SII-SWORD/CoKE huggingface dataset:
D-lysine 5,6-aminomutase beta subunit KamE, N-terminal domain superfamily (KamE_N_sf)
Type: Homologous_superfamily

D-lysine 5,6-aminomutase beta subunit KamE catalyses the 1,2-migration of the D-lysine epsilon amino group to the δ-carbon with concomitant reverse migration of a hydrogen atom to produce 2,5-diaminohexanoic acid .
Hint domain superfamily (Hint_dom_sf)
Type: Homologous_superfamily

This entry represents a domain superfamily found in the pretoxin HINT domain protein and the C-terminal of protein hedgehog.

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 autoprocessing domain shows similarity with the β-strand core of intein splicing domains. It has hence been termed the Hedgehog/Intein (Hint) domain .
RecG, N-terminal domain superfamily (RecG_N_sf)
Type: Homologous_superfamily

ATP-dependent DNA helicase RecG is involved in the processing of stalled replication forks. It acts by reversing the fork past the damage to create a four-way junction that allows template switching and lesion bypass . RecG comprises three structural domains: N-terminal domain 1 (residues 1-350) and C-terminal domain 2 (residues 351-549) and domain3 (residues 550-780). This entry represents an antiparallel four helix bundle motif of the domain 1 .
GM2-AP, lipid-recognition domain superfamily (GM2-AP_sf)
Type: Homologous_superfamily

Ganglioside GM2 activator (GM2-AP) is a is a lysosomal lipid transfer protein that is essential for the hydrolytic conversion of ganglioside GM2 to GM3 by beta-hexosaminidase A . The crystal structure of apo-GM2-AP consists of a novel β-cup fold with a spacious hydrophobic interior .
Ribosome maturation factor RimP, C-terminal domain superfamily (RimP_C_sf)
Type: Homologous_superfamily

The RimP protein (also known as YlxS in Bacillus subtilis) facilitates maturation of the 30S ribosomal subunit, and is required for the efficient production of translationally competent ribosomes .

The C-terminal domain of RimP contains a SH3-type barrel.
Haemocyanin C-terminal domain superfamily (Haemocyanin_C_sf)
Type: Homologous_superfamily

This antiparallel β sandwich domain occurs in the C-terminal of mollusc haemocyanins, which are copper-containing oxygen carriers occurring freely dissolved in the hemolymph of many mollusks and arthropods. Each mollusc haemocyanin contains several globular oxygen binding functional units. Each unit consists of an α-helical copper binding domain (

) and an antiparallel β sandwich domain .
Enolase-like, C-terminal domain superfamily (Enolase-like_C_sf)
Type: Homologous_superfamily

The C-terminal domain of the enolase adopts a TIM barrel fold that contains a metal binding site . Proteins containing this domain also include D-glucarate dehydratase-like proteins and some uncharacterised proteins .
Nucleoside diphosphate kinase-like domain superfamily (NDK-like_dom_sf)
Type: Homologous_superfamily

Nucleoside diphosphate kinases (

) (NDK) are enzymes required for the synthesis of nucleoside triphosphates (NTP) other than ATP. They provide NTPs for nucleic acid synthesis, CTP for lipid synthesis, UTP for polysaccharide synthesis and GTP for protein elongation, signal transduction and microtubule polymerisation.

NDK are proteins of 17 Kd that act via a ping-pong mechanism in which a histidine residue is phosphorylated, by transfer of the terminal phosphate group from ATP. In the presence of magnesium, the phosphoenzyme can transfer its phosphate group to any NDP, to produce an NTP.

NDK isozymes have been sequenced from prokaryotic and eukaryotic sources. It has also been shown that the Drosophila awd (abnormal wing discs) protein, is a microtubule-associated NDK. Mammalian NDK is also known as metastasis inhibition factor nm23. The sequence of NDK has been highly conserved through evolution. There is a single histidine residue conserved in all known NDK isozymes, which is involved in the catalytic mechanism .

This entry represents the Nucleoside diphosphate kinase-like domain that contains an α/β fold. It is also found at the C-terminal of retinitis pigmentosa 2 protein (XRP2/RP2) . XRP2, a GTPase-activating protein, is required for the maintenance of rod and cone photoreceptor cells in the retina . NDK is a hexamer composed of identical subunits with a novel mononucleotide binding fold. Each subunit contains an α/β domain with a four stranded, anti-parallel β-sheet .
Chloroperoxidase-like superfamily (Chloroperoxidase-like_sf)
Type: Homologous_superfamily

Chloroperoxidase (CPO), also known as Heme haloperoxidase, is a ~250 residue heme-containing glycoprotein that is secreted by various fungi. Chloroperoxidase was first identified in Caldariomyces fumago where it catalyses the hydrogen peroxide-dependent chlorination of cyclopentanedione during the biosynthesis of the antibiotic caldarioymcin. Additionally, Heme haloperoxidase catalyses the iodination and bromination of a wide range of substrates. Besides performing H2O2-dependent halogenation reactions, the enzyme catalyses dehydrogenation reactions. Chloroperoxidase also functions as a catalase, facilitating the decomposition of hydrogen peroxide to oxygen and water. Furthermore, chloroperoxidase catalyses P450-like oxygen insertion reactions. The capability of chloroperoxidase to perform these diverse reactions makes it one of the most versatile of all known heme proteins .

Despite functional similarities with other heme enzymes, chloroperoxidase folds into a novel tertiary structure dominated by eight helical segments . Structurally, chloroperoxidase is unique, but it shares features with both peroxidases and P450 enzymes. As in cytochrome P450 enzymes, the proximal heme ligand is a cysteine, but similar to peroxidases, the distal side of the heme is polar. However, unlike other peroxidases, the normally conserved distal arginine is lacking and the catalytic acid base is a glutamic acid and not a histidine .
Peptidase S8/S53 domain superfamily (Peptidase_S8/S53_dom_sf)
Type: Homologous_superfamily

These proteins contain a domain superfamily found in serine peptidases belonging to the MEROPS peptidase families S8 (subfamilies S8A (subtilisin) and S8B (kexin) and S53 (sedolisin), both of which are members of clan SB .

The subtilisin family is one of the largest serine peptidase families characterised to date. Over 200 subtilises are presently known, more than 170 of which with their complete amino acid sequence . It is widespread, being found in eubacteria, archaebacteria, eukaryotes and viruses . The vast majority of the family are endopeptidases, although there is an exopeptidase, tripeptidyl peptidase . Structures have been determined for several members of the subtilisin family: they exploit the same catalytic triad as the chymotrypsins, although the residues occur in a different order (HDS in chymotrypsin and DHS in subtilisin), but the structures show no other similarity . Some subtilisins are mosaic proteins, while others contain N- and C-terminal extensions that show no sequence similarity to any other known protein .

The proprotein-processing endopeptidases kexin, furin and related enzymes form a distinct subfamily known as the kexin subfamily (S8B). These preferentially cleave C-terminally to paired basic amino acids. Members of this subfamily can be identified by subtly different motifs around the active site . Members of the kexin subfamily, along with endopeptidases R, T and K from the yeast Tritirachium and cuticle-degrading peptidase from Metarhizium, require thiol activation. This can be attributed to the presence of a cysteine near to the active site histidine . Only one viral member of the subtilisin family is known, a 56kDa protease from herpes virus 1, which infects the channel catfish .
Large ribosomal subunit protein uL14 superfamily (Ribosomal_uL14_sf)
Type: Homologous_superfamily

This entry represents the large ribosomal subunit protein uL14 (formerly known as L14) from all domains of life. In eubacteria, uL14 is known to bind directly to the 23S rRNA. It belongs to a family of ribosomal proteins, which have been grouped on the basis of sequence similarities. Based on amino-acid sequence homology, it is predicted that ribosomal protein L14 is a member of a recently identified family of structurally related RNA-binding proteins . L14 is a protein of 119 to 137 amino-acid residues.

Ribosomes are the particles that catalyse mRNA-directed protein synthesis in all organisms. The codons of the mRNA are exposed on the ribosome to allow tRNA binding. This leads to the incorporation of amino acids into the growing polypeptide chain in accordance with the genetic information. Incoming amino acid monomers enter the ribosomal A site in the form of aminoacyl-tRNAs complexed with elongation factor Tu (EF-Tu) and GTP. The growing polypeptide chain, situated in the P site as peptidyl-tRNA, is then transferred to aminoacyl-tRNA and the new peptidyl-tRNA, extended by one residue, is translocated to the P site with the aid the elongation factor G (EF-G) and GTP as the deacylated tRNA is released from the ribosome through one or more exit sites . About 2/3 of the mass of the ribosome consists of RNA and 1/3 of protein. The proteins are named in accordance with the subunit of the ribosome which they belong to the small (S1 to S31) and the large (L1 to L44). Usually they decorate the rRNA cores of the subunits.

Many ribosomal proteins, particularly those of the large subunit, are composed of a globular, surfaced-exposed domain with long finger-like projections that extend into the rRNA core to stabilise its structure. Most of the proteins interact with multiple RNA elements, often from different domains. In the large subunit, about 1/3 of the 23S rRNA nucleotides are at least in van der Waal's contact with protein, and L22 interacts with all six domains of the 23S rRNA. Proteins S4 and S7, which initiate assembly of the 16S rRNA, are located at junctions of five and four RNA helices, respectively. In this way proteins serve to organise and stabilise the rRNA tertiary structure. While the crucial activities of decoding and peptide transfer are RNA based, proteins play an active role in functions that may have evolved to streamline the process of protein synthesis. In addition to their function in the ribosome, many ribosomal proteins have some function 'outside' the ribosome .
Zinc finger, CCCH-type superfamily (Znf_CCCH_sf)
Type: Homologous_superfamily

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.

This entry represents C-x8-C-x5-C-x3-H (CCCH) type Zinc finger (Znf) domains superfamily. Proteins containing CCCH Znf domains include Znf proteins from eukaryotes involved in cell cycle or growth phase-related regulation, e.g. human TIS11B (butyrate response factor 1), a probable regulatory protein involved in regulating the response to growth factors, and the mouse TTP growth factor-inducible nuclear protein, which has the same function. The mouse TTP protein is induced by growth factors. Another protein containing this domain is the human splicing factor U2AF 35kDa subunit, which plays a critical role in both constitutive and enhancer-dependent splicing by mediating essential protein-protein interactions and protein-RNA interactions required for 3' splice site selection. It has been shown that different CCCH-type Znf proteins interact with the 3'-untranslated region of various mRNA . This type of Znf is very often present in two copies.
Aldehyde oxidase/xanthine dehydrogenase, a/b hammerhead superfamily (Ald_Oxase/Xan_DH_a/b_sf)
Type: Homologous_superfamily

Aldehyde oxidase (

) catalyses the conversion of an aldehyde in the presence of oxygen and water to an acid and hydrogen peroxide. The enzyme is a homodimer, and requires FAD, molybdenum and two 2FE-2S clusters as cofactors. Xanthine dehydrogenase (

) catalyses the hydrogenation of xanthine to urate, and also requires FAD, molybdenum and two 2FE-2S clusters as cofactors. This activity is often found in a bifunctional enzyme with xanthine oxidase (

) activity too. The enzyme can be converted from the dehydrogenase form to the oxidase form irreversibly by proteolysis or reversibly through oxidation of sulphydryl groups.

The aldehyde oxidase and xanthine dehydrogenase, a/b hammerhead domain is an evolutionary conserved protein domain . The core structure of this domain has a β-β-α-β-β-β-α fold and contains a β-hammerhead motif similar to that in barrel-sandwich hybrids.
Thyroglobulin type-1 superfamily (Thyroglobulin_1_sf)
Type: Homologous_superfamily

Thyroglobulin (Tg) is a large glycoprotein specific to the thyroid gland and is the precursor of the iodinated thyroid hormones thyroxine (T4) and triiodothyronine (T3). The N-terminal section of Tg contains 10 repeats of a domain of about 65 amino acids which is known as the Tg type-1 repeat . Such a domain has also been found as a single or repeated sequence in the HLA class II associated invariant chain ; human pancreatic carcinoma marker proteins GA733-1 and GA733-2 ; nidogen (entactin), a sulphated glycoprotein which is widely distributed in basement membranes and that is tightly associated with laminin; insulin-like growth factor binding proteins (IGFBP) ; saxiphilin, a transferrin-like protein from Rana catesbeiana (Bull frog) that binds specifically to the neurotoxin saxitoxin ; chum salmon egg cysteine proteinase inhibitor, and equistatin, a thiol-protease inhibitor from Actinia equina (sea anemone) . The existence of Thyr-1 domains in such a wide variety of proteins raises questions about their activity and function, and their interactions with neighbouring domains. The Thyr-1 and related domains belong to MEROPS proteinase inhibitor family I31, clan IX.

Equistatin from A. equina is composed of three Thyr-1 domains; as with other proteins that contains Thyr-1 domains, the thyropins, they bind reversibly and tightly to cysteine proteases (inhibitor family C1). In equistatin inhibition of papain is a function of domain-1. Unusually domain-2 inhibits cathepsin D, an aspartic protease (inhibitor family A1) and has no activity against papain. Domain-3, does not inhibit either papain or cathepsin D, and its function or its target peptidase has yet to be determined .

The thyroglobulin type-1 domain has an α+β fold.
Cyclin-dependent kinase, regulatory subunit superfamily (Cyclin-dep_kinase_reg-sub_sf)
Type: Homologous_superfamily

In eukaryotes, cyclin-dependent protein kinases interact with cyclins to regulate cell cycle progression, and are required for the G1 and G2 stages of cell division . The proteins bind to a regulatory subunit, cyclin-dependent kinase regulatory subunit (CKS), which is essential for their function. This regulatory subunit is a small protein of 79 to 150 residues. In yeast (gene CKS1) and in fission yeast (gene suc1) a single isoform is known, while mammals have two highly related isoforms. The regulatory subunits exist as hexamers, formed by the symmetrical assembly of 3 interlocked homodimers, creating an unusual 12-stranded β-barrel structure . Through the barrel centre runs a 12A diameter tunnel, lined by 6 exposed helix pairs . Six kinase units can be modelled to bind the hexameric structure, which may thus act as a hub for cyclin-dependent protein kinase multimerisation .
CAP Gly-rich domain superfamily (CAP-Gly_dom_sf)
Type: Homologous_superfamily

Cytoskeleton-associated proteins (CAPs) are involved in the organisation of microtubules and transportation of vesicles and organelles along the cytoskeletal network. A conserved glycine-rich domain, CAP-Gly, has been identified in a number of CAPs, including CLIP-170 and dynactins. The crystal structure of the Caenorhabditis elegans F53F4.3 protein CAP-Gly domain has been solved. The domain contains three β-strands. The most conserved sequence, GKNDG, is located in two consecutive sharp turns on the surface, forming the entrance to a groove .
SH2 domain superfamily (SH2_dom_sf)
Type: Homologous_superfamily

The Src homology 2 (SH2) domain is a protein domain of about 100 amino-acid residues first identified as a conserved sequence region between the oncoproteins Src and Fps . Similar sequences were later found in many other intracellular signal-transducing proteins . SH2 domains function as regulatory modules of intracellular signalling cascades by interacting with high affinity to phosphotyrosine-containing target peptides in a sequence-specific, SH2 domains recognise between 3-6 residues C-terminal to the phosphorylated tyrosine in a fashion that differs from one SH2 domain to another, and strictly phosphorylation-dependent manner . They are found in a wide variety of protein contexts e.g., in association with catalytic domains of phospholipase Cy (PLCy) and the non-receptor protein tyrosine kinases; within structural proteins such as fodrin and tensin; and in a group of small adaptor molecules, i.e Crk and Nck. The domains are frequently found as repeats in a single protein sequence and will then often bind both mono- and di-phosphorylated substrates.

The structure of the SH2 domain belongs to the α+β class, its overall shape forming a compact flattened hemisphere. The core structural elements comprise a central hydrophobic anti-parallel β-sheet, flanked by 2 short α-helices. The loop between strands 2 and 3 provides many of the binding interactions with the phosphate group of its phosphopeptide ligand, and is hence designated the phosphate binding loop, the phosphorylated ligand binds perpendicular to the β-sheet and typically interacts with the phosphate binding loop and a hydrophobic binding pocket that interacts with a pY+3 side chain. The N- and C-termini of the domain are close together in space and on the opposite face from the phosphopeptide binding surface and it has been speculated that this has facilitated their integration into surface-exposed regions of host proteins .
Endochitinase-like superfamily (Endochitinase-like_sf)
Type: Homologous_superfamily

A number of plant and fungal proteins that bind N-acetylglucosamine (e.g. solanaceous lectins of tomato and potato, plant endochitinases, the wound-induced proteins: hevein, win1 and win2, and the Kluyveromyces lactis killer toxin alpha subunit) contain this domain . The domain may occur in one or more copies and is thought to be involved in recognition or binding of chitin subunits . In chitinases, as well as in the potato wound-induced proteins, the 43-residue domain directly follows the signal sequence and is therefore at the N terminus of the mature protein; in the killer toxin alpha subunit it is located in the central section of the protein.
Integrase, C-terminal domain superfamily, retroviral (Integrase_C_dom_sf_retrovir)
Type: Homologous_superfamily

Integrase comprises three domains capable of folding independently and whose three-dimensional structures are known. However, the manner in which the N-terminal, catalytic core, and C-terminal domains interact in the holoenzyme remains obscure. Numerous studies indicate that the enzyme functions as a multimer, minimally a dimer. The integrase proteins from Human immunodeficiency virus 1 (HIV-1) and Avian sarcoma virus (have been studied most carefully with respect to the structural basis of catalysis. Although the active site of avian virus integrase does not undergo significant conformational changes on binding the required metal cofactor, that of HIV-1 does. This active site-mediated conformational change in HIV-1 reorganises the catalytic core and C-terminal domains and appears to promote an interaction that is favourable for catalysis .
Photosystem II reaction centre protein H superfamily (PSII_PsbH_sf)
Type: Homologous_superfamily

Oxygenic photosynthesis uses two multi-subunit photosystems (I and II) located in the cell membranes of cyanobacteria and in the thylakoid membranes of chloroplasts in plants and algae. Photosystem II (PSII) has a P680 reaction centre containing chlorophyll 'a' that uses light energy to carry out the oxidation (splitting) of water molecules, and to produce ATP via a proton pump. Photosystem I (PSI) has a P700 reaction centre containing chlorophyll that takes the electron and associated hydrogen donated from PSII to reduce NADP+ to NADPH. Both ATP and NADPH are subsequently used in the light-independent reactions to convert carbon dioxide to glucose using the hydrogen atom extracted from water by PSII, releasing oxygen as a by-product .

PSII is a multisubunit protein-pigment complex containing polypeptides both intrinsic and extrinsic to the photosynthetic membrane . Within the core of the complex, the chlorophyll and β-carotene pigments are mainly bound to the antenna proteins CP43 (PsbC) and CP47 (PsbB), which pass the excitation energy on to the reaction centre proteins D1 (Qb, PsbA) and D2 (Qa, PsbD) that bind all the redox-active cofactors involved in the energy conversion process. The PSII oxygen-evolving complex (OEC) oxidises water to provide protons for use by PSI, and consists of OEE1 (PsbO), OEE2 (PsbP) and OEE3 (PsbQ). The remaining subunits in PSII are of low molecular weight (less than 10kDa), and are involved in PSII assembly, stabilisation, dimerisation, and photo-protection .

This superfamily represents the low molecular weight phosphoprotein PsbH found in PSII. The phosphorylation site of PsbH is located in the N terminus, where reversible phosphorylation is light-dependent and redox-controlled. PsbH is necessary for the photoprotection of PSII, being required for: (1) the rapid degradation of photodamaged D1 core protein to prevent further oxidative damage to the PSII core, and (2) the insertion of newly synthesised D1 protein into the thylakoid membrane . PsbH may also regulate the transfer of electrons from D2 (Qa) to D1 (Qb) in the reaction core.
Zn(2)-C6 fungal-type DNA-binding domain superfamily (Zn2-C6_fun-type_DNA-bd_sf)
Type: Homologous_superfamily

The N-terminal region of a number of fungal transcriptional regulatory proteins contains a Cys-rich motif that is involved in zinc-dependent binding of DNA. The region forms a binuclear Zn cluster, in which two Zn atoms are bound by six Cys residues . A wide range of proteins are known to contain this domain. These include the proteins involved in arginine, proline, pyrimidine, quinate, maltose and galactose metabolism, amide and GABA catabolism, leucine biosynthesis, amongst others. The structure of Zn2Cys6 DNA-binding domain from different proteins has been determined in free and DNA bound state (

) revealing details of the molecular basis of DNA recognition .