SII-SWORD/CoKE huggingface dataset:
Thrombospondin, type 3 repeat (Thrombospondin_3_rpt)
Type: Repeat

Thrombospondins are multimeric multidomain glycoproteins that function at cell surfaces and in the extracellular matrix milieu. They act as regulators of cell interactions in vertebrates. They are divided into two subfamilies, A and B, according to their overall molecular organisation. The subgroup A proteins TSP-1 and -2 contain an N-terminal domain, a VWFC domain, three TSP1 repeats, three EGF-like domains, TSP3 repeats and a C-terminal domain. They are assembled as trimer. The subgroup B thrombospondins, designated TSP-3, -4, and COMP (cartilage oligomeric matrix protein, also designated TSP-5) are distinct in that they contain unique N-terminal regions, lack the VWFC domain and TSP1 repeats, contain four copies of EGF-like domains, and are assembled as pentamers . EGF, TSP3 repeats and the C-terminal domain are thus the hallmark of a thrombospondin.

The calcium-binding TSP3 repeats are a tandem of aspartic acid-rich motifs, which resembles EF hands in the acidic side chains. But unlike EF hands, the calcium-binding loops of the TSP3 repeats are not flanked by secondary structure elements. The structure of the TSP3 repeats has been solved . They form a wire draped around the calcium ions. The individual calcium-binding repeats are linked by disulphide bonds to each other.
Vacuolar protein sorting-associated, VPS28, N-terminal (VPS28_N)
Type: Domain

The Endosomal Sorting Complex Required for Transport (ESCRT) complexes form the machinery driving protein sorting from endosomes to lysosomes. ESCRT complexes are central to receptor down-regulation, lysosome biogenesis, and budding of HIV. Yeast ESCRT-I consists of three protein subunits, Vps23, Vps28, and Vps37. In humans, ESCRT-I comprises TSG101, VPS28, and one of four potential human VPS37 homologues. The main role of ESCRT-I is to recognise ubiquitinated cargo via the UEV domain of the VPS23/TSG101 subunit. The assembly of the ESCRT-I complex is directed by the C-terminal steadiness box (SB) of VPS23, the N-terminal half of VPS28, and the C-terminal half of VPS37. The structure is primarily composed of three long, parallel helical hairpins, each corresponding to a different subunit. The additional domains and motifs extending beyond the core serve as gripping tools for ESCRT-I critical functions .

This entry represents the N-terminal domain of VPS28.
Vacuolar protein sorting-associated, VPS28, C-terminal (VPS28_C)
Type: Domain

The Endosomal Sorting Complex Required for Transport (ESCRT) complexes form the machinery driving protein sorting from endosomes to lysosomes. ESCRT complexes are central to receptor down-regulation, lysosome biogenesis, and budding of HIV. Yeast ESCRT-I consists of three protein subunits, Vps23, Vps28, and Vps37. In humans, ESCRT-I comprises TSG101, VPS28, and one of four potential human VPS37 homologues. The main role of ESCRT-I is to recognise ubiquitinated cargo via the UEV domain of the VPS23/TSG101 subunit. The assembly of the ESCRT-I complex is directed by the C-terminal steadiness box (SB) of VPS23, the N-terminal half of VPS28, and the C-terminal half of VPS37. The structure is primarily composed of three long, parallel helical hairpins, each corresponding to a different subunit. The additional domains and motifs extending beyond the core serve as gripping tools for ESCRT-I critical functions .

This entry represents the C-terminal domain of VPS28.
4Fe-4S ferredoxin, iron-sulphur binding, conserved site (4Fe4S_Fe_S_CS)
Type: Conserved_site

This entry represents a conserved site of Fe-4S ferredoxin, iron-sulphur binding domain

Ferredoxins are iron-sulphur proteins that mediate electron transfer in a range of metabolic reactions; they fall into several subgroups according to the nature of their iron-sulphur cluster(s) . One group, originally found in bacteria, has been termed "bacterial-type", in which the active centre is a 4Fe-4S cluster. 4Fe-4S ferredoxins may in turn be subdivided into further groups, based on their sequence properties. Most contain at least one conserved domain, including four Cys residues that bind to a 4Fe-4S centre.
C-CAP/cofactor C-like domain (C-CAP_CF_C-like)
Type: Domain

The C-CAP/cofactor C-like domain is present in several cytoskeleton-related proteins, which also contain a number of additional domains :

Eukaryotic cyclase-associated protein (CAP or SRV2), a modular actin monomer binding that directly regulates filament dynamics and has been implicated in a number of complex developmental and morphological processes, including mRNA localisation and the establishment of cell polarity.

Vertebrate retinitis pigmentosa 2 (XRP2). In Homo sapiens (Human), it is the protein responsible for X-linked forms of retinitis pigmentosa, a disease characterised by severe retinal degeneration.

Eukaryotic tubulin-specific chaperone cofactor C (TBCC), a GTPase- activating component of the tubulin-folding supercomplex, which directs the assembly of the alpha- and beta-tubulin heterodimer.

The cyclase-associated protein C-CAP/cofactor C-like domain binds G-actin and is responsible for oligomerisation of the entire CAP molecule , whereas the XRP2 C-CAP/cofactor C-like domain is required for binding of ADP ribosylation factor-like protein 3 (Arl3) .

The central core of the C-CAP/cofactor C-like domain is composed of six coils of right-handed parallel β-helices, termed coils 1-6, which form an elliptical barrel with a tightly packed interior. Each β-helical coil is composed of three relatively short β-strands, designated a-c, separated by sharp turns. Flanking the central β-helical core is an N-terminal β-strand, β0, that packs antiparallel to the core, and strand β7 packs antiparallel to the core near the C-terminal end of the parallel β-helix .
COS domain (COS_domain)
Type: Domain

N-terminal RING finger/B-box/coiled coil (RBCC) or tripartite motif (TRIM) proteins, which are found in metazoa, are involved in a vast array of intracellular functions. They appear to function as part of large protein complexes and possess ubiquitin-protein isopeptide ligase activity. The following RBCC proteins contain an ~60-residue COS (C-terminal subgroup one signature) domain, which is also found in a distantly related non-RBCC microtubule-binding protein, GLFND:

Vertebrate MID1 and MID2, which associate with microtubules through homo- and heterodimerization

Animal TRIM9, which plays a regulatory role in synaptic vesicle exocytosis

Mammalian TRIM nine-like (TNL)

Mammalian TRIM36, which could play a regulatory role in exocytosis of the sperm vesicle

Mammalian tripartite, fibronectin type III and C-terminal B30.2/SPRY (TRIFIC)

Mammalian muscle-specific RING finger (MURF) family. MURF proteins have an ability to form both homo- and heterodimers with each other and to associate with the microtubule cytoskeleton

In addition to RBCC, the COS domain is also found in association with B30.2/SPRY or fibronectin type-III (FN3) domains.

The COS domain is predicted to consist of two α-helical coils .
ADF/Cofilin (ADF/Cofilin)
Type: Family

Actin depolymerization factor/cofilin-like domains (ADF domains) are present in a family of essential eukaryotic actin regulatory proteins. These proteins enhance the turnover rate of actin, and interact with actin monomers (G-actin) as well as actin filaments (F-actin), typically with a preference for ADP-G-actin subunits . The basic function of cofilin is to promote disassembly of aged actin filaments. Vertebrates have three isoforms of cofilin: cofilin-1 (Cfl1, non-muscle cofilin), cofilin-2 (muscle cofilin), and ADF (destrin) . The modes of action of ADF/cofilins highly depend on their concentration. When ADF/cofilins are present in low concentrations they prefer to sever the actin filaments and promote the depolymerization of the pointed end of the filament. At high concentrations they can increase the polymerization by nucleating new actin filaments .
ERV/ALR sulfhydryl oxidase domain (ERV/ALR_sulphydryl_oxidase)
Type: Domain

The ~100-residue ERV/ALR sulphydryl oxidase domain is a versatile module adapted for catalysis of disulphide bond formation in various organelles and biological settings. The ERV/ALR sulphydryl oxidase domain has a Cys-X-X-Cys dithiol/disulphide motif adjacent to a bound FAD cofactor, enabling transfer of electrons from thiol substrates to non-thiol electron acceptors. ERV/ALR family members differ in their N- or C-terminal extensions, which typically contain at least one additional disulphide bond, the hypothesised 'shuttle' disulphide. In yeast ERV1, a mitochondrial enzyme, the shuttle disulphide is N-terminal to the catalytic core; in yeast ERV2, present in the endoplasmic reticulum, it is C-terminal. The N- and C-terminal extensions can be entire domains, such as the thioredoxin-like domains (

) or short segments that do not seem to be distinct domains. Proteins of the ERV/ALR family are encoded by all eukaryotes and cytoplasmic DNA viruses (poxviruses, African swine fever virus, iridoviruses, and Paramecium bursaria Chlorella virus 1) .

The ERV/ALR sulphydryl oxidase domain contains a four-helix bundle (helices α1-α4) and an additional single turn of helix (α5) packed perpendicular to the bundle . The FAD prosthetic group is housed at the mouth of the 4-helix bundle and communicates with the pair of juxtaposed cysteine residues that form the proximal redox active site .
Zinc finger, RING-type, conserved site (Znf_RING_CS)
Type: Conserved_site

A number of eukaryotic and viral proteins contain a conserved cysteine-rich domain of 40 to 60 residues (called C3HC4 zinc-finger or 'RING' finger) that binds two atoms of zinc. There are two different variants, the C3HC4-type and the C3H2C3-type, which is clearly related despite the different cysteine/histidine pattern. The latter type is sometimes referred to as "RING-H2 finger". The 3D structure of the zinc ligation system is referred to as the "cross-brace" motif. This atypical conformation is also shared by the FYVE (see

) and PHD (see

) domains. Many proteins containing a RING finger play a key role in the ubiquitination pathway. The ubiquitination pathway generally involves three types of enzyme, know as E1, E2 and E3. E1 and E2 are ubiquitin conjugating enzymes. E1 acts first and passes ubiquitin to E2. E3 are ubiquitin protein ligases, responsible for substrate recognition. It has been shown that several RING fingers act as E3 enzymes in the ubiquitination process.

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.
Colipase, N-terminal (Colipase_N)
Type: Domain

This entry represents the N-terminal domain of colipase proteins. Colipase is a small protein cofactor needed by pancreatic lipase for efficient dietary lipid hydrolyisis. It also binds to the bile-salt covered triacylglycerol interface, thus allowing the enzyme to anchor itself to the water-lipid interface. Efficient absorption of dietary fats is dependent on the action of pancreatic triglyceride lipase. Colipase binds to the C-terminal, non-catalytic domain of lipase, thereby stabilising as active conformation and considerably increasing the overall hydrophobic binding site. Structural studies of the complex and of colipase alone have revealed the functionality of its architecture .

Colipase is a small protein with five conserved disulphide bonds. Structural analogies have been recognised between a developmental protein (Dickkopf), the pancreatic lipase C-terminal domain, the N-terminal domains of lipoxygenases and the C-terminal domain of alpha-toxin. These non-catalytic domains in the latter enzymes are important for interaction with membrane. It has not been established if these domains are also involved in eventual protein cofactor binding as is the case for pancreatic lipase .
Colipase, C-terminal (Colipase_C)
Type: Domain

This entry represents the C-terminal domain of colipase proteins. Colipase is a small protein cofactor needed by pancreatic lipase for efficient dietary lipid hydrolyisis. It also binds to the bile-salt covered triacylglycerol interface, thus allowing the enzyme to anchor itself to the water-lipid interface. Efficient absorption of dietary fats is dependent on the action of pancreatic triglyceride lipase. Colipase binds to the C-terminal, non-catalytic domain of lipase, thereby stabilising as active conformation and considerably increasing the overall hydrophobic binding site. Structural studies of the complex and of colipase alone have revealed the functionality of its architecture .

Colipase is a small protein with five conserved disulphide bonds. Structural analogies have been recognised between a developmental protein (Dickkopf), the pancreatic lipase C-terminal domain, the N-terminal domains of lipoxygenases and the C-terminal domain of alpha-toxin. These non-catalytic domains in the latter enzymes are important for interaction with membrane. It has not been established if these domains are also involved in eventual protein cofactor binding as is the case for pancreatic lipase .
Colipase, conserved site (Colipase_CS)
Type: Conserved_site

Colipase is a small protein cofactor needed by pancreatic lipase for efficient dietary lipid hydrolyisis. It also binds to the bile-salt covered triacylglycerol interface, thus allowing the enzyme to anchor itself to the water-lipid interface. Efficient absorption of dietary fats is dependent on the action of pancreatic triglyceride lipase. Colipase binds to the C-terminal, non-catalytic domain of lipase, thereby stabilising as active conformation and considerably increasing the overall hydrophobic binding site. Structural studies of the complex and of colipase alone have revealed the functionality of its architecture .

Colipase is a small protein with five conserved disulphide bonds. Structural analogies have been recognised between a developmental protein (Dickkopf), the pancreatic lipase C-terminal domain, the N-terminal domains of lipoxygenases and the C-terminal domain of alpha-toxin. These non-catalytic domains in the latter enzymes are important for interaction with membrane. It has not been established if these domains are also involved in eventual protein cofactor binding as is the case for pancreatic lipase .

This entry represents a conserved site within colipase enzymes, covering two of the cysteines involved in disulphide bond formation, as well as three tyrosine residues which seem to be involved in the interfacial binding.
Steadiness box (SB) domain (SB_dom)
Type: Domain

The Endosomal Sorting Complex Required for Transport (ESCRT) complexes form the machinery driving protein sorting from endosomes to lysosomes. ESCRT complexes are central to receptor down-regulation, lysosome biogenesis, and budding of HIV. Yeast ESCRT-I consists of three protein subunits, Vps23, Vps28, and Vps37. In humans, ESCRT-I comprises TSG101, VPS28, and one of four potential human VPS37 homologues. The main role of ESCRT-I is to recognise ubiquitinated cargo via the UEV domain of the VPS23/TSG101 subunit. The assembly of the ESCRT-I complex is directed by the C-terminal steadiness box (SB) of VPS23, the N-terminal half of VPS28, and the C-terminal half of VPS37. The structure is primarily composed of three long, parallel helical hairpins, each corresponding to a different subunit. The additional domains and motifs extending beyond the core serve as gripping tools for ESCRT-I critical functions .

This entry represents the Steadiness box domain.
Nitrogen regulatory protein PII, conserved site (N-reg_PII_CS)
Type: Conserved_site

The P-II protein (gene glnB) is a bacterial protein important for the control of glutamine synthetase . In nitrogen-limiting conditions, when the ratio of glutamine to 2-ketoglutarate decreases, P-II is uridylylated on a tyrosine residue to form P-II-UMP. P-II-UMP allows the deadenylation of glutamine synthetase (GS), thus activating the enzyme. Conversely, in nitrogen excess, P-II-UMP is deuridylated and then promotes the adenylation of GS. P-II also indirectly controls the transcription of the GS gene (glnA) by preventing NR-II (ntrB) to phosphorylate NR-I (ntrC) which is the transcriptional activator of glnA. Once P-II is uridylylated, these events are reversed.

P-II is a protein of about 110 amino acid residues extremely well conserved. The tyrosine, which is uridylated, is located in the central part of the protein. In cyanobacteria, P-II seems to be phosphorylated on a serine residue rather than being uridylated. In the red alga, Porphyra purpurea, there is a glnB homologue encoded in the chloroplast genome. Other proteins highly similar to glnB include Bacillus subtilis protein nrgB ; and Escherichia coli hypothetical protein ybaI .

This entry represents a conserved site in the C-terminal region of the P-II protein.
Transcription factor TFE/TFIIEalpha HTH domain (TFIIE/TFIIEa_HTH)
Type: Domain

Initiation of eukaryotic mRNA transcription requires melting of promoter DNA with the help of the general transcription factors TFIIE and TFIIH. In higher eukaryotes, the general transcription factor TFIIE consists of two subunits: the large alpha subunit (

) and the small beta (

). TFIIE beta has been found to bind to the region where the promoter starts to open to be single-stranded upon transcription initiation by RNA polymerase II. The approximately 120-residue central core domain of TFIIE beta plays a role in double-stranded DNA binding of TFIIE .

The TFIIE β-central core DNA-binding domain consists of three helices with a β-hairpin at the C terminus, resembling the winged helix proteins. It shows a novel double-stranded DNA-binding activity where the DNA-binding surface locates on the opposite side to the previously reported winged helix motif by forming a positively charged furrow .

Archaea contain a TFIIE homologue, called TFE, which corresponds to the N-terminal half of TFIIEalpha. It appears that archaeal TFE corresponds to the minimal essential region of eukaryotic TFIIEalpha. In archaea TFE contains an N-terminal, weakly conserved, helix-turn-helix (HTH) motif within a leucine-rich region and a C-terminal zinc ribbon . It has been proposed that the TFE/IIEalpha-type HTH domain acts as a bridging factor or adapter between the TATA box-binding protein, the polymerase, and possibly promoter DNA .

The TFE/IIEalpha-type HTH domain adopts a winged HTH (winged helix) fold, comprising three α-helices and three β-strands in the canonical order α1-β1-α2-α3-β2-β3. Conserved residues within helices α1-α3 form the tightly packed hydrophobic core of the winged helix domain. A specific feature of the structure is the extension of the canonical winged helix fold at the N and C termini by the additional helices α0 and α4, respectively. Hydrophobic residues from the additional helix α0 extend the hydrophobic core of the winged helix domain, and helix α0 is tightly packed against the canonical winged helix fold. Helix alpha4 comprises only one turn .
COMM domain (COMM)
Type: Domain

The leucine-rich, 70-85 amino acid long COMM domain is predicted to form a β-sheet .

COMM (copper metabolism gene MURR1) domain proteins constitute a family initially identified as interacting partners of COMMD1 (previously known as MURR1), the prototype member of this protein family. COMMD1 is a multifunctional protein that has been shown to participate in two apparently distinct activities, regulation of the transcription factor NF-kappa-B and control of copper metabolism. The family is defined by the presence of a C-terminal motif termed COMM domain, which functions as an interface for protein-protein interactions. The proteins designated as COMMD or COMM domain containing 1-10 are extensively conserved in multicellular eukaryotic organisms .
Zinc finger, CTCHY-type (Znf_CTCHY)
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.

Pirh2 is an eukaryotic ubiquitin protein ligase, which has been shown to promote p53 degradation in mammals. Pirh2 physically interacts with p53 and promotes ubiquitination of p53 independently of MDM2. Like MDM2, Pirh2 is thought to participate in an autoregulatory feedback loop that controls p53 function. Pirh2 proteins contain three distinct zinc fingers, the CHY-type, the CTCHY-type which is C-terminal to the CHY-type zinc finger and a RING finger. The CHY-type zinc finger has no known functions but the region encompassing the CTCHY-type zinc finger is required for binding to p53 in mammals .

The CTCHY-type zinc finger has so far only been found in Pirh2 proteins. It binds 3 zinc atoms as shown in the following schematic representation:

The CTCHY-type zinc finger:

+--+------------+------+
| | | |
CxxCxxxxxxxxxxHCxxCxxCxxxxxxxxxHCxxCxxCxxxxxxxxHxC
| | | | | | | |
+--+----------+------+ +--+-----------+-+

'C': conserved cysteine involved in the binding of one zinc atom.
'H': conserved histidine involved in the binding of one zinc atom.