), where a single zinc atom is held in place by Cys(2)His(2) (C2H2) residues in a tetrahedral array. C2H2 Znf's can be divided into three groups based on the number and pattern of fingers: triple-C2H2 (binds single ligand), multiple-adjacent-C2H2 (binds multiple ligands), and separated paired-C2H2 . C2H2 Znf's are the most common DNA-binding motifs found in eukaryotic transcription factors, and have also been identified in prokaryotes . Transcription factors usually contain several Znf's (each with a conserved β/β/α structure) capable of making multiple contacts along the DNA, where the C2H2 Znf motifs recognise DNA sequences by binding to the major groove of DNA via a short α-helix in the Znf, the Znf spanning 3-4 bases of the DNA . C2H2 zinc fingers can also bind to RNA and protein targets .

This entry represents U1-type zinc finger domains, a family of C2H2-type zinc fingers present in matrin, U1 small nuclear ribonucleoprotein C and other RNA-binding proteins .
GS domain (GS_dom)
Type: Domain

Transforming growth factor beta (TGF-beta) is a member of a large family of secreted growth factors of central importance in eukaryotic development and homeostasis. Members of this family, which includes the activins, inhibins and bone morphogenic proteins (BMPs), bind to receptors that consist of two transmembrane serine/threonine (Ser/Thr) kinases called the type I and type II receptors. Type II activates Type I upon formation of the ligand receptor complex by multiply phosphorylating the GS domain, a short (~30 residues), highly conserved regulatory sequence just N-terminal to the kinase domain on the cytoplasmic side of the receptor. The GS domain is found only in the type I receptor family and is named for the TTSGSGSG sequence at its core. At least three, and perhaps four to five of the serines and threonines in the GS domain, must be phosphorylated to fully activate TbetaR-1 .

The GS domain forms a helix-loop-helix structure in which the sites of activating phosphorylation are situated in a loop known as the GS loop. One key role for phosphorylation is to block the adoption of an inactivating configuration by the GS domain .
HD/PDEase domain (HD/PDEase_dom)
Type: Domain

This entry represents the HD domain, which is found in a superfamily of enzymes with a predicted or known phosphohydrolase activity. It also represents a related phosphodiesterase (PDEase) domain that is found in eukaryotic 3',5'-cGMP phosphodiesterase (

), which is located in photoreceptor outer segments and it is light activated, playing a pivotal role in signal transduction .
PAN/Apple domain (Pan_app)
Type: Domain

Plasma kallikrein (

) and coagulation factor XI (

) are two related plasma serine proteases activated by factor XIIA and which share the same domain topology: an N-terminal region that contains four tandem repeats of about 90 amino acids and a C-terminal catalytic domain. The 90 amino-acid repeated domain contains 6 conserved cysteines. It has been shown that three disulfide bonds link the first and sixth, second and fifth, and third and fourth cysteines. The domain can be drawn in the shape of an apple and has been accordingly called the 'apple domain'.

The apple domains of plasma prekallikrein are known to mediate its binding to high molecular weight kininogen , the apple domains of factor XI bind to factor XIIa, platelets, kininogen, factor IX and heparin .

The apple domains display some sequence similarity with the N domain of plasminogen/hepatocyte growth factor (HGF) and to some nematode and protozoan proteins . They all belong to the same domain superfamily that have been called the PAN module . The N domain of hepatocyte growth factor binds to the c-Met receptor and to the heparin molecule. The structure of the PAN module of HGF has been solved. It contains a characteristic hairpin-loop structure stabilised by two disulfide bridges, Cys-1 and 6 are not conserved in HGF PAN modules .

Apart from the cysteines, there are a number of other conserved positions in the apple domain. This entry represents the PAN domain of the plasma kalllikrein/coagulation factor XI subgroup proteins.
Carbohydrate binding module family 5/12 (CBM5/12)
Type: Domain

This entry represents

and

. These modules have a core structure consisting of a 3-stranded meander β-sheet, which contain six aromatic groups that may be important for binding. CBM5/12 is found in proteins such as chitinase A1, chitinase B , and endoglucanase Z .

The overall topology of the CBM is structurally similar to the C-terminal chitin-binding domains (ChBD) of chitinase A1 and chitinase B, however the binding mechanism for the ChBD may be different from that of the CBM .

A carbohydrate-binding module (CBM) is defined as a contiguous amino acid sequence within a carbohydrate-active enzyme with a discreet fold having carbohydrate-binding activity. A few exceptions are CBMs in cellulosomal scaffolding proteins and rare instances of independent putative CBMs. The requirement of CBMs existing as modules within larger enzymes sets this class of carbohydrate-binding protein apart from other non-catalytic sugar binding proteins such as lectins and sugar transport proteins.

CBMs were previously classified as cellulose-binding domains (CBDs) based on the initial discovery of several modules that bound cellulose . However, additional modules in carbohydrate-active enzymes are continually being found that bind carbohydrates other than cellulose yet otherwise meet the CBM criteria, hence the need to reclassify these polypeptides using more inclusive terminology.

Previous classification of cellulose-binding domains were based on amino acid similarity. Groupings of CBDs were called "Types" and numbered with roman numerals (e.g. Type I or Type II CBDs). In keeping with the glycoside hydrolase classification, these groupings are now called families and numbered with Arabic numerals. Families 1 to 13 are the same as Types I to XIII. For a detailed review on the structure and binding modes of CBMs see .
Nuclease associated modular domain 3 (NUMOD3)
Type: Domain

NUMOD3 (nuclease associated modular domain 3) is a DNA-binding motif found in homing endonucleases and related proteins. It occurs on its own or in tandem repeats in GIY-YIG and HTH proteins. It constitutes a β-turn-loop-helix subregion of the the DNA-binding domain of I-TevI homing endonuclease (

) .
U-box domain (Ubox_domain)
Type: Domain

This entry represents the U-box domain.

The molecular mechanism underlying the transfer of ubiquitin (Ub) to a substrate consists of three key enzymatic steps. First, ubiquitin itself is adenylated at its C-terminal glycine residue by an activating enzyme (E1). Second, the adenylated Ub forms a covalent linkage to a conjugating enzyme (E2). Finally, a ligating enzyme (E3) recruits both the Ub-charged E2 species and the target protein. There are three classes of E3 enzymes- HECT, RING, and U-box, which are distinguished on the basis of their E2-recruiting domains.
Knottin, scorpion toxin-like (Scorpion_toxin-like)
Type: Domain

Knottins are small proteins characterised by a cystine-knot . They constitute a large family of structurally related peptides with diverse biological functions, including inhibitors, anti-microbial peptides and toxins .

The scorpion toxin-like domain is found in a subgroup of metazoan knottins mainly from the arthropoda, which include the antibacterial defensins and the scorpion alpha and beta-neurotoxins . The plant sequences include members of the gamma-thionin family, which are plant defensins that have no antifungal activity. Other members are insect alpha-amylase inhibitors, cysteine-rich antifungal proteins and proteins annotated as proteinase inhibitors; those that are characterised belong to MEROPS inhibitor family I18, clan I.
HNH nuclease (HNH_nuc)
Type: Domain

This domain is found in HNH family of nucleases that includes yeast intron 1 protein, human DNA annealing helicase and endonuclease ZRANB3, bacterial CRISPR-associated endonuclease Cas9, colicins, pyocins and endonuclease HphI. Members in this group are found in all domains of life.
Post-SET domain (Post-SET_dom)
Type: Domain

This region is found in a number of histone lysine methyltransferases (HMTase), C-terminal to the SET domain; it is generally described as the post-SET domain.

Histone lysine methylation is part of the histone code that regulated chromatin function and epigenetic control of gene function. Histone lysine methyltransferases (HMTase) differ both in their substrate specificity for the various acceptor lysines as well as in their product specificity for the number of methyl groups (one, two, or three) they transfer. With just one exception , the HMTases belong to SET family that can be classified according to the sequences surrounding the SET domain . Structural studies on the human SET7/9, a mono-methylase, have revealed the molecular basis for the specificity of the enzyme for the histone-target and the roles of the invariant residues in the SET domain in determining the methylation specificities .
Transcription elongation factor, TFIIS/CRSP70, N-terminal, sub-type (TFIIS/CRSP70_N_sub)
Type: Domain

Transcription factor S-II (TFIIS) induces mRNA cleavage by enhancing the intrinsic nuclease activity of RNA polymerase (Pol) II, past template-encoded pause sites. It is widely distributed being found in mammals, Drosophila, yeast and in the archaebacteria Sulfolobus acidocaldarius . S-II proteins have a relatively conserved C-terminal region but variable N-terminal region, and some members of this family are expressed in a tissue-specific manner .

TFIIS is a modular factor that comprises an N-terminal domain I, a central domain II, and a C-terminal domain III . The weakly conserved domain I forms a four-helix bundle and is not required for TFIIS activity. Domain II forms a three-helix bundle, and domain III adopts a zinc-ribbon fold with a thin protruding β-hairpin. Domain II and the linker between domains II and III are required for Pol II binding, whereas domain III is essential for stimulation of RNA cleavage. TFIIS extends from the polymerase surface via a pore to the internal active site, spanning a distance of 100 Angstroms. Two essential and invariant acidic residues in a TFIIS loop complement the Pol II active site and could position a metal ion and a water molecule for hydrolytic RNA cleavage. TFIIS also induces extensive structural changes in Pol II that would realign nucleic acids in the active centre.

This domain is found in the N-terminal region of transcription elongation factor S-II (TFIIS) and in several hypothetical proteins.
Transcription elongation factor S-II, central domain (TFIIS_cen_dom)
Type: Domain

This domain is found in the central region of transcription elongation factor S-II and in several hypothetical proteins.

Transcription factor S-II (TFIIS) induces mRNA cleavage by enhancing the intrinsic nuclease activity of RNA polymerase (Pol) II, past template-encoded pause sites. It is widely distributed being found in mammals, Drosophila, yeast and in the archaebacteria Sulfolobus acidocaldarius . S-II proteins have a relatively conserved C-terminal region but variable N-terminal region, and some members of this family are expressed in a tissue-specific manner .

TFIIS is a modular factor that comprises an N-terminal domain I, a central domain II, and a C-terminal domain III . The weakly conserved domain I forms a four-helix bundle and is not required for TFIIS activity. Domain II forms a three-helix bundle, and domain III adopts a zinc-ribbon fold with a thin protruding β-hairpin. Domain II and the linker between domains II and III are required for Pol II binding, whereas domain III is essential for stimulation of RNA cleavage. TFIIS extends from the polymerase surface via a pore to the internal active site, spanning a distance of 100 Angstroms. Two essential and invariant acidic residues in a TFIIS loop complement the Pol II active site and could position a metal ion and a water molecule for hydrolytic RNA cleavage. TFIIS also induces extensive structural changes in Pol II that would realign nucleic acids in the active centre.
MAD homology 1, Dwarfin-type (MAD_homology1_Dwarfin-type)
Type: Domain

Mammalian dwarfins are phosphorylated in response to transforming growth factor beta and are implicated in control of cell growth . The dwarfin family also includes the Drosophila protein MAD that is required for the function of decapentaplegic (DPP) and may play a role in DPP signalling. Drosophila Mad binds to DNA and directly mediates activation of vestigial by Dpp . This domain is also found in nuclear factor I (NF-I) or CCAAT box-binding transcription factor (CTF).

This entry represents the MH1 (MAD homology 1) domain is found at the amino terminus of MAD related proteins such as Smads. This domain is separated from the MH2 domain by a non-conserved linker region. The crystal structure of the MH1 domain shows that a highly conserved 11 residue β hairpin is used to bind the DNA consensus sequence GNCN in the major groove, shown to be vital for the transcriptional activation of target genes. Not all examples of MH1 can bind to DNA however. Smad2 cannot bind DNA and has a large insertion within the hairpin that presumably abolishes DNA binding. A basic helix (H2) in MH1 with the nuclear localisation signal KKLKK has been shown to be essential for Smad3 nuclear import. Smads also use the MH1 domain to interact with transcription factors such as Jun, TFE3, Sp1, and Runx .
Urocortin/corticotropin-releasing factor (Urocortin_CRF)
Type: Family

Corticotropin-releasing factor (CRF), urotensin-I, urocortin and sauvagine form a family of related neuropeptides in vertebrates. The family can be grouped into 2 separate paralogous lineages, with urotensin-I, urocortin and sauvagine in one group and CRF forming the other group. Urocortin and sauvagine appear to represent orthologues of fish urotensin-I in mammals and amphibians, respectively. The peptides have a variety of physiological effects on stress and anxiety, vasoregulation, thermoregulation, growth and metabolism, metamorphosis and reproduction in various species, and are all released as preprohormones .

CRF is a hormone found mainly in the paraventricular nucleus of the mammalian hypothalamus that regulates the release of corticotropin (ACTH) from the pituitary gland. From here, CRF is transported to the anterior pituitary, stimulating adrenocorticotropic hormone (ACTH) release via CRF type 1 receptors, thereby activating the hypothalamo-pituitary-adrenocortical axis (HPA) and thus glucocorticoid release.

CRF is evolutionary related to a number of other active peptides. Urocortin acts in vitro to stimulate the secretion of adrenocorticotropic hormone. Urotensin is found in the teleost caudal neurosecretory system and may play a role in osmoregulation and as a corticotropin-releasing factor. Urotensin-I is released from the urophysis of fish, and produces ACTH and subsequent cortisol release in vivo. The nonhormonal portion of the prohormone is thought to be the urotensin binding protein (urophysin). Sauvagine is an active peptide from the skin of Phyllomedusa sauvagei, a frog from Central and South America, which possesses a number of pharmacological actions on diuresis, the cardiovascular system and endocrine glands .
Leukemia inhibitory factor (Leukemia_IF)
Type: Family

Leukemia inhibitory factor is a small cytokine that has the capacity to induce terminal differentiation in leukemic cells. It also induces hematopoietic differentiation in normal and myeloid leukemia cells, and neuronal cell differentiation, as well as stimulating acute-phase protein synthesis in hepatocytes.
Parathyroid hormone (PTH)
Type: Family

Parathyroid hormone (PTH) is a polypeptidic hormone that elevates calcium level by dissolving the salts in bone and preventing their renal excretion. It stimulates [1-14C]-2-deoxy-D-glucose (2DG) transport and glycogen synthesis in osteoblastic cells . Defects in PTH are a cause of familial isolated hypoparathyroidism .
Parathyroid hormone-related protein (PTH-rel)
Type: Family

Parathyroid hormone-related protein (PTH-rP) is structurally related to parathyroid hormone (PTH) and seems to play a physiological role in lactation, possibly as a hormone for the mobilisation and/or transfer of calcium to the milk. It also regulates chondrocytic differentiation and bone formation .

This family also includes the zebrafish PTH family member Pth4, unique to noneutherian vertebrates, which is a regulator of bone mineral accrual acting through phosphate homeostasis .

.
Neurokinin-B/Tachykinin-3 (Neurokinin-B/TAC3)
Type: Family

Tachykinins are a group of biologically active peptides which excite neurons, evoke behavioral responses, are potent vasodilatators and contract (directly or indirectly) many smooth muscles. This family includes neurokinin B (also known as Tachykinin-3), as well as many other peptides. Like other tachykinins, neurokinins are synthesized as larger protein precursors that are enzymatically converted to their mature forms. Neurokinin B is a critical central regulator of human gonadal function .
Na-Ca exchanger/integrin-beta4 (Calx_beta)
Type: Domain

The calx-β motif is present as a tandem repeat in the cytoplasmic domains of Calx Na-Ca exchangers, which are used to expel calcium from cells. This motif overlaps domains used for calcium binding and regulation. The calx-β motif is also present in the cytoplasmic tail of mammalian integrin-beta4, which mediates the bi-directional transfer of signals across the plasma membrane, as well as in some cyanobacterial proteins. This motif is also found in Fras1/Frem family of extracellular proteins (extracellular matrix organizing protein FRAS1 and FRAS1-related extracellular matrix proteins FRAM1, 2 and 3) required for proper organogenesis during embryonic development and whose mutations lead to Fraser Syndrome, a rare congenital disorder characterised by multisystem malformation usually comprising abnormal brain formation, cryptophthalmos, syndactyly and renal defects . This motif contains a series of β-strands and turns that form a self-contained β-sheet .
Follistatin-like, N-terminal (Fol_N)
Type: Domain

This EGF-like domain resembles the follistatin-N-terminal domain, and is distinct from the kazal-like sequence. Follistatin binds to activin and is a specific inhibitor of the biosynthesis and secretion of pituitary follicle stimulating hormone . This domain is also found in SPARC, a protein involved in the regulation of cell growth through interactions with the extracellular matrix and cytokines , and the heparan sulfate basal lamina glycoprotein Agrin .