SII-SWORD/CoKE huggingface dataset:
Small GTPase Rho (Small_GTPase_Rho)
Type: Family

This entry represents the Rho subfamily of Ras-like small GTPases. The small GTPase-like protein LIP2 (light insensitive period 2) from
Arabidopsis thaliana
is implicated in control of the plant circadian rhythm . The crystal structures of a number of the members of this entry have been determined: Rnd3/RhoE , RhoA and Cdc42 .

Small GTPases form an independent superfamily within the larger class of regulatory GTP hydrolases. This superfamily contains proteins that control a vast number of important processes and possess a common, structurally preserved GTP-binding domain . Sequence comparisons of small G proteins from various species have revealed that they are conserved in primary structures at the level of 30-55% similarity .

Crystallographic analysis of various small G proteins revealed the presence of a 20kDa catalytic domain that is unique for the whole superfamily . The domain is built of five α helices (A1-A5), six β-strands (B1-B6) and five polypeptide loops (G1-G5). A structural comparison of the GTP- and GDP-bound forms allows one to distinguish two functional loop regions: switch I and switch II that surround the gamma-phosphate group of the nucleotide. The G1 loop (also called the P-loop) that connects the B1 strand and the A1 helix is responsible for the binding of the phosphate groups. The G3 loop provides residues for Mg2 and phosphate binding and is located at the N terminus of the A2 helix. The G1 and G3 loops are sequentially similar to Walker A and Walker B boxes that are found in other nucleotide binding motifs. The G2 loop connects the A1 helix and the B2 strand and contains a conserved Thr residue responsible for Mg2 binding. The guanine base is recognised by the G4 and G5 loops. The consensus sequence NKXD of the G4 loop contains Lys and Asp residues directly interacting with the nucleotide. Part of the G5 loop located between B6 and A5 acts as a recognition site for the guanine base .

The small GTPase superfamily can be divided into at least 8 different families, including:

Arf small GTPases. GTP-binding proteins involved in protein trafficking by modulating vesicle budding and uncoating within the Golgi apparatus.

Ran small GTPases. GTP-binding proteins involved in nucleocytoplasmic transport. Required for the import of proteins into the nucleus and also for RNA export.

Rab small GTPases. GTP-binding proteins involved in vesicular traffic.

Rho small GTPases. GTP-binding proteins that control cytoskeleton reorganisation.

Ras small GTPases. GTP-binding proteins involved in signalling pathways.

Sar1 small GTPases. Small GTPase component of the coat protein complex II (COPII) which promotes the formation of transport vesicles from the endoplasmic reticulum (ER).

Mitochondrial Rho (Miro). Small GTPase domain found in mitochondrial proteins involved in mitochondrial trafficking.

Roc small GTPases domain. Small GTPase domain always found associated with the COR domain.
ShKT domain (ShKT_dom)
Type: Domain

BgK, a 37-residue peptide toxin from the sea anemone Bunodosoma granulifera, and ShK, a 35-residue peptide toxin from the sea anemone Stichodactyla helianthus, are potent inhibitors of K channels. There is a large superfamily of proteins that contains domains (referred to as ShKT domains) resembling these two toxins. Many of these proteins are metallopeptidases, whereas others are prolyl-4-hydroxylases, tyrosinases, peroxidases, oxidoreductases, or proteins containing epidermal growth factor-like domains, thrombospondin-type repeats, or trypsin-like serine protease domains . The ShKT domain has also been called NC6 (nematode six-cysteine) domain , SXC (six-cysteine) domain and ICR (ion channel regulator) . The ShKT domain is short (36 to 42 amino acids), with six conserved cysteines and a number of other conserved residues. The fold adopted by the ShKT domain contains two nearly perpendicular stretches of helices, with no additional canonical secondary structures . The globular architecture of the ShKT domain is stabilised by three disulfides, one of them linking the two helices. In venomous creatures, the ShKT domain may have been modified to give rise to potent ion channel blockers, whereas the incorporation of this domain into plant oxidoreductases and prolyl hydroxylases and into worm astacin-like metalloproteases and trypsin-like serine proteases produced enzymes with potential channel-modulatory activity.

Some proteins known to contain a ShKT domain are listed below:

Caribbean sea anemone ShK, a potassium channel toxin .

Sea anemone BgK, a potassium channel toxin .

Toxocara canis family of secreted mucins Tc-MUC-1 to -5, which are implicated in immune evasion. They combine two evolutionarily distinct modules, the mucin and ShkT domains .

Some Caenorhabditis elegans astacin-like proteins (nematode astacins, NAS), metalloproteases .

Vertebrate cysteine-rich secretory proteins (Crisp) .

Mammalian microfibrillar-associated protein 2 (MFAP2 or MAGP1), a matrix protein.

Plant prolyl 4-hydroxylase.
Helix-hairpin-helix DNA-binding motif, class 1 (Hlx-hairpin-Hlx_DNA-bd_motif)
Type: Domain

The HhH motif is a stretch of approximately 20 amino acids that is present in prokaryotic and eukaryotic non-sequence-specific DNA binding proteins . The HhH motif is similar to, but distinct from, the HtH motif. Both of these motifs have two helices connected by a short turn. In the HtH motif the second helix binds to DNA with the helix in the major groove. This allows the contact between specific base and residues throughout the protein. In the HhH motif the second helix does not protrude from the surface of the protein and therefore cannot lie in the major groove of the DNA. Crystallographic studies suggest that the interaction of the HhH domain with DNA is mediated by amino acids located in the strongly conserved loop (L-P-G-V) and at the N-terminal end of the second helix . This interaction could involve the formation of hydrogen bonds between protein backbone nitrogens and DNA phosphate groups . The structural difference between the HtH and HhH domains is reflected at the functional level: whereas the HtH domain, found primarily in gene regulatory proteins and binds DNA in a sequence specific manner, the HhH domain is rather found in proteins involved in enzymatic activities and binds DNA with no sequence specificity .
Neurexin/syndecan/glycophorin C (Neurexin-like)
Type: Domain

The putative band 4.1 homologues' binding motif is found in neurexins, syndecans and glycophorin C intracellular C-termini. Syndecans are cell surface proteoglycans and glycophorin C is a minor sialoglycoprotein in human erythrocyte membranes, which play an important role in regulating the stability of red cells.

Syndecan-4, a transmembrane heparan sulphate proteoglycan, is a coreceptor with integrins in cell adhesion. It has been suggested to form a ternary signalling complex with protein kinase Calpha and phosphatidylinositol 4,5-bisphosphate (PIP2). Structural studies have demonstrated that the cytoplasmic domain undergoes a conformational transition and forms a symmetric dimer in the presence of phospholipid activator PIP2, and whose overall structure in solution exhibits a twisted clamp shape having a cavity in the centre of dimeric interface. In addition, it has been observed that the syndecan-4 variable domain interacts, strongly, not only with fatty acyl groups but also the anionic head group of PIP2. These findings indicate that PIP2 promotes oligomerisation of the syndecan-4 cytoplasmic domain for transmembrane signalling and cell-matrix adhesion .

Some of the proteins in this group are responsible for the molecular basis of the blood group antigens, surface markers on the outside of the red blood cell membrane. Most of these markers are proteins, but some are carbohydrates attached to lipids or proteins [Reid M.E., Lomas-Francis C. The Blood Group Antigen FactsBook Academic Press, London / San Diego, (1997)]. Glycophorin C (PAS-2') belongs to the Gerbich blood group system and is associated with An(a), Dh(A), Ls(a) and Wb antigens.
Hint domain C-terminal (Hint_dom_C)
Type: Domain

This entry represents the C-terminal region of the hint domain.

Hedgehog proteins are a family of secreted signal molecules required for embryonic cell differentiation. They are synthesised as inactive precursors with an N-terminal signalling domain linked to a C-terminal autoprocessing domain. The three-dimensional structure of the autolytic domain of the hedgehog protein of shows similarity with the β-strand core of intein splicing domains. It has hence been termed the hint (Hedgehog/Intein) domain .
Hint domain N-terminal (Hint_dom_N)
Type: Domain

This entry represents the N-terminal region of the hint domain.

Hedgehog proteins are a family of secreted signal molecules required for embryonic cell differentiation. They are synthesised as inactive precursors with an N-terminal signalling domain linked to a C-terminal autoprocessing domain. The three-dimensional structure of the autolytic domain of the hedgehog protein of shows similarity with the β-strand core of intein splicing domains. It has hence been termed the hint (Hedgehog/Intein) domain .
Leucine-rich repeat, typical subtype (Leu-rich_rpt_typical-subtyp)
Type: Repeat

Leucine-rich repeats (LRR) consist of 2-45 motifs of 20-30 amino acids in length that generally folds into an arc or horseshoe shape . LRRs occur in proteins ranging from viruses to eukaryotes, and appear to provide a structural framework for the formation of protein-protein interactions .Proteins containing LRRs include tyrosine kinase receptors, cell-adhesion molecules, virulence factors, and extracellular matrix-binding glycoproteins, and are involved in a variety of biological processes, including signal transduction, cell adhesion, DNA repair, recombination, transcription, RNA processing, disease resistance, apoptosis, and the immune response .

Sequence analyses of LRR proteins suggested the existence of several different subfamilies of LRRs. The significance of this classification is that repeats from different subfamilies never occur simultaneously and have most probably evolved independently. It is, however, now clear that all major classes of LRR have curved horseshoe structures with a parallel β sheet on the concave side and mostly helical elements on the convex side. At least six families of LRR proteins, characterised by different lengths and consensus sequences of the repeats, have been identified. Eleven-residue segments of the LRRs (LxxLxLxxN/CxL), corresponding to the β-strand and adjacent loop regions, are conserved in LRR proteins, whereas the remaining parts of the repeats (herein termed variable) may be very different. Despite the differences, each of the variable parts contains two half-turns at both ends and a "linear" segment (as the chain follows a linear path overall), usually formed by a helix, in the middle. The concave face and the adjacent loops are the most common protein interaction surfaces on LRR proteins.
3D structure of some LRR proteins-ligand complexes show that the concave surface of LRR domain is ideal for interaction with α-helix, thus supporting earlier conclusions that the elongated and curved LRR structure provides an outstanding framework for achieving diverse protein-protein interactions . Molecular modeling suggests that the conserved pattern LxxLxL, which is shorter than the previously proposed LxxLxLxxN/CxL is sufficient to impart the characteristic horseshoe curvature to proteins with 20-to 30-residue repeats .

This entry represents a most populated subfamily of leucine-rich repeats.
AAA+ ATPase domain (AAA+_ATPase)
Type: Domain

This entry represents the AAA+ ATPase domain found in a range of proteins, including Holliday junction ATP-dependent DNA helicase RuvB from Mycobacterium sp, ATP synthases, and related ATP-dependent proteins.

The proteins in this superfamily are characterised by the structural conservation of a central ATPase domain of about 250 amino acids called the AAA module. Typically, the AAA domain can be divided into two structural subdomains, an N-terminal P-loop NTPase α-β-α subdomain that is connected to a smaller C-terminal all-α subdomain. The α-β-α subdomain adopts a Rossman fold and contains several motifs involved in ATP binding and hydrolysis, including classical motifs Walker A and Walker B . The all-α subdomain , is much less conserved across AAA proteins.

The AAA+ superfamily of ATPases is found in all kingdoms of living organisms where they participate in diverse cellular processes including membrane fusion, proteolysis and DNA replication. Although the terms AAA+ and AAA are often used loosely and interchangeably, the classical AAA family members are distinguished by their possession of the SRH region in the AAA module. Many AAA+ proteins are involved in similar processes to those of AAA proteins (facilitation of protein folding and unfolding, assembly or disassembly of proteins complexes, protein transport and degradation), but others function in replication, recombination, repair and transcription. For a review see .
Histidine kinase/HSP90-like ATPase domain (HATPase_dom)
Type: Domain

This domain is found in several ATP-binding proteins, including: histidine kinase , DNA gyrase B, topoisomerases , heat shock protein HSP90 , phytochrome-like ATPases and DNA mismatch repair proteins. The fold of this domain consists of two layers, α/β, which contains an 8-stranded mixed β-sheet.
Protein-tyrosine phosphatase, catalytic (Tyr_Pase_cat)
Type: Domain

This entry represents the PTP-signature motif that characterises the catalytic site, and which encompasses only part of the PTPase domain structure.

Protein tyrosine (pTyr) phosphorylation is a common post-translational modification which can create novel recognition motifs for protein interactions and cellular localisation, affect protein stability, and regulate enzyme activity. Consequently, maintaining an appropriate level of protein tyrosine phosphorylation is essential for many cellular functions. Tyrosine-specific protein phosphatases (PTPase;

) catalyse the removal of a phosphate group attached to a tyrosine residue, using a cysteinyl-phosphate enzyme intermediate. These enzymes are key regulatory components in signal transduction pathways (such as the MAP kinase pathway) and cell cycle control, and are important in the control of cell growth, proliferation, differentiation and transformation . The PTP superfamily can be divided into four subfamilies :

(1) pTyr-specific phosphatases

(2) dual specificity phosphatases (dTyr and dSer/dThr)

(3) Cdc25 phosphatases (dTyr and/or dThr)

(4) LMW (low molecular weight) phosphatases

Based on their cellular localisation, PTPases are also classified as:

Receptor-like, which are transmembrane receptors that contain PTPase domains

Non-receptor (intracellular) PTPases

All PTPases carry the highly conserved active site motif C(X)5R (PTP signature motif), employ a common catalytic mechanism, and share a similar core structure made of a central parallel β-sheet with flanking α-helices containing a β-loop-α-loop that encompasses the PTP signature motif . Functional diversity between PTPases is endowed by regulatory domains and subunits.
Immunoglobulin C1-set (Ig_C1-set)
Type: Domain

The basic structure of immunoglobulin (Ig) molecules is a tetramer of two light chains and two heavy chains linked by disulphide bonds. There are two types of light chains: kappa and lambda, each composed of a constant domain (CL) and a variable domain (VL). There are five types of heavy chains: alpha, delta, epsilon, gamma and mu, all consisting of a variable domain (VH) and three (in alpha, delta and gamma) or four (in epsilon and mu) constant domains (CH1 to CH4). Ig molecules are highly modular proteins, in which the variable and constant domains have clear, conserved sequence patterns. The domains in Ig and Ig-like molecules are grouped into four types: V-set (variable;

), C1-set (constant-1;

), C2-set (constant-2;

) and I-set (intermediate;

) . Structural studies have shown that these domains share a common core Greek-key β-sandwich structure, with the types differing in the number of strands in the β-sheets as well as in their sequence patterns .

Immunoglobulin-like domains that are related in both sequence and structure can be found in several diverse protein families. Ig-like domains are involved in a variety of functions, including cell-cell recognition, cell-surface receptors, muscle structure and the immune system .

This entry represents C1-set domains, which are classical Ig-like domains resembling the antibody constant domain. C1-set domains are found almost exclusively in molecules involved in the immune system, such as in immunoglobulin light and heavy chains, in the major histocompatibility complex (MHC) class I and II complex molecules , and in various T-cell receptors.
Immunoglobulin subtype 2 (Ig_sub2)
Type: Domain

This entry represents a subtype of the immunoglobulin domain, and is found in a diverse range of protein families that includes glycoproteins, fibroblast growth factor receptors, vascular endothelial growth factor receptors, interleukin-6 receptor, and neural cell adhesion molecules .

The basic structure of immunoglobulin (Ig) molecules is a tetramer of two light chains and two heavy chains linked by disulphide bonds. There are two types of light chains: kappa and lambda, each composed of a constant domain (CL) and a variable domain (VL). There are five types of heavy chains: alpha, delta, epsilon, gamma and mu, all consisting of a variable domain (VH) and three (in alpha, delta and gamma) or four (in epsilon and mu) constant domains (CH1 to CH4). Ig molecules are highly modular proteins, in which the variable and constant domains have clear, conserved sequence patterns. The domains in Ig and Ig-like molecules are grouped into four types: V-set (variable;

), C1-set (constant-1;

), C2-set (constant-2;

) and I-set (intermediate;

) . Structural studies have shown that these domains share a common core Greek-key β-sandwich structure, with the types differing in the number of strands in the β-sheets as well as in their sequence patterns .

Immunoglobulin-like domains that are related in both sequence and structure can be found in several diverse protein families. Ig-like domains are involved in a variety of functions, including cell-cell recognition, cell-surface receptors, muscle structure and the immune system .
Immunoglobulin domain subtype (Ig_sub)
Type: Domain

This entry represents a subtype of the immunoglobulin domain which is found in a group of proteins that includes:

Cell surface receptors containing an immunoglobulin domain.

Killer cell inhibitory receptors.

Cell adhesion molecules.

The basic structure of immunoglobulin (Ig) molecules is a tetramer of two light chains and two heavy chains linked by disulphide bonds. There are two types of light chains: kappa and lambda, each composed of a constant domain (CL) and a variable domain (VL). There are five types of heavy chains: alpha, delta, epsilon, gamma and mu, all consisting of a variable domain (VH) and three (in alpha, delta and gamma) or four (in epsilon and mu) constant domains (CH1 to CH4). Ig molecules are highly modular proteins, in which the variable and constant domains have clear, conserved sequence patterns. The domains in Ig and Ig-like molecules are grouped into four types: V-set (variable;

), C1-set (constant-1;

), C2-set (constant-2;

) and I-set (intermediate;

) . Structural studies have shown that these domains share a common core Greek-key β-sandwich structure, with the types differing in the number of strands in the β-sheets as well as in their sequence patterns .

Immunoglobulin-like domains that are related in both sequence and structure can be found in several diverse protein families. Ig-like domains are involved in a variety of functions, including cell-cell recognition, cell-surface receptors, muscle structure and the immune system .
DNA topoisomerase, type IA, domain 2 (Topo_IA_2)
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 domain 2 found in type IA topoisomerases, which may be an extension of the Toprim domain. 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 forms the active site of the enzyme, while domains 2 and 4 form a single-strand DNA-binding groove . The Toprim domain (

) forms a compact Rossmann fold that coordinates the Mg+2 ion .