Adenosylhomocysteinase (S-adenosyl-L-homocysteine hydrolase,
) (AdoHcyase) is an enzyme of the activated methyl cycle, responsible for the reversible hydration of S-adenosyl-L-homocysteine into adenosine and homocysteine. This enzyme is ubiquitous, highly conserved, and may play a key role in the regulation of the intracellular concentration of adenosylhomocysteine. AdoHcyase requires NAD+ as a cofactor and contains a central glycine-rich region which is thought to be involved in NAD-binding. Since AdoHyc is a potent inhibitor of S-adenosyl-L-methionine dependent methyltransferases, AdoHycase plays a critical role in the modulation of the activity of various methyltransferases. The enzyme forms homotetramers, with each monomer binding one molecule of NAD+ [
,
,
,
].This family also includes S-adenosylhomocysteine hydrolase-like 1 (Ahcyl1), also known as IRBIT, and S-adenosylhomocysteine hydrolase-like protein 2 (Ahcyl2). Ahcyl1/IRBIT was shown to interact with inositol 1,4,5-trisphosphate receptors (IP3Rs), which function as intracellular Ca(2+) channels, and suppresses IP3 binding of IP3R [
,
]. By competing with IP3, it modulates the threshold IP3 concentration required for the activation of the receptor []. Further studies indicate that Ahcyl1/IRBIT is in fact a multifunctional protein that regulates several ion channels and ion transporters [,
]. Despite its homology to S-adenosylhomocysteine hydrolases, Ahcyl1 has neither enzyme activity nor any effects on the enzyme activity of S-adenosylhomocysteine hydrolase []. Ahcyl2 lacks binding activity to IP3R []. Ahcyl2 upregulates NBCe1-B, which plays an important role in intracellular pH regulation [].
S-adenosyl-L-homocysteine hydrolase, conserved site
Type:
Conserved_site
Description:
Adenosylhomocysteinase (S-adenosyl-L-homocysteine hydrolase,
) (AdoHcyase) is an enzyme of the activated methyl cycle, responsible for the reversible hydration of S-adenosyl-L-homocysteine into adenosine and homocysteine. This enzyme is ubiquitous, highly conserved, and may play a key role in the regulation of the intracellular concentration of adenosylhomocysteine. AdoHcyase requires NAD+ as a cofactor and contains a central glycine-rich region which is thought to be involved in NAD-binding. Since AdoHyc is a potent inhibitor of S-adenosyl-L-methionine dependent methyltransferases, AdoHycase plays a critical role in the modulation of the activity of various methyltransferases. The enzyme forms homotetramers, with each monomer binding one molecule of NAD+ [
,
,
,
].This entry represents two highly conserved regions. The first pattern is located in the N-terminal section; the second is derived from a glycine-rich region in the central part of S-adenosyl-L-homocysteine hydrolase, a region thought to be involved in NAD-binding.
S-adenosyl-L-homocysteine hydrolase, NAD binding domain
Type:
Domain
Description:
S-adenosyl-L-homocysteine hydrolase (
) (AdoHcyase) is an enzyme of the activated methyl cycle, responsible for the reversible hydration of S-adenosyl-L-homocysteine into adenosine and homocysteine. AdoHcyase is an ubiquitous enzyme which binds and requires NAD
+as a cofactor.
AdoHcyase is a highly conserved protein [] of about 430 to 470 amino acids. This entry represents the glycine-rich region in the central part of AdoHcyase, which is thought to be involved in NAD-binding [
].
Serine hydroxymethyltransferase, pyridoxal phosphate binding site
Type:
Binding_site
Description:
Synonym(s): Serine hydroxymethyltransferase, Serine aldolase, Threonine aldolase
Serine hydroxymethyltransferase (SHMT) is a pyridoxal phosphate (PLP) dependent enzyme and belongs to the aspartate aminotransferase superfamily (fold type I) [
]. The pyridoxal-P group is attached to a lysine residue around which the sequence is highly conserved in all forms of the enzyme []. The enzyme carries out interconversion of serine and glycine using PLP as the cofactor. SHMT catalyses the transfer of a hydroxymethyl group from N5, N10- methylene tetrahydrofolate to glycine, resulting in the formation of serine and tetrahydrofolate. Both eukaryotic and prokaryotic SHMT enzymes form tight obligate homodimers and the mammalian enzyme forms a homotetramer [,
]. PLP dependent enzymes were previously classified into alpha, beta and gamma classes, based on the chemical characteristics (carbon atom involved) of the reaction they catalysed. The availability of several structures allowed a comprehensive analysis of the evolutionary classification of PLP dependent enzymes, and it was found that the functional classification did not always agree with the evolutionary history of these enzymes. Structure and sequence analysis has revealed that the PLP dependent enzymes can be classified into four major groups of different evolutionary origin: aspartate aminotransferase superfamily (fold type I), tryptophan synthase beta superfamily (fold type II), alanine racemase superfamily (fold type III), D-amino acid superfamily (fold type IV) and glycogen phophorylase family (fold type V) [,
].In vertebrates, glycine hydroxymethyltransferase exists in a cytoplasmic and a mitochondrial form whereas
only one form is found in prokaryotes.The signature of this entry contains the lysine residue to which the pyridoxal phosphate group is attached. The region surrounding this lysine residue is highly conserved in all forms of the enzyme.
This entry includes serine hydroxymethyltransferases and other uncharacterised proteins. Serine hydroxymethyltransferase (SHMT) is a pyridoxal phosphate-dependent enzyme that catalyzes the reversible conversion of serine and tetrahydrofolate to glycine and methylenetetrahydrofolate [
]. This reaction generates single carbon units for purine, thymidine, and methionine biosynthesis. It belongs to the aspartate aminotransferase superfamily (fold type I) []. The pyridoxal-P group is attached to a lysine residue around which the sequence is highly conserved in all forms of the enzyme []. SHMT catalyses the transfer of a hydroxymethyl group from N5, N10- methylene tetrahydrofolate to glycine, resulting in the formation of serine and tetrahydrofolate. Both eukaryotic and prokaryotic SHMT enzymes form tight obligate homodimers and the mammalian enzyme forms a homotetramer [,
].
Replication factor A (RP-A) binds and subsequently stabilises single-stranded DNA intermediates and thus prevents complementary DNA from reannealing. It also plays an essential role in several cellular processes in DNA metabolism including replication, recombination and repair of DNA [
,
]. Replication factor-A protein is also known as Replication protein A 70kDa DNA-binding subunit.This entry is found at the C terminus of Replication factor A and similar proteins found and eukaryotes and archaea.
Acyl-CoA dehydrogenases (
) are a family of flavoproteins that catalyse the alpha,beta-dehydrogenation of acyl-CoA thioesters to the corresponding trans 2,3-enoyl CoA-products with the concomitant reduction of enzyme-bound FAD. Different family members share a high sequence identity, catalytic mechanisms, and structural properties, but differ in the position of their catalytic bases and in their substrate binding specificity. Butyryl-CoA dehydrogenase [
] prefers short chain substrates, medium chain- and long-chain acyl-CoA dehydrogenases prefer medium and long chain substrates, respectively, and Isovaleryl-CoA dehydrogenase [] prefers branched-chain substrates.The monomeric enzyme is folded into three domains of approximately equal size, where the N-terminal domain is all-α, the middle domain is an open [
,
] barrel, and the C-terminal domain is a four-helical bundle. This entry represents the C-terminal domain found in medium chain acyl-CoA dehydrogenases, as well as in the related peroxisomal acyl-CoA oxidase-II enzymes, where this domain occurs as a tandem duplication. Acyl-CoA oxidase (ACO; ) catalyses the first and rate-determining step of the peroxisomal beta-oxidation of fatty acids [].
Acyl-CoA oxidase (ACO) acts on CoA derivatives of fatty acids with chain lengths from 8 to 18. It catalyses the first and rate-determining step of the peroxisomal beta-oxidation of fatty acids [
].Acyl-CoA oxidase is a homodimer and the polypeptide chain of the subunit is folded into the N-terminal alpha-domain, beta-domain, and C-terminal alpha-domain [
]. Functional differences between the peroxisomal acyl-CoA oxidases and the mitochondrial acyl-CoA dehydrogenases are attributed to structural differences in the FAD environments []. Experimental data indicate that, in the pumpkin, the expression pattern of ACOX is very similar to that of the glyoxysomal enzyme 3-ketoacyl-CoA thiolase [
]. In humans, defects in ACOX1 are the cause of pseudoneonatal adrenoleukodystrophy, also known as peroxisomal acyl-CoA oxidase deficiency. Pseudo-NALD is a peroxisomal single-enzyme disorder. Clinical features include mental retardation, leukodystrophy, seizures, mild hepatomegaly and hearing deficit. Pseudo-NALD is characterised by increased plasma levels of very-long chain fatty acids due to a decrease in, or absence of, peroxisome acyl-CoA oxidase activity, despite the peroxisomes being intact and functioning.This entry represents the Acyl-CoA oxidase C-terminal.
Acyl-CoA oxidase (ACO) acts on CoA derivatives of fatty acids with chain lengths from 8 to 18. It catalyses the first and rate-determining step of the peroxisomal beta-oxidation of fatty acids and a major producer of hydrogen peroxide (H2O2) [
,
].Acyl-CoA oxidase is a homodimer and the polypeptide chain of the subunit is folded into the N-terminal alpha-domain, beta-domain, and C-terminal alpha-domain [
,
]. Functional differences between the peroxisomal acyl-CoA oxidases and the mitochondrial acyl-CoA dehydrogenases are attributed to structural differences in the FAD environments [
]. Experimental data indicate that in the pumpkin, the expression pattern of ACOX is very similar to that of the glyoxysomal enzyme 3-ketoacyl-CoA thiolase [
]. In humans, defects in ACOX1 are the cause of pseudoneonatal adrenoleukodystrophy, also known as peroxisomal acyl-CoA oxidase deficiency. Clinical features include mental retardation, leukodystrophy, seizures, mild hepatomegaly and hearing deficit. Pseudo-NALD is characterised by increased plasma levels of very-long chain fatty acids due to a decrease in, or absence of, peroxisome acyl-CoA oxidase activity, despite the peroxisomes being intact and functioning [].
Translins are DNA-binding proteins that specifically recognise consensus sequences at the breakpoint junctions in chromosomal translocations, mostly involving immunoglobulin (Ig)/T-cell receptor gene segments. They seem to recognise single-sranded DNA ends generated by staggered breaks occuring at recombination hot spots [
].Translin folds into an α-α superhelix, consisting of two curved layers of alpha/alpha topology [
,
]. This structure can be divided into two α-bundle subdomains. This entry represents the N-terminal alpha bundle subdomain.
This approximately 50-residue region is found in a number of sequences derived from hypothetical plant proteins. This region features a highly basic 5 amino-acid stretch towards its centre.
Tyrosine specific protein phosphatases (PTPases) (
) contain two conserved cysteines, the second one has been shown to be absolutely required for activity. This entry represents the PTPase domain that centre on the active site cysteine. A number of conserved residues in its immediate vicinity have also been shown to be important. This domain can be found in dual specificity phosphatases.
Dual specificity phosphatases (DUSPs) are members of the superfamily of protein tyrosine phosphatases [
,
]. They remove the phosphate group from both phospho-tyrosine and phospho-serine/threonine residues. They are structurally similar to tyrosine-specific phosphatases but with a shallower active site cleft and a distinctive active site signature motif, HCxxGxxR [,
,
]. They are characterized as VHR- [,
] or Cdc25-like [,
].In general, DUSPs are classified into the following subgroups [
]:Slingshot phosphatasesPhosphatase of regenerating liver (PRL)Cdc14 phosphatasesPhosphatase and tensin homologue deleted on chromosome 10 (PTEN)-like and myotubularin phosphatasesMitogen-activated protein kinase phosphatases (MKPs)Atypical DUSPs
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) phosphatasesBased 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. This entry represents dual specificity protein-tyrosine phosphatases. Ser/Thr and Tyr dual specificity phosphatases are a group of enzymes with both Ser/Thr (
) and tyrosine specific protein phosphatase (
) activity able to remove both the serine/threonine or tyrosine-bound phosphate group from a wide range of phosphoproteins, including a number of enzymes which have been phosphorylated
under the action of a kinase. Dual specificity protein phosphatases (DSPs) regulate mitogenic signal transduction and control the cell cycle. The crystal structure of a human DSP, vaccinia H1-related phosphatase (or VHR), has been determined at 2.1 angstrom resolution []. A shallow active site pocket in VHR allows for the hydrolysis of phosphorylated serine, threonine, or tyrosine protein residues, whereas the deeper active site of protein tyrosine phosphatases (PTPs) restricts substrate specificity to only phosphotyrosine. Positively charged crevices near the active site may explain the enzyme's preference for substrates with two phosphorylated residues. The VHR structure defines a conserved structural scaffold for both DSPs and PTPs. A "recognition region"connecting helix alpha1 to strand beta1, may determine differences in substrate specificity between VHR, the PTPs, and other DSPs.
These proteins may also have inactive phosphatase domains, and dependent on the domain composition this loss of catalytic activity has different effects on protein function. Inactive single domain phosphatases can still specifically bind substrates, and protect again dephosphorylation, while the inactive domains of tandem phosphatases can be further subdivided into two classes. Those which bind phosphorylated tyrosine residues may recruit multi-phosphorylated substrates for the adjacent active domains and are more conserved, while the other class have accumulated several variable amino acid substitutions and have a complete loss of tyrosine binding capability. The second class shows a release of evolutionary constraint for the sites around the catalytic centre, which emphasises a difference in function from the first group. There is a region of higher conservation common to both classes, suggesting a new regulatory centre [
].
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) phosphatasesBased 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. Tyrosine specific protein phosphatases (PTPases) contain two conserved cysteines, the second one has been shown to be absolutely required for activity. This entry represents the PTPase domain that centre on the active site cysteine. A number of conserved residues in its immediate vicinity have also been shown to be important.
This entry includes proteins of two subfamilies: Ser/Thr (
) and Tyr dual specificity protein phosphatase and tyrosine specific protein phosphatase (
). Both of these subfamilies may also have inactive phosphatase domains, and dependent on the domain composition this loss of catalytic activity has different effects on protein function. Inactive single domain phosphatases can still specifically bind substrates, and protect against dephosphorylation, while the inactive domains of tandem phosphatases can be further subdivided into two classes. Those which bind phosphorylated tyrosine residues may recruit multi-phosphorylated substrates for the adjacent active domains and are more conserved, while the other class have accumulated several variable amino acid substitutions and have a complete loss of tyrosine binding capability. The second class shows a release of evolutionary constraint for the sites around the catalytic centre, which emphasises a difference in function from the first group. There is a region of higher conservation common to both classes, suggesting a regulatory centre [
].Ser/Thr and Tyr dual specificity phosphatases are a group of enzymes with both Ser/Thr (
) and tyrosine specific protein
phosphatase () activity able to remove both the serine/threonine or tyrosine-bound phosphate group from a wide
range of phosphoproteins, including a number of enzymes which have been phosphorylated under the action of a kinase. Dual specificity protein phosphatases (DSPs) regulate mitogenic signal transduction and control the cell cycle. Tyrosine specific protein phosphatases catalyze the removal of a phosphate group attached to a tyrosine residue. They are also very important in the control of cell growth, proliferation, differentiation and transformation.
Homeodomain leucine zipper (HDZip) genes encode putative transcription factors that are unique to plants. This observation suggests that homeobox-leucine zipper genes evolved after the
divergence of plants and animals, perhaps to mediate specific regulatory events [].This domain is the N-terminal of plant homeobox-leucine zipper proteins. Its function is unknown.
This entry represents a domain found in a group of glycosyltransferases, including Arabidopsis arabinosyltransferase RRA1/2/3/XEG113 [
], beta-arabinofuranosyltransferase RAY1 [] and UDP-D-xylose:L-fucose alpha-1,3-D-xylosyltransferases [].The biosynthesis of disaccharides, oligosaccharides and polysaccharides involves the action of hundreds of different glycosyltransferases. These enzymes catalyse the transfer of sugar moieties from activated donor molecules to specific acceptor molecules, forming glycosidic bonds. A classification of glycosyltransferases using nucleotide diphospho-sugar, nucleotide monophospho-sugar and sugar phosphates ([intenz:2.4.1.-]) and related proteins into distinct sequence based families has been described []. This classification is available on the CAZy (CArbohydrate-Active EnZymes) web site. The same three-dimensional fold is expected to occur within each of the families. Because 3-D structures are better conserved than sequences, several of the families defined on the basis of sequence similarities may have similar 3-D structures and therefore form 'clans'.
Allicin is a thiosulphinate that gives rise to dithiines, allyl sulphides and ajoenes, the three groups of active compounds in Allium species. Allicin is synthesised from sulphoxide cysteine derivatives by alliinase, whose C-S lyase activity cleaves C(beta)-S(gamma) bonds. It is thought that this enzyme forms part of a primitive plant defence system [
].
Regulation of transcription is, in part, modulated by reversible histone acetylation on several lysine. Histone deacetylases (HDA) catalyse the removal
of the acetyl group. Histone deacetylases, acetoin utilization proteins and acetylpolyamine amidohydrolases are all members of this ancient protein superfamily [].HDAs function in multi-subunit complexes, reversing the acetylation of
histones by histone acetyltransferases [,
], and are also believed to deacetylate general transcription factors such as TFIIF and sequence-specific transcription factors such as p53 []. Thus, HDAs contribute to the regulation of transcription, in particular transcriptional repression []. At N-terminal tails of histones, removal of the acetyl group from the ε-amino group of a lysine side chain will restore its positivecharge, which may stabilise the histone-DNA interaction and prevent activating transcription factors binding to promoter elements []. HDAs play important roles in the cell cycle and differentiation, and their deregulation can contribute to the development of cancer [,
].
Regulation of transcription is, in part, modulated by reversible histone acetylation on several lysine. Histone deacetylases (HDA) catalyse the removal
of the acetyl group. Histone deacetylases, acetoin utilization proteins and acetylpolyamine amidohydrolases are all members of this ancient protein superfamily [].HDAs function in multi-subunit complexes, reversing the acetylation of
histones by histone acetyltransferases [,
], and are also believed to deacetylate general transcription factors such as TFIIF and sequence-specific transcription factors such as p53 []. Thus, HDAs contribute to the regulation of transcription, in particular transcriptional repression []. At N-terminal tails of histones, removal of the acetyl group from the ε-amino group of a lysine side chain will restore its positivecharge, which may stabilise the histone-DNA interaction and prevent activating transcription factors binding to promoter elements []. HDAs play important roles in the cell cycle and differentiation, and their deregulation can contribute to the development of cancer [,
].This entry represents the structural domain found in histone deacetylases. It consists of a 3-layer(α-β-alpha) sandwich.
Histones can be reversibly acetylated on several lysine residues. Regulation of transcription is caused in part by this mechanism. Histone deacetylases catalyse the removal of the acetyl group. Histone deacetylases, acetoin utilization proteins and acetylpolyamine amidohydrolases are all members of this ancient protein superfamily [
].
Amine oxidases (AO) are enzymes that catalyse the oxidation of a wide range of biogenic amines including many neurotransmitters, histamine and xenobiotic amines. There are two classes of amine oxidases: flavin-containing (
) and copper-containing (
). Copper-containing AO act as a disulphide-linked homodimer. They catalyse the oxidation of primary amines to aldehydes, with the subsequent release of ammonia and hydrogen peroxide, which requires one copper ion per subunit and topaquinone as cofactor [
]: RCH
2NH
2+ H
2O + O
2= RCHO + NH
3+ H
2O
2Copper-containing amine oxidases are found in bacteria, fungi, plants and animals. In prokaryotes, the enzyme enables various amine substrates to be used as sources of carbon and nitrogen [
,
]. In eukaryotes they have a broader range of functions, including cell differentiation and growth, wound healing, detoxification and cell signalling [].The copper amine oxidases occur as mushroom-shaped homodimers of 70-95kDa, each monomer containing a copper ion and a covalently bound redox cofactor, topaquinone (TPQ). TPQ is formed by post-translational modification of a conserved tyrosine residue. The copper ion is coordinated with three histidine residues and two water molecules in a distorted square pyramidal geometry, and has a dual function in catalysis and TPQ biogenesis. The catalytic domain is the largest of the 3-4 domains found in copper amine oxidases, and consists of a beta sandwich of 18 strands in two sheets. The active site is buried and requires a conformational change to allow the substrate access. The two N-terminal domains share a common structural fold, its core consisting of a five-stranded antiparallel β-sheet twisted around an α-helix. The D1 domains from the two subunits comprise the stalk, of the mushroom-shaped dimer, and interact with each other but do not pack tightly against each other [
,
]. This entry represents the C-terminal catalytic domain of copper amine oxidases, and has a super-sandwich fold consisting of 18 β-strands in 2 sheets [
]. A domain with a similar structural fold can be found as the third domain in lysyl oxidase PplO [].
Amine oxidases (AO) are enzymes that catalyse the oxidation of a wide range of biogenic amines including many neurotransmitters, histamine and xenobiotic amines. There are two classes of amine oxidases: flavin-containing (
) and copper-containing (
). Copper-containing AO act as a disulphide-linked homodimer. They catalyse the oxidation of primary amines to aldehydes, with the subsequent release of ammonia and hydrogen peroxide, which requires one copper ion per subunit and topaquinone as cofactor [
]: RCH
2NH
2+ H
2O + O
2= RCHO + NH
3+ H
2O
2Copper-containing amine oxidases are found in bacteria, fungi, plants and animals. In prokaryotes, the enzyme enables various amine substrates to be used as sources of carbon and nitrogen [
,
]. In eukaryotes they have a broader range of functions, including cell differentiation and growth, wound healing, detoxification and cell signalling [].The copper amine oxidases occur as mushroom-shaped homodimers of 70-95kDa, each monomer containing a copper ion and a covalently bound redox cofactor, topaquinone (TPQ). TPQ is formed by post-translational modification of a conserved tyrosine residue. The copper ion is coordinated with three histidine residues and two water molecules in a distorted square pyramidal geometry, and has a dual function in catalysis and TPQ biogenesis. The catalytic domain is the largest of the 3-4 domains found in copper amine oxidases, and consists of a beta sandwich of 18 strands in two sheets. The active site is buried and requires a conformational change to allow the substrate access. The two N-terminal domains share a common structural fold, its core consisting of a five-stranded antiparallel β-sheet twisted around an α-helix. The D1 domains from the two subunits comprise the stalk, of the mushroom-shaped dimer, and interact with each other but do not pack tightly against each other [
,
]. This entry represents a family of copper amine oxidase enzymes.
Amine oxidases (AO) are enzymes that catalyse the oxidation of a wide range of biogenic amines including many neurotransmitters, histamine and xenobiotic amines. There are two classes of amine oxidases: flavin-containing (
) and copper-containing (
). Copper-containing AO act as a disulphide-linked homodimer. They catalyse the oxidation of primary amines to aldehydes, with the subsequent release of ammonia and hydrogen peroxide, which requires one copper ion per subunit and topaquinone as cofactor [
]: RCH
2NH
2+ H
2O + O
2= RCHO + NH
3+ H
2O
2Copper-containing amine oxidases are found in bacteria, fungi, plants and animals. In prokaryotes, the enzyme enables various amine substrates to be used as sources of carbon and nitrogen [
,
]. In eukaryotes they have a broader range of functions, including cell differentiation and growth, wound healing, detoxification and cell signalling [].The copper amine oxidases occur as mushroom-shaped homodimers of 70-95kDa, each monomer containing a copper ion and a covalently bound redox cofactor, topaquinone (TPQ). TPQ is formed by post-translational modification of a conserved tyrosine residue. The copper ion is coordinated with three histidine residues and two water molecules in a distorted square pyramidal geometry, and has a dual function in catalysis and TPQ biogenesis. The catalytic domain is the largest of the 3-4 domains found in copper amine oxidases, and consists of a beta sandwich of 18 strands in two sheets. The active site is buried and requires a conformational change to allow the substrate access. The two N-terminal domains share a common structural fold, its core consisting of a five-stranded antiparallel β-sheet twisted around an α-helix. The D1 domains from the two subunits comprise the stalk, of the mushroom-shaped dimer, and interact with each other but do not pack tightly against each other [
,
]. This entry represents one (N3) of the two N-terminal domains (N2/N3) that share a similar structure.
Amine oxidases (AO) are enzymes that catalyse the oxidation of a wide range of biogenic amines including many neurotransmitters, histamine and xenobiotic amines. There are two classes of amine oxidases: flavin-containing (
) and copper-containing (
). Copper-containing AO act as a disulphide-linked homodimer. They catalyse the oxidation of primary amines to aldehydes, with the subsequent release of ammonia and hydrogen peroxide, which requires one copper ion per subunit and topaquinone as cofactor [
]: RCH
2NH
2+ H
2O + O
2= RCHO + NH
3+ H
2O
2Copper-containing amine oxidases are found in bacteria, fungi, plants and animals. In prokaryotes, the enzyme enables various amine substrates to be used as sources of carbon and nitrogen [
,
]. In eukaryotes they have a broader range of functions, including cell differentiation and growth, wound healing, detoxification and cell signalling [].The copper amine oxidases occur as mushroom-shaped homodimers of 70-95kDa, each monomer containing a copper ion and a covalently bound redox cofactor, topaquinone (TPQ). TPQ is formed by post-translational modification of a conserved tyrosine residue. The copper ion is coordinated with three histidine residues and two water molecules in a distorted square pyramidal geometry, and has a dual function in catalysis and TPQ biogenesis. The catalytic domain is the largest of the 3-4 domains found in copper amine oxidases, and consists of a beta sandwich of 18 strands in two sheets. The active site is buried and requires a conformational change to allow the substrate access. The two N-terminal domains share a common structural fold, its core consisting of a five-stranded antiparallel β-sheet twisted around an α-helix. The D1 domains from the two subunits comprise the stalk, of the mushroom-shaped dimer, and interact with each other but do not pack tightly against each other [
,
]. This entry represents the N-terminal region of copper amine oxidases, and has a core structure consisting of α-β(4), where the helix packs against the coiled antiparallel β-sheet [
]. A domain with a similar structural fold can be found as the first and second domains in lysyl oxidase PplO [].
Amine oxidases (AO) are enzymes that catalyse the oxidation of a wide range of biogenic amines including many neurotransmitters, histamine and xenobiotic amines. There are two classes of amine oxidases: flavin-containing (
) and copper-containing (
). Copper-containing AO act as a disulphide-linked homodimer. They catalyse the oxidation of primary amines to aldehydes, with the subsequent release of ammonia and hydrogen peroxide, which requires one copper ion per subunit and topaquinone as cofactor [
]: RCH
2NH
2+ H
2O + O
2= RCHO + NH
3+ H
2O
2Copper-containing amine oxidases are found in bacteria, fungi, plants and animals. In prokaryotes, the enzyme enables various amine substrates to be used as sources of carbon and nitrogen [
,
]. In eukaryotes they have a broader range of functions, including cell differentiation and growth, wound healing, detoxification and cell signalling [].The copper amine oxidases occur as mushroom-shaped homodimers of 70-95kDa, each monomer containing a copper ion and a covalently bound redox cofactor, topaquinone (TPQ). TPQ is formed by post-translational modification of a conserved tyrosine residue. The copper ion is coordinated with three histidine residues and two water molecules in a distorted square pyramidal geometry, and has a dual function in catalysis and TPQ biogenesis. The catalytic domain is the largest of the 3-4 domains found in copper amine oxidases, and consists of a beta sandwich of 18 strands in two sheets. The active site is buried and requires a conformational change to allow the substrate access. The two N-terminal domains share a common structural fold, its core consisting of a five-stranded antiparallel β-sheet twisted around an α-helix. The D1 domains from the two subunits comprise the stalk, of the mushroom-shaped dimer, and interact with each other but do not pack tightly against each other [
,
]. This entry represents one (N2) of the two N-terminal domains (N2/N3) that share a similar structure.
RNA helicases from the DEAD-box family are found in almost all organisms and
have important roles in RNA metabolism such as splicing, RNA transport,ribosome biogenesis, translation and RNA decay. They are enzymes that unwind
double-stranded RNA molecules in an energy dependent fashion through thehydrolysis of NTP. DEAD-box RNA helicases belong to superfamily 2 (SF2) of
helicases. As other SF1 and SF2 members they contain seven conserved motifswhich are characteristic of these two superfamilies [
].DEAD-box is named after the amino acids of motif II or Walker B (Mg2+-binding
aspartic acid). Besides these seven motifs, DEAD-box RNA helicases contain aconserved cluster of nine amino-acids (the Q motif) with an invariant
glutamine located N-terminally of motif I. An additional highly conserved butisolated aromatic residue is also found upstream of these nine residues [
].The Q motif is characteristic of and unique to DEAD box family of helicases.
It is supposed to control ATP binding and hydrolysis, and therefore itrepresents a potential mechanism for regulating helicase activity.
Several structural analyses of DEAD-box RNA helicases have been reported [
,
]. The Q motif is located in close proximity to motif I. Theconserved glutamine and aromatic residues interact with the ADP molecule.
Some proteins known to contain a Q motif:
Eukaryotic initiation factor 4A (eIF4A). An ATP-dependent RNA helicase
which is a subunit of the eIF4F complex involved in cap recognition andrequired for mRNA binding to ribosome.Various eukaryotic helicases involved in ribosome biogenesis (DBP3, DRS1,
SPB4, MAK5, DBP6, DBP7, DBP9, DBP10).Eukaryotic DEAD-box proteins involved in pre-mRNA splicing (Prp5p, Prp28p
and Sub2p).DEAD-box proteins required for mitochondrial genome expression (MSS116 and
MRH4).Fungi ATP-dependent RNA helicase DHH1. It is required for decapping and
turnover of mRNA.Fungi ATP-dependent RNA helicase DBP5. It is involved in nucleo-cytoplasmic
transport of poly(A) RNA.Bacterial ATP-dependent RNA helicase rhlB. It is involved in the RNA
degradosome, a multi-enzyme complex important in RNA processing andmessenger RNA degradation.Bacterial cold-shock DEAD box protein A.This entry represents a region stretching from the conserved aromatic residue to one amino acid after the glutamine of the Q motif.
Among the blue copper proteins with a single type I (or "blue") mononuclear
copper site, the plant-specific phytocyanins constitute a distinct subfamilythat can be further subdivided into the families of uclacyanins, stellacyanins,
plantacyanins, and early nodulins. Stellacyanins have a blue coppercoordinated by two His, one Cys and one Gln. In plantacyanins and uclacyanins,
the ligands of the type-I Cu sites are two His, one Cys and one Met [,
,
,
]. Early nodulins lack amino acid residues that coordinate Cu, so they are believed to be involved in unknown processes without binding Cu []. Phytocyanins are found in chloropasts of higher plants.The phytocyanin domain has a core of seven polypeptide strands arranged as a
β-sandwich comprising two β-sheets, β-sheet I and β-sheet II. β-sheet I consists of three β-strands and β-sheet IIconsists of four β-strands. A disulfide bridge close the metal centre is
characteristic for phytocyanins, in contrast to azurins, pseudoazurins, andplastocyanins, where a disulfide bond is located on the distal side of the
β-barrel. This disuldide bridge may play a crucial role in maintaining thetertiary structure of the protein and/or the formation of the copper binding
centre because one of the His ligands of copper is followed directly by abridging Cys residue [
,
,
,
]. Some members of this family (P93328) may not bind copper due to the lack of key residues. Some proteins known to contain a phytocyanin domain are listed below:Cucumber basic protein (CBP).Spinach basic protein (SBP).Cucumber stellacyanin (CST).Zucchini mavicyanin.Horseradish umecyanin [
,
]. Some of the proteins in this family are allergens. The allergens in this family include allergens with the following designations: Amb a 3.
Pitcher plants are insectivorous and secrete a digestive fluid into the pitcher. This fluid contains a mixture of enzymes including peptidases. One of these is neprosin, characterized from the pitcher plant Nepenthes ventrata. This peptidase is of unknown catalytic type and is unaffected by standard peptidase inhibitors. Unusually, activity is directed towards prolyl bonds, but unlike most peptidase that cleave after proline, there is no restriction on sequence length or position of the proline residue. The peptidase is secreted and is presumed to possess an N-terminal activation peptide. The neprosin domain corresponds to the mature peptidase [
]. It is not known if other proteins with this domain are peptidases.
Pitcher plants are insectivorous and secrete a digestive fluid into the pitcher. This fluid contains a mixture of enzymes including peptidases. One of these is neprosin, characterized from the pitcher plant Nepenthes ventrata. This peptidase is of unknown catalytic type and is unaffected by standard peptidase inhibitors. Unusually, activity is directed towards prolyl bonds, but unlike most peptidase that cleave after proline, there is no restriction on sequence length or position of the proline residue. The peptidase is secreted and is presumed to possess an N-terminal activation peptide [
]. This domain corresponds to the presumed activation peptide.
Clathrin is a triskelion-shaped cytoplasmic protein that polymerises into a polyhedral lattice on intracellular membranes to form protein-coated membrane vesicles. Lattice formation induces the sorting of membrane proteins during endocytosis and organelle biogenesis by interacting with membrane-associated adaptor molecules. Clathrin functions as a trimer, and these trimers, or triskelions, are comprised of three legs joined by a central vertex. Each leg consists of one heavy chain and one light chain. The clathrin heavy-chain contains a 145-residue repeat that is present in seven copies [
,
]. The clathrin heavy-chain repeat (CHCR) is also found in nonclathrin proteins such as Pep3, Pep5, Vam6, Vps41, and Vps8 from Saccharomyces cerevisiae and their orthologs from other eukaryotes [,
,
,
]. These proteins, like clathrins, are involved in vacuolar maintenance and protein sorting. The CHCR repeats in these proteins could mediate protein-protein interactions, or possibly represent clathrin-binding domains, or perform clathrin-like functions. CHCR repeats in the clathrin heavy chain, Saccharomyces cerevisiae Vamp2 and human Vamp6 have been implicated in homooligomerization, suggesting that this may be the primary function of this repeat.The CHCR repeat folds into an elongated right-handed superhelix coil of short α-helices [
]. Individual 'helix-turn-helix-loop' or helix hairpin units comprise the canonical repeat and stack along the superhelix axis to form a single extended domain. The canonical hairpin repeat of the clathrin superhelix resembles a tetratrico peptide repeat (TPR), but is shorter and lacks the characteristic spacing of the hydrophobic residues in TPRs.
This entry includes E3 ubiquitin-protein ligase Pep5 (also known as vacuolar protein sorting-associated protein 11, Vps11) from fungi, and its homologues from plants and animals. Pep5 is a peripheral vacuolar membrane protein required for protein trafficking and vacuole biogenesis [
]. It is also identified as an E3 ubiquitin ligase that regulates histone protein levels in Saccharomyces cerevisiae []. Human Vps11 may play a role in vesicle-mediated protein trafficking [].
Vps 11 is one of the evolutionarily conserved class C vacuolar protein sorting genes (c-vps: vps11, vps16, vps18, and vps33), whose products physically associate to form the c-vps protein complex required for vesicle docking and fusion. This entry represents the C-terminal domain of vps11.
The chaperonins are 'helper' molecules required for correct folding and subsequent assembly of some proteins [
]. These are required for normal cell growth [], and are stress-induced, acting to stabilise or protect disassembled polypeptides under heat-shock conditions. Type I chaperonins present in eubacteria, mitochondria and chloroplasts require the concerted action of 2 proteins, chaperonin 60 (cpn60) and chaperonin 10 (cpn10) []. The 10kDa chaperonin (cpn10 - or groES in bacteria) exists as a ring-shaped oligomer of between six to eight identical subunits, while the 60kDa chaperonin (cpn60 - or groEL in bacteria) forms a structure comprising 2 stacked rings, each ring containing 7 identical subunits [
]. These ring structures assemble by self-stimulation in the presence of Mg2+-ATP. The central cavity of the cylindrical cpn60 tetradecamer provides as isolated environment for protein folding whilst cpn-10 binds to cpn-60 and synchronizes the release of the folded protein in an Mg
2+-ATP dependent manner [
]. The binding of cpn10 to cpn60 inhibits the weak ATPase activity of cpn60.Escherichia coli GroES has also been shown to bind ATP cooperatively, and with an affinity comparable to that of GroEL [
]. Each GroEL subunit contains three structurally distinct domains: an apical, an intermediate and an equatorial domain. The apical domain contains the binding sites for both GroES and the unfolded protein substrate. The equatorial domain contains the ATP-binding site and most of the oligomeric contacts. The intermediate domain links the apical and equatorial domains and transfers allosteric information between them. The GroEL oligomer is a tetradecamer, cylindrically shaped, that is organised in two heptameric rings stacked back to back. Each GroEL ring contains a central cavity, known as the 'Anfinsen cage', that provides an isolated environment for protein folding. The identical 10kDa subunits of GroES form a dome-like heptameric oligomer in solution. ATP binding to GroES may be important in charging the seven subunits of the interacting GroEL ring with ATP, to facilitate cooperative ATP binding and hydrolysis for substrate protein release.
SWR1-complex protein 5/Craniofacial development protein 1/2
Type:
Family
Description:
This family includes SWR1-complex protein 5 (Swc5) from fungi, and craniofacial development protein 1 (CFDP1) and 2 (CFDP2) from animals.Swc5 is a component of the SWR1 complex which mediates the ATP-dependent exchange of histone H2A for the H2A variant HZT1 leading to transcriptional regulation of selected genes by chromatin remodeling. It is involved in chromosome stability [
,
,
].Gene duplication of the ancestral bnct (bucentaur) gene leads to the h-type bnct (cfdp1) gene and the p97bcnt (cfdp2) gene. Cfdp2 is rumiant-specific, containing a region derived from the endonuclease domain of a retrotransposable element RTE-1 not found in human and mouse [
]. For this reason bcnt has been used as a model for molecular evolution [,
,
]. CFDP1, also known as Cp27, may play a role during embryogenesis [].
O-Glycosyl hydrolases (
) are a widespread group of enzymes that hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. A classification system for glycosyl hydrolases, based on sequence similarity, has led to the definition of 85 different families [
,
]. This classification is available on the CAZy (CArbohydrate-Active EnZymes) website.
Glycoside hydrolase family 10
comprises enzymes with a number of known activities; xylanase (
); endo-1,3-beta-xylanase (
); cellobiohydrolase (
). These enzymes were formerly known as cellulase family F.
The microbial degradation of cellulose and xylans requires several types of enzymes such as endoglucanases (
), cellobiohydrolases (
) (exoglucanases), or xylanases (
) [
,
]. Fungi and bacteria produces a spectrum of cellulolytic enzymes (cellulases) and xylanases which, on the basis of sequence similarities, can be classified into families. One of these families is known as the cellulase family F [] or as the glycosyl hydrolases family 10 [].The overall structure of the GH10 domain corresponds to an eightfold alpha/β-barrel (TIM-barrel) with a typical deep groove in the centre, allowing an 'endo' type of action on the large polysaccharide backbone [
], [].
Accurate transcription
in vivorequires at least six general transcription initiation factors, in addition to RNA polymerase II. Transcription initiation factor IIF (TFIIF) is a tetramer consisting of two large subunits (TFIIF alpha or RAP74) and two small subunits (TFIIF beta or RAP30) [
]. The beta subunit of TFIIF is required for recruitment of RNA polymerase II onto the promoter.
This entry includes a range of sulfotransferase proteins including flavonol 3-sulfotransferase, aryl sulfotransferases, alcohol sulfotransferases, estrogen sulfotransferases and phenol-sulphate phenol sulfotransferase. These enzymes are responsible for the transfer of sulphate groups to specific compounds [
].
The 33-residue LIS1 homology (LisH) motif (
) is found in eukaryotic intracellular
proteins involved in microtubule dynamics, cell migration, nucleokinesis andchromosome segregation. The LisH motif is likely to possess a conserved
protein-binding function and it has been proposed that LisH motifs contributeto the regulation of microtubule dynamics, either by mediating dimerization,
or else by binding cytoplasmic dynein heavy chain or microtubules directly.The LisH motif is found associated to other domains, such as WD-40 (see
), SPRY, Kelch, AAA ATPase, RasGEF, or HEAT (see
)
[,
,
].The secondary structure of the LisH domain is predicted to be two alpha-
helices [].Some proteins known to contain a LisH motif are listed below:Animal LIS1. It regulates cytoplasmic dynein function. In Homo sapiens (human) children
with defects in LIS1 suffer from Miller-Dieker lissencephaly, a brainmalformation that results in severe retardation, epilepsy and an early
death.Emericella nidulans (Aspergillus nidulans) nuclear migration protein nudF, the orthologue of LIS1.Eukaryotic RanBPM, a Ran binding protein involved in microtubule
nucleation.Eukaryotic Nopp140, a nucleolar phosphoprotein.Mammalian treacle, a nucleolar protein. In human, defects in treacle are
the cause of Treacher Collins syndrome (TCS), an autosomal dominantdisorder of craniofacial development.Animal muskelin. It acts as a mediator of cell spreading and cytoskeletal
responses to the extracellular matrix component thrombospondin 1.Animal transducin beta-like 1 protein (TBL1).Plant tonneau.Arabidopsis thaliana LEUNIG, a putative transcriptional corepressor that
regulates AGAMOUS expression during flower development.Fungal aimless RasGEF.Leishmania major katanin-like protein.The C-terminal to LisH (CTLH) motif is a predicted α-helical sequence of
unknown function that is found adjacent to the LisH motif in a number of theseproteins but is absent in other (e.g. LIS1) [
,
,
]. The CTLH domain can alsobe found in the absence of the LisH motif, like in:
Arabidopsis thaliana (Mouse-ear cress) hypothetical protein MUD21.5.Saccharomyces cerevisiae yeast protein RMD5.
RanBPM is a scaffolding protein and is important in regulating cellular function in both the immune system and the nervous system. The RanBPM protein contains multiple conserved domains that provide potential protein-protein interaction sites [
]. This entry represents a domain at the C terminus of RanBPM containing the CT11-RanBPM (CRA) motif. The CRA motif was found to be important for the interaction of RanBPM with fragile X messenger ribonucleoprotein 1 (FMRP), but its functional significance has yet to be determined []. The region comprising this domain contains the CTLH and CRA domains annotated by SMART; however, these may be a single domain, and is referred to as a C-terminal to LisH motif [].
Dynamin is a microtubule-associated force-producing protein of 100kDa which is involved in membrane remodelling and is critical for endocytic membrane fission. At the N terminus of dynamin is a GTPase domain (see
), and at the C terminus is a PH domain (see
). This entry represents the stalk (or middle) region which lies between these two domains, and dimerises in a cross-like fashion forming a dynamin dimer in which the two G-domains are oriented in opposite directions [
]. This domain is found in dynamin and related proteins.
The P-loop guanosine triphosphatases (GTPases) control a
multitude of biological processes, ranging from cell division, cell cycling,and signal transduction, to ribosome assembly and protein synthesis. GTPases
exert their control by interchanging between an inactive GDP-bound state andan active GTP-bound state, thereby acting as molecular switches. The common
denominator of GTPases is the highly conserved guanine nucleotide-binding (G)domain that is responsible for binding and hydrolysis of guanine nucleotides.Members of the dynamin GTPase family appear to be ubiquitous. They catalyse
diverse membrane remodelling events in endocytosis, cell division, and plastidmaintenance. Their functional versatility also extends to other core cellular
processes, such as maintenance of cell shape or centrosome cohesion. Membersof the dynamin family are characterised by their common structure and by
conserved sequences in the GTP-binding domain. The minimal distinguishingarchitectural features that are common to all dynamins and are distinct from
other GTPases are the structure of the large GTPase domain (~280 amino acids)and the presence of two additional domains: the middle domain and the GTPase
effector domain (GED), which are involved in oligomerisationand regulation of the GTPase activity. In many dynamin family members, the
basic set of domains is supplemented by targeting domains, such as:pleckstrin-homology (PH) domain, proline-rich domains
(PRDs), or by sequences that target dynamins to specific organelles, such asmitochondria and chloroplasts [
,
,
].The dynamin-type G domain consists of a central eight-stranded β-sheet
surrounded by seven alpha helices and two one-turn helices.It contains the five canonical guanine nucleotide binding motifs (G1-5). The
P-loop (G1) motif (GxxxxGKS/T) is also present in ATPases (Walker A motif) andfunctions as a coordinator of the phosphate groups of the bound nucleotide. A
conserved threonine in switch-I (G2) and the conserved residues DxxG ofswitch-II (G3) are involved in Mg(2+) binding and GTP hydrolysis. The
nucleotide binding affinity of dynamins is typically low, with specificity forGTP provided by the mostly conserved N/TKxD motif (G4). The G5 or G-cap motif
is involved in binding the ribose moiety [,
,
].This entry represents a conserved site in the dynamin-type G domain and is based on a highly conserved region downstream of the ATP/GTP-binding motif 'A' (P-loop).
Membrane transport between compartments in eukaryotic cells requires proteins that allow the budding and scission of nascent cargo vesicles from one compartment and their targeting and fusion with another. Dynamins are large GTPases that belong to a protein superfamily [
] that, in eukaryotic cells, includes classical dynamins, dynamin-like proteins,OPA1, Mx proteins, mitofusins and guanylate-binding proteins/atlastins [
,
,
,
,
], and are involved in the scission of a wide range of vesicles and organelles. They play a role in many processes including budding of transport vesicles, division of organelles, cytokinesis and pathogen resistance. The minimal distinguishing architectural features that are common to all dynamins and are distinct from other GTPases are the structure of the large GTPase domain (300 amino acids) and the presence of two additional domains; the middle domain and the GTPase effector domain (GED), which are involved in oligomerization and regulation of the GTPase activity.This entry represents the GTPase domain, containing the GTP-binding motifs that are needed for guanine-nucleotide binding and hydrolysis. The conservation of these motifs is absolute except for the the final motif in guanylate-binding proteins. The GTPase catalytic activity can be stimulated by oligomerisation of the protein, which is mediated by interactions between the GTPase domain, the middle domain and the GED.
This entry represents the dynamin GTPase effector domain (GED) found in proteins related to dynamin. Its C-terminal region constitutes one of the helices of the bundle signalling element (BSE) or neck together with the N- and C-terminal regions from the Gtpase domain, being in close proximity and functionally linked to it. The N-terminal region of GED is part of the stalk domain [
].Dynamin is a GTP-hydrolysing protein that is an essential participant in clathrin-mediated endocytosis by cells. It self-assembles into 'collars' in vivo at the necks of invaginated coated pits; the self-assembly of dynamin being coordinated by the GTPase domain. Mutation studies indicate that dynamin functions as a molecular regulator of receptor-mediated endocytosis [
,
].
Membrane transport between compartments in eukaryotic cells requires proteins that allow the budding and scission of nascent cargo vesicles from one compartment and their targeting and fusion with another. Dynamins are large GTPases that belong to a protein superfamily [] that, in eukaryotic cells, includes classical dynamins, dynamin-like proteins, OPA1, Mx proteins, mitofusins and guanylate-binding proteins/atlastins [,
,
,
], and are involved in the scission of a wide range of vesicles and organelles. They play a role in many processes including budding of transport vesicles, division of organelles, cytokinesis and pathogen resistance.The minimal distinguishing architectural features that are common to all dynamins and are distinct from other GTPases are the structure of the large GTPase domain (300 amino acids) and the presence of two additional domains; the middle domain and the GTPase effector domain (GED), which are involved in oligomerization and regulation of the GTPase activity.
Dynamin superfamily members are large GTPases, conserved through evolution, mainly described as mechanochemical enzymes involved in membrane scission events. The dynamin superfamily has been subdivided into several subgroups based on domain organisation: classical dynamin, dynamin-like proteins (Dlps), Mc proteins, optic atrophy 1 protein (OPA1), Mitofusins, guanylate-binding proteins (GBP) and alastatins. All members display a common architecture: a large GTPase (see
) domain followed by a 'middle domain' of ill-defined function and a downstream coiled-coil GTPase effector domain (GED) that functions in higher order assembly and as a GTPase activating protein (GAP) for dynamin's GTPase activity. Most members contain additional domains that characterise the different subgroups. For example, classical dynamins contain a lipid binding Pleckstrin-homology (PH) (see
) domain between the middle domain and the GED domain as well as a C-terminal proline-arginine rich domain (PRD) that interacts with numerous SH3 domain-containing binding partners while Dlps lack the PRD but have a PH domain, which may, however, be highly divergent. These various domains confer a variety of biochemical properties and cellular localisations to dynamin, that may explain the diversity of their biological implications in endocytosis, intracellular traffic, organelle fission and fusion, cytokinesis and pathogen resistance [
,
,
,
].The GED is seen to be largely helical in nature, and its oligomerisation occurs via intermolecular packing of the helices [
].
This entry represents the N terminus (approximately 200 residues) of the proline-rich protein BAT2 (also known as PRRC2A). BAT2 is similar to other proteins with large proline-rich domains, such as some nuclear proteins, collagens, elastin, and synapsin [
].
Cell cycle progression is negatively controlled by cyclin-dependent kinases inhibitors (CDIs). CDIs are involved in cell cycle arrest at the G1 phase. This entry represents a domain found in CDIs [
].
Heat shock proteins, Hsp70 chaperones help to fold many proteins. Hsp70 assisted folding involves repeated cycles of substrate binding and release. Hsp70 activity is ATP dependent. Hsp70 proteins are made up of two regions: the amino terminus is the ATPase domain and the carboxyl terminus is the substrate binding region [
].Hsp70 proteins have an average molecular weight of 70kDa [
,
,
]. In most species, there are many proteins that belong to the Hsp70 family. Some of these are only expressed under stress conditions (strictly inducible), while some are present in cells under normal growth conditions and are not heat-inducible (constitutive or cognate) [,
]. Hsp70 proteins can be found in different cellular compartments (nuclear, cytosolic, mitochondrial, endoplasmic reticulum, for example).This entry represents the Hsp70 family, and includes chaperone protein DnaK and luminal-binding proteins. It also includes heat shock protein 110 (Hsp110) from Caenorhabditis elegans which helps prevent the aggregation of denatured proteins in neurons [
]. Also included is endoplasmic reticulum (ER) chaperone BiP (HSPA5) which is important for protein folding and quality control in the ER [].
Functionally characterised members of the 6-8 TMS Triose-phosphate Transporter (TPT) family are derived from the inner envelope
membranes of chloroplasts and non-green plastids of plants. Under normal physiological conditions, chloroplast TPTs mediate a strict antiport of substrates, frequently exchanging an organic three carbon compound phosphate ester for inorganic phosphate (Pi) [,
].Normally, a triose-phosphate, 3-phosphoglycerate, or another phosphorylated C3
compound made in the chloroplast during photosynthesis, exits the organelle into thecytoplasm of the plant cell in exchange for Pi. However, experiments with reconstituted translocator in artificial membranes indicate that transport can also occur by a channel-like uniport mechanism with up to 10-fold higher transport rates. Channel opening may be induced by a membrane potential of large magnitude and/or by high substrate concentrations. Non-green plastid and chloroplast carriers, such as those from maize endosperm and root membranes, mediate transport of C3 compounds phosphorylated at carbon atom 2, particularly phosphoenolpyruvate, in exchange for Pi. These are the phosphoenolpyruvate:Pi antiporters (PPT). Glucose-6-P has also been shown to be a substrate of some plastid translocators (GPT). The three types of proteins (TPT, PPT and GPT) are divergent in sequence as well as substrate specificity, but their substrate specificities overlap.TPT paralogues are also present in Saccharomyces cerevisiae, which are functionally uncharacterised.
This entry represents the bacterial protein ApaG that contains a single ApaG domain, which is ~125 amino acids in length. The Salmonella typhimurium ApaG domain protein, CorD, is involved in Co(2+) resistance and Mg(2+) efflux. Tertiary structures from different ApaG proteins show a fold of several β-sheets. The ApaG domain may be involved in protein-protein interactions which could be implicated in substrate-specificity [
,
,
].
The apaG domain is a ~125 amino acids domain present in bacterial apaG
proteins and in eukaryotic F-box proteins. The domain is named after thebacterial apaG protein, of which it forms the core. The domain also occurs in
the C-terminal part of eukaryotic proteins with an N-terminal F-box domain. The Salmonella typhimurium apaG domain protein corD isinvolved in Co(2+) resistance and Mg(2+) efflux. Tertiary structures from
different apaG proteins show a fold of several β-sheets.The apaG domain may be involved in protein-protein interactions which could be
implicated in substrate-specificity [,
,
,
].
During the process of Escherichia coli nucleotide excision repair, DNA damage
recognition and processing are achieved by the action of the uvrA, uvrB,and uvrC gene products [
]. UvrB and UvrC share a common domain of around 35amino acids, the so called UVR domain. This domain in UvrB can interact with
the homologous domain in UvrC throughout a putative coiled coil structure.This interaction is important for the incision of the damaged strand [
].A conserved region similar to the UVR domain is also found in the ATP-binding subunit of bacterial and chloroplastic Clp ATPases [
], which suggest that the UVR domain is not only involved in the interaction between uvrB and uvrC.
U3 small nucleolar ribonucleoprotein complex, subunit Mpp10
Type:
Family
Description:
Mpp10 (M phase phosphoprotein 10) is a component of the 60-80S U3 small nucleolar ribonucleoprotein (U3 snoRNP) required for three cleavage events that generate the mature 18S rRNA from the pre-rRNA [
,
].
Very-long-chain aldehyde decarbonylase CER1 is an aldehyde decarbonylase involved in the conversion of aldehydes to alkanes. It is the core component of a very-long-chain alkane synthesis complex and it is involved in epicuticular wax biosynthesis and pollen fertility. CER1 is also linked to responses to biotic and abiotic stresses [
,
,
,
].This is the C-terminal domain of CER1 from Arabidopsis and GL1 1-7 from rice. This domain has a conserved LEGW sequence motif. It is about 170 amino acids in length. This domain is found associated with
. It shares similarity to short chain dehydrogenases [
].
This entry includes NDUFAF3, an essential factor for the assembly of mitochondrial NADH:ubiquinone oxidoreductase complex (complex I) [], and the Mth938 domain-containing protein []. The crystal structure of NDUFAF3 revealed a 3-layer beta+alpha/beta/alpha topology [].NADH:ubiquinone oxidoreductase (complex I) (
) is a respiratory-chain enzyme that catalyses the transfer of two electrons from NADH to ubiquinone in a reaction that is associated with proton translocation across the membrane (NADH + ubiquinone = NAD+ + ubiquinol) [
]. Complex I is a major source of reactive oxygen species (ROS) that are predominantly formed by electron transfer from FMNH(2). Complex I is found in bacteria, cyanobacteria (as a NADH-plastoquinone oxidoreductase), archaea [], mitochondria, and in the hydrogenosome, a mitochondria-derived organelle. In general, the bacterial complex consists of 14 different subunits, while the mitochondrial complex contains homologues to these subunits in addition to approximately 31 additional proteins [].
Phosphoglycerate/bisphosphoglycerate mutase, active site
Type:
Active_site
Description:
Phosphoglycerate mutase (
) (PGAM) and bisphosphoglycerate mutase (
)
(BPGM) are structurally related enzymes that catalyse reactions involving the transfer of phospho groups between the three carbon atoms of phosphoglycerate [
,
,
]. Both enzymes can catalyse three different reactions with different specificities, the isomerization of 2-phosphoglycerate (2-PGA) to 3-phosphoglycerate (3-PGA) with 2,3-diphosphoglycerate (2,3-DPG) as the primer of the reaction, the synthesis of 2,3-DPG from 1,3-DPG with 3-PGA as a primer and the degradation of 2,3-DPG to 3-PGA (phosphatase activity).
In mammals, PGAM is a dimeric protein with two isoforms, the M (muscle) and B (brain) forms. In yeast, PGAM is a tetrameric protein.BPGM is a dimeric protein and is found mainly in erythrocytes where it plays a major role in regulating haemoglobin oxygen affinity as a consequence of controlling 2,3-DPG concentration. The catalytic mechanism of both PGAM and BPGM involves the formation of a phosphohistidine intermediate [
].A number of other proteins including, the bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase [
] that catalyses both the synthesis and the degradation of fructose-2,6-bisphosphate and bacterial alpha-ribazole-5'-phosphate phosphatase, which is involved in cobalamin biosynthesis, belong to this family [].This entry contains the active site phosphohistidine residue.
The histidine phosphatase superfamily is so named because catalysis
centres on a conserved His residue that is transiently phosphorylatedduring the catalytic cycle. Other conserved residues contribute to a
'phosphate pocket' and interact with the phospho group of substratebefore, during and after its transfer to the His residue. Structure and
sequence analyses show that different families contribute differentadditional residues to the 'phosphate pocket' and, more surprisingly,
differ in the position, in sequence and in three dimensions, of acatalytically essential acidic residue. The superfamily may be divided
into two main branches. The relationship between the two branches isnot evident by (PSI-)BLAST but is clear from more sensitive sequence
searches and structural comparisons [].The larger clade-1 contains a wide variety of catalytic functions, the best known being fructose 2,6-bisphosphatase (found in a bifunctional protein with 2-phosphofructokinase) and cofactor-dependent phosphoglycerate mutase. The latter is an unusual example of a mutase activity in the superfamily: the vast majority of members appear to be phosphatases. The bacterial regulatory protein phosphatase SixA is also in clade-1 and has a minimal, and possible ancestral-like structure, lacking the large domain insertions that contribute to binding of small molecules in clade-1 members.
This superfamily represents a structural domain with a thiolase-like 3-layer α/β/α topology. This domain usually occurs in two similar copies that are related by a pseudo-dyad, and which arose through duplication. The proteins in this entry can be split into two groups: those related to thiolase, and those related to chalcone synthase. The thiolase-like enzymes include:Thiolase, where the topology of each domain is similar to the first domain of phosphoglucomutase [
]
Beta-ketoacyl-ACP synthases types I (
), II (
) [
,
] and III ()
Actinorhodin polyketide beta-ketoacyl synthases 1 and 2 [
]
Fatty oxidation complex beta subunit (3-ketoacyl-CoA thiolase;
) [
]
The chalcone synthase-like enzymes include:Chalcone synthase (
) [
]
Ketoacyl-ACP synthase III (FabH;
) [
]
Polyketide synthases [
]
3-hydroxy-3-methylglutaryl CoA synthase (
) [
]
Dihydropinosylvin synthase [
]
This group represents 3-ketoacyl-CoA synthases (KCSs) from plants [
,
]. They are also known as very long-chain fatty acid (VLCFA) condensing enzymes, and they catalyse the first committed step during the fatty acid elongation process, which is the condensation of C2 units to acyl-CoA. Arabidopsis contains 21 KCS members [].
Beta-ketoacyl-[acyl-carrier-protein] synthase III, C-terminal
Type:
Domain
Description:
This domain is found in beta-ketoacyl-[acyl-carrier-protein] synthase III (also known as 3-Oxoacyl-[acyl-carrier-protein (ACP)]synthase III)
, the enzyme responsible for initiating the chain of reactions of the fatty acid synthase in plants and bacteria [
].
This domain is found in proteins that are described as 3-ketoacyl-CoA synthases, type III polyketide synthases, fatty acid elongases and fatty acid condensing enzymes, and are found in both prokaryotic and eukaryotic (mainly plant) species. The region contains the active site residues, as well as motifs involved in substrate binding [
].
Peroxisomal membrane protein PEX14, or peroxin-14, is a core component of the peroxisomal translocation machinery or importomer [
,
]. PEX14 is involved in the docking of PEX5-bound protein onto the peroxisomal membrane, and it may be involved in the translocation step into the peroxisome matrix []. In addition to its role in protein docking, a role in transcriptional regulation has also been suggested for PEX14 [].
Peroxisome membrane anchor protein Pex14p, N-terminal
Type:
Domain
Description:
This conserved region defines a group of peroxisomal membrane anchor proteins which bind the PTS1 (peroxisomal targeting signal) receptor and are required for the import of PTS1-containing proteins into peroxisomes. Loss of functional Pex14p results in defects in both the PTS1 and PTS2-dependent import pathways. Deletion analysis of this conserved region implicates it in selective peroxisome degradation. In the majority of members this region is situated at the N terminus of the protein [
,
].
1-deoxy-D-xylulose 5-phosphate reductoisomerase synthesises 2-C-methyl-D-erythritol 4-phosphate from 1-deoxy-D-xylulose 5-phosphate in a single step by intramolecular rearrangement and reduction and is responsible for terpenoid biosynthesis in some organisms [
,
]. In Arabidopsis thaliana 1-deoxy-D-xylulose 5-phosphate reductoisomerase is the first committed enzyme of the non-mevalonate pathway for isoprenoid biosynthesis. The enzyme requires Mn2+, Co2+ or Mg2+ for activity, with the first being most effective.The structure of this enzyme has been solved, showing the protein forms a dimeric assembly and contains a metal ion in the active site [
]. This domain is found to the C terminus of
domains in bacterial and plant 1-deoxy-D-xylulose 5-phosphate reductoisomerases. This domain has been related to the dimer formation, for providing residues necessary for active site metal binding, and for positioning the substrate [
].
1-deoxy-D-xylulose 5-phosphate reductoisomerase synthesises 2-C-methyl-D-erythritol 4-phosphate from 1-deoxy-D-xylulose 5-phosphate in a single step by intramolecular rearrangement and reduction and is responsible for terpenoid biosynthesis in some organisms [,
]. In Arabidopsis thaliana 1-deoxy-D-xylulose 5-phosphate reductoisomerase is the first committed enzyme of the non-mevalonate pathway for isoprenoid biosynthesis. The enzyme requires Mn2+, Co2+ or Mg2+ for activity, with the first being most effective.The structure of this enzyme has been solved, showing the protein forms a dimeric assembly and contains a metal ion in the active site [
].
This entry represents the C-terminal domain of the 1-deoxy-D-xylulose-5-phosphate reductoisomerase enzyme. This domain forms a left handed super-helix.
DXP reductoisomerase catalyses the NADP-dependent rearrangement and reduction of 1-deoxy-D-xylulose-5-phosphate (DXP) to 2-C-methyl-D-erythritol 4-phosphate (MEP) [].
1-deoxy-D-xylulose 5-phosphate reductoisomerase synthesises 2-C-methyl-D-erythritol 4-phosphate from 1-deoxy-D-xylulose 5-phosphate in a single step by intramolecular rearrangement and reduction and is responsible for terpenoid biosynthesis in some organisms [
,
]. In Arabidopsis thaliana 1-deoxy-D-xylulose 5-phosphate reductoisomerase is the first committed enzyme of the non-mevalonate pathway for isoprenoid biosynthesis. The enzyme requires Mn2+, Co2+ or Mg2+ for activity, with the first being most effective.The structure of this enzyme has been solved, showing the protein forms a dimeric assembly and contains a metal ion in the active site [
]. This domain is found at the N terminus of bacterial and plant 1-deoxy-D-xylulose 5-phosphate reductoisomerases. It is responsible for the binding to NADPH [
].
The RST (for RCD1 SRO TAF4) domain is a plant-specific domain found in WWE- PARPs (poly(ADP-ribose) polymerase) and TAF4s (TBP-Associated Factor 4), a component of several multimeric protein complexes including primarily the general transcription factor TFIID involved in transcriptional initiation. The RST domain is a protein-protein interaction domain suggested to be critical for the interaction with several, mostly plant-specific transcription factors [
,
]. The RST domain structure has a unique helical arrangement composed of four alpha helices flanked by disordered termini. The four-helix fold of the RST domain organizes in an open, hydrophobic L-shape with room for catching the ligand [
]. A strong conservation of a large number of aliphatic amino acids in the N- and C-termini of the RST domain, with a conserved tyrosine in the middle of the domain and two conserved positively charged amino acids in the second half of the domain, is striking []. This entry represents the RST domain.
Pantothenate kinase, acetyl-CoA regulated, two-domain type
Type:
Family
Description:
Pantothenate kinase (PanK,
) catalyses the conversion of CAATP and pantothenate to ADP and D-4'-phosphopantothenate, the key regulatory step in the biosynthesis of coenzyme A (CoA) [
]. Members in this entry represents a two-domain form with an additional C-terminal domain of unknown function. This type of pantothenate kinase is typical for eukaryotes. It is not related by sequence to bacterial PanK () and differs in a number of biochemical properties (such as inhibition by acetyl-CoA) [
,
]. However, this group also includes proteins from several Gram-positive bacteria () that are suggested to have originated from the eukaryotic form by lateral transfer [
].Hallervorden-Spatz syndrome is caused by a defect in a pantothenate kinase gene [
].For additional information please see [
].
This domain is found in Damage-control phosphatases ARMT1, YMR027W from S. cerevisiae (
) and At2g17340 from Arabidopsis thaliana, and it is also found at the C-terminal portion of eukaryotic pantothenate kinases [
,
]. Despite the characterization of ARMT1 as a carboxyl methyltransferase, a second study suggests that these proteins are hydrolases whose function is to limit potentially harmful buildups of phosphometabolites []. They are metal-dependent phosphatases involved in metabolic damage-control processes termed "damage pre-emption"or "housecleaning". Crystal structure of damage-control phosphatase At2g17340 revealed a novel protein fold and several conserved residues coordinating a metal ion (probably Mg2) with high degree of conservation suggesting that the metal-binding site is central for the function of this domain [
].
Pantothenate kinase (PanK or CoaA) catalyses the first step of the universal five step coenzyme A (CoA) biosynthesis pathway. CoA is a ubiquitous and essential cofactor in all living organsims. Pantothenate kinase catalyses the first and rate limiting step in the CoA biosynthetic pathway, which involves transferring a phosphoryl group from ATP to pantothenate, also known as vitamin B5. Three distinct types of pantothenate kinase enzymes have been identified: type I PanK enzymes are typified by the E. coli CoaA protein, type II enzymes are primarily found in eukaryotic organisms whilst type III enzymes have a wider phylogenic distribution and are not feedback inhibited by CoA [
].This family describes the type II form of pantothenate kinase PanK, characterised from the fungus Emericella nidulans and with similar forms known in several other eukaryotes. It also includes forms from several Gram-positive bacteria suggested to have originated from the eukaryotic form by lateral transfer. It differs in a number of biochemical properties (such as inhibition by acetyl-CoA) from type I PanK enzymes and shows little sequence similarity [
,
].
U3 small nucleolar RNA-associated protein 13, C-terminal
Type:
Domain
Description:
A large ribonuclear protein complex is required for the processing of the small-ribosomal-subunit rRNA - the small-subunit (SSU) processome [,
]. This preribosomal complex contains the U3 snoRNA and at least 40 proteins, which have the following properties: They are nucleolar.They are able to coimmunoprecipitate with the U3 snoRNA and Mpp10 (a protein specific to the SSU processome). They are required for 18S rRNA biogenesis.There appears to be a linkage between polymerase I transcription and the formation of the SSU processome; as some, but not all, of the SSU processome components are required for pre-rRNA transcription initiation. These SSU processome components have been termed t-Utps. They form a pre-complex with pre-18S rRNA in the absence of snoRNA U3 and other SSU processome components. It has been proposed that the t-Utp complex proteins are both rDNA and rRNA binding proteins that are involved in the initiation of pre18S rRNA transcription. Initially binding to rDNA then associating with the 5' end of the nascent pre18S rRNA. The t-Utpcomplex forms the nucleus around which the rest of the SSU processome components, including snoRNA U3, assemble [
]. From electron microscopy the SSU processome may correspond to the terminal knobs visualized at the 5' ends of nascent 18S rRNA. Utp13 is a nucleolar protein and component of the small subunit (SSU) processome containing the U3 snoRNA that is involved in processing of pre-18S rRNA [
]. Upt13 is also a component of the Pwp2 complex that forms part of a stable particle subunit independent of the U3 small nucleolar ribonucleoprotein that is essential for the initial assembly steps of the 90S pre-ribosome [
]. Components of the Pwp2 complex are:Utp1 (Pwp2), Utp6, Utp12 (Dip2), Utp13, Utp18, and Utp21. The relationship between the Pwp2 complex and the t-Utps complex [
] that also associates with the 5' end of nascent pre-18S rRNA is unclear. This is the C-terminal helical domain of yeast Utp13 and its orthologue from human, Transducin beta-like protein 3, whose function is not clear. This domain is also found in protein TORMOZ EMBRYO DEFECTIVE from plants, which is an essential protein involved in the regulation of cell division planes during embryogenesis and defines cell patterning [
].
This entry represents inositol-tetrakisphosphate 1-kinase, which is also called inositol 1,3,4-trisphosphate 5/6-kinase.Inositol-tetrakisphosphate 1-kinase can phosphorylate various inositol polyphosphates, such as Ins(3,4,5,6)P4 or Ins(1,3,4)P3. Phosphorylation of Ins(3,4,5,6)P4 at position 1 forms Ins(1,3,4,5,6)P5 which has regulatory importance, since Ins(3,4,5,6)P4 is an inhibitor of plasma membrane Ca(2+)-activated Cl(-) channels. Phosphorylation of Ins(1,3,4)P3 on O-5 and O-6 forms Ins(1,3,4,6)P4, an essential molecule in the hexakisphosphate (InsP6) pathway [
,
,
,
,
].
The ATP-grasp superfamily currently includes 17 groups of enzymes, catalyzing ATP-dependent ligation of a carboxylate containing molecule to an amino or thiol group-containing molecule [
]. They contribute predominantly to macromolecular synthesis. ATP-hydrolysis is used to activate a substrate. For example, DD-ligase transfers phosphate from ATP to D-alanine on the first step of catalysis. On the second step the resulting acylphosphate is attacked by a second D-alanine to produce a DD dipeptide following phosphate elimination [].The ATP-grasp domain contains three conserved motifs, corresponding to the phosphate binding loop and the Mg(2+) binding site [
]. The fold is characterised by two α-β subdomains that grasp the ATP molecule between them. Each subdomain provides a variable loop that formspart of the active site, with regions from other domains also contributing to the active site, even though these other domains are not conserved between the various ATP-grasp enzymes [
].
Iron-sulphur (FeS) clusters are important cofactors for numerous proteins involved in electron transfer, in redox and non-redox catalysis, in gene regulation, and as sensors of oxygen and iron. These functions depend on the various FeS cluster prosthetic groups, the most common being [2Fe-2S] and [4Fe-4S][
]. FeS cluster assembly is a complex process involving the mobilisation of Fe and S atoms from storage sources, their assembly into [Fe-S]form, their transport to specific cellular locations, and their transfer to recipient apoproteins. So far, three FeS assembly machineries have been identified, which are capable of synthesising all types of [Fe-S] clusters: ISC (iron-sulphur cluster), SUF (sulphur assimilation), and NIF (nitrogen fixation) systems.The ISC system is conserved in eubacteria and eukaryotes (mitochondria), and has broad specificity, targeting general FeS proteins [
,
]. It is encoded by the isc operon (iscRSUA-hscBA-fdx-iscX). IscS is a cysteine desulphurase, which obtains S from cysteine (converting it to alanine) and serves as a S donor for FeS cluster assembly. IscU and IscA act as scaffolds to accept S and Fe atoms, assembling clusters and transferring them to recipient apoproteins. HscA is a molecular chaperone and HscB is a co-chaperone. Fdx is a [2Fe-2S]-type ferredoxin. IscR is a transcription factor that regulates expression of the isc operon. IscX (also known as YfhJ) appears to interact with IscS and may function as an Fe donor during cluster assembly [
].The SUF system is an alternative pathway to the ISC system that operates under iron starvation and oxidative stress. It is found in eubacteria, archaea and eukaryotes (plastids). The SUF system is encoded by the suf operon (sufABCDSE), and the six encoded proteins are arranged into two complexes (SufSE and SufBCD) and one protein (SufA). SufS is a pyridoxal-phosphate (PLP) protein displaying cysteine desulphurase activity. SufE acts as a scaffold protein that accepts S from SufS and donates it to SufA [
]. SufC is an ATPase with an unorthodox ATP-binding cassette (ABC)-like component. SufA is homologous to IscA [], acting as a scaffold protein in which Fe and S atoms are assembled into [FeS]cluster forms, which can then easily be transferred to apoproteins targets.
In the NIF system, NifS and NifU are required for the formation of metalloclusters of nitrogenase in Azotobacter vinelandii, and other organisms, as well as in the maturation of other FeS proteins. Nitrogenase catalyses the fixation of nitrogen. It contains a complex cluster, the FeMo cofactor, which contains molybdenum, Fe and S. NifS is a cysteine desulphurase. NifU binds one Fe atom at its N-terminal, assembling an FeS cluster that is transferred to nitrogenase apoproteins [
]. Nif proteins involved in the formation of FeS clusters can also be found in organisms that do not fix nitrogen [].This entry represents the N-terminal of NifU and homologous proteins. NifU contains two domains: an N-terminal and a C-terminal domain (
) [
]. These domains exist either together or on different polypeptides, both domains being found in organisms that do not fix nitrogen (e.g. yeast), so they have a broader significance in the cell than nitrogen fixation.
Bicarbonate (HCO
3-) transport mechanisms are the principal regulators of pH in animal cells. Such transport also plays a vital role in acid-base movements in the stomach, pancreas, intestine, kidney, reproductive organs and the central nervous system. Functional studies have suggested four different HCO
3-transport modes. Anion exchanger proteins exchange HCO
3-for Cl
-in a reversible, electroneutral manner [
]. Na+/HCO
3-co-transport proteins mediate the coupled movement of Na
+and HCO
3-across plasma membranes, often in an electrogenic manner [
]. Na+driven Cl
-/HCO
3-exchange and K
+/HCO
3-exchange activities have also been detected in certain cell types, although the molecular identities of the proteins responsible remain to be determined.
Sequence analysis of the two families of HCO
3-transporters that have been cloned to date (the anion exchangers and Na
+/HCO
3-co-transporters) reveals that they are homologous. This is not entirely unexpected, given that they both transport HCO
3-and are inhibited by a class of pharmacological agents called disulphonic stilbenes [
]. They share around ~25-30% sequence identity, which is distributed along their entire sequence length, and have similar predicted membrane topologies, suggesting they have ~10 transmembrane (TM) domains.This entry represents transmembrane segments of bicarbonate transporters and related proteins.In animals, this domain is found at the C terminus of many bicarbonate and similar multifunctional transporters. The crystal structure of Band 3 anion transport protein, the founding member of the solute carrier 4 (SLC4) family of bicarbonate transporters, has been solved. This protein functions both as a transporter that mediates electroneutral anion exchange across the cell membrane and as a structural protein [
,
,
,
].Boron transporters from plants and yeast comprise only transmembrane segments, confirmed by the solved structures [
,
,
]. In plants, boron is essential for maintaining the integrity of cell walls; this transporter mediates boron translocation from roots to shoots under boron limitation []. Boron transporter 1 from Saccharomyces cerevisiae protects yeast cells from boron toxicity and is involved in the trafficking of proteins to the vacuole. The mechanism of its activity seems to be consistent with this described for other members of the family [,
].
Bicarbonate (HCO
3-) transport mechanisms are the principal regulators of pH in animal cells. Such transport also plays a vital role in acid-base movements in the stomach, pancreas, intestine, kidney, reproductive organs and the central nervous system. Functional studies have suggested four different HCO
3-transport modes. Anion exchanger proteins exchange HCO
3-for Cl
-in a reversible, electroneutral manner [
]. Na+/HCO
3-co-transport proteins mediate the coupled movement of Na
+and HCO
3-across plasma membranes, often in an electrogenic manner [
]. Na+driven Cl
-/HCO
3-exchange and K
+/HCO
3-exchange activities have also been detected in certain cell types, although the molecular identities of the proteins responsible remain to be determined.
Sequence analysis of the two families of HCO
3-transporters that have been cloned to date (the anion exchangers and Na
+/HCO
3-co-transporters) reveals that they are homologous. This is not entirely unexpected, given that they both transport HCO
3-and are inhibited by a class of pharmacological agents called disulphonic stilbenes [
]. They share around ~25-30% sequence identity, which is distributed along their entire sequence length, and have similar predicted membrane topologies, suggesting they have ~10 transmembrane (TM) domains.
Alcohol dehydrogenase (
) (ADH) catalyses the reversible oxidation of alcohols to their corresponding acetaldehyde or ketone with the concomitant reduction of NAD:
alcohol + NAD = aldehyde or ketone + NADH
Currently three structurally and catalytically different types of alcohol dehydrogenases are known:Zinc-containing 'long-chain' alcohol dehydrogenases.Insect-type, or 'short-chain' alcohol dehydrogenases.Iron-containing alcohol dehydrogenases.Zinc-containing ADH's [
,
] are dimeric or tetrameric enzymes that bind two atoms of zinc per subunit. One of the zinc atoms is essential for catalytic activity while the other is not. Both zinc atoms are coordinated by either cysteine or histidine residues; the catalytic zinc is coordinated by two cysteines and one histidine. Zinc-containing ADH's are found in bacteria, mammals, plants, and in fungi. In many species there is more than one isozyme (for example, humans have at least six isozymes, yeast have three, etc.). A number of other zinc-dependent dehydrogenases are closely related to zinc ADH [] and are included in this family:Sorbitol dehydrogenase (
)
L-threonine 3-dehydrogenase (
)
Glutathione-dependent formaldehyde dehydrogenase (
)
Mannitol dehydrogenase (
)
In addition, this family includes NADP-dependent quinone oxidoreductase (
), an enzyme found in bacteria (gene qor), in yeast and in mammals where, in some species such as rodents, it has been recruited as an eye lens protein and is known as zeta-crystallin [
]. The sequence of quinone oxidoreductase is distantly related to that other zinc-containing alcohol dehydrogenases and it lacks the zinc-ligand residues. The torpedo fish and mammalian synaptic vesicle membrane protein vat-1 is related to qor.This entry represents the cofactor-binding domain of these enzymes, which is normally found towards the C terminus. Structural studies indicate that it forms a classical Rossman fold that reversibly binds NAD(H) [
,
,
].
The PucC protein is required for high-level transcription of the PUC operon. It is an integral membrane protein. The entry includes PucC and other proteins from the Major Facilitator Superfamily.
Atg101 is a critical autophagy factor that functions together with ULK, Atg13 and FIP200 [
,
]. In fission yeasts, it has a role in meiosis and sporulation [].
Cyclophilin-type peptidyl-prolyl cis-trans isomerase, conserved site
Type:
Conserved_site
Description:
Cyclophilins exhibit peptidyl-prolyl cis-trans isomerase (PPIase) activity (
), accelerating protein folding by catalysing the cis-trans isomerisation of proline imidic peptide bonds in oligopeptides [
,
]. They also have protein chaperone-like functions [] and are the major high-affinity binding proteins for the immunosuppressive drug cyclosporin A (CSA) in vertebrates [].Cyclophilins are found in all prokaryotes and eukaryotes, and have been structurally conserved throughout evolution, implying their importance in cellular function []. They share a common 109 amino acid cyclophilin-like domain (CLD) and additional domains unique to each member of the family. The CLD domain contains the PPIase activity, while the unique domains are important for selection of protein substrates and subcellular compartmentalisation [].This entry represents a conserved site in the central part of these enzymes.
Ribosomal protein L25/Gln-tRNA synthetase, anti-codon-binding domain superfamily
Type:
Homologous_superfamily
Description:
The bacterial ribosomal protein L25 is bound to 5S rRNA along with L5 and L18, forming a separate domain of the ribosome [
]. The solution structure of protein L25 uncomplexed with RNA shows two significantly disordered loops and a closed β-barrel domain with a complex topology that has significant structural similarities to the N-terminal domain of the Thermus thermophilus ribosomal protein TL5, to the general stress protein CTC, and to the C-terminal anticodon-binding domain of Escherichia coli glutaminyl-tRNA synthetase (GlnRS) [,
]. GlnRS contains a duplication consisting of two L25-like β-barrels domains with the swapping of N-terminal strands.
The bacterial ribosomal protein L25 is bound to 5S rRNA along with L5 and L18, forming a separate domain of the ribosome [
]. The solution structure of protein L25 uncomplexed with RNA shows two significantly disordered loops and a closed β-barrel domain with a complex topology that has significant structural similarities to the N-terminal domain of the Thermus thermophilus ribosomal protein TL5, to the general stress protein CTC, and to the C-terminal anticodon-binding domain of Escherichia coli glutaminyl-tRNA synthetase (GlnRS) [,
]. GlnRS contains a duplication consisting of two L25-like β-barrels domains with the swapping of N-terminal strands.This entry represents a domain with a mainly β-strand structure found in ribosomal L25-like proteins.
Ribosomal protein L25/Gln-tRNA synthetase, N-terminal
Type:
Homologous_superfamily
Description:
The bacterial ribosomal protein L25 is bound to 5S rRNA along with L5 and L18, forming a separate domain of the ribosome [
]. The solution structure of protein L25 uncomplexed with RNA shows two significantly disordered loops and a closed β-barrel domain with a complex topology that has significant structural similarities to the N-terminal domain of the Thermus thermophilus ribosomal protein TL5, to the general stress protein CTC, and to the C-terminal anticodon-binding domain of Escherichia coli glutaminyl-tRNA synthetase (GlnRS) [,
]. GlnRS contains a duplication consisting of two L25-like β-barrels domains with the swapping of N-terminal strands.This superfamily represents the N-terminal domain, which has a β-barrel structure.
Aldehyde dehydrogenases (
and
) are enzymes that oxidize a wide variety of aliphatic and aromatic aldehydes using NADP as a cofactor. In mammals at least four different forms of the enzyme are known [
]: class-1 (or Ald C) a tetrameric cytosolic enzyme, class-2 (or Ald M) a tetrameric mitochondrial enzyme, class- 3 (or Ald D) a dimeric cytosolic enzyme, and class IV a microsomal enzyme. Aldehyde dehydrogenases have also been sequenced from fungal and bacterial species. A number of enzymes are known to be evolutionary related to aldehyde dehydrogenases. A glutamic acid and a cysteine residue have been implicated in the catalytic activity of mammalian aldehyde dehydrogenase. These residues are conserved in all the enzymes of this entry. This entry represents the cysteine active site.
This superfamily represents a structural domain found at the N-terminal of aldehyde dehydrogenases [
]. These proteins contain two similar domains, each with a 3-layer alpha/beta/alpha structure, which probably arose from a duplication; this entry covers the N-terminal a/b/a domain. These enzymes binds NAD differently from other NAD(P)-dependent oxidoreductases. Aldehyde dehydrogenases (
and
) are enzymes that oxidize a wide variety of aliphatic and aromatic aldehydes using NADP as a cofactor. In mammals at least four different forms of the enzyme are known [
]: class-1 (or Ald C) a tetrameric cytosolic enzyme, class-2 (or Ald M) a tetrameric mitochondrial enzyme, class- 3 (or Ald D) a dimeric cytosolic enzyme, and class IV a microsomal enzyme. Aldehyde dehydrogenases have also been sequenced from fungal and bacterial species. A number of enzymes are known to be evolutionary related to aldehyde dehydrogenases. A glutamic acid and a cysteine residue have been implicated in the catalytic activity of mammalian aldehyde dehydrogenase.This domain superfamily is also found in gamma-glutamyl phosphate reductases, also known as glutamate-5-semialdehyde dehydrogenases.
This entry represents a structural domain found in aldehyde dehydrogenases [
] and histidinol dehydrogenases []. These proteins contain two similar domains, each with a 3-layer α/β/α structure, which probably arose from a duplication. These enzymes bind NAD differently from other NAD(P)-dependent oxidoreductases. Aldehyde dehydrogenases (
and
) are enzymes that oxidize a wide variety of aliphatic and aromatic aldehydes using NADP as a cofactor. In mammals at least four different forms of the enzyme are known [
]: class-1 (or Ald C) a tetrameric cytosolic enzyme, class-2 (or Ald M) a tetrameric mitochondrial enzyme, class- 3 (or Ald D) a dimeric cytosolic enzyme, and class IV a microsomal enzyme. Aldehyde dehydrogenases have also been sequenced from fungal and bacterial species. A number of enzymes are known to be evolutionary related to aldehyde dehydrogenases. A glutamic acid and a cysteine residue have been implicated in the catalytic activity of mammalian aldehyde dehydrogenase.
Histidinol dehydrogenase (
) (HDH) catalyses the terminal step in the biosynthesis of histidine in bacteria, fungi, and plants, the four-electron oxidation of L-histidinol to histidine. In 4-electron dehydrogenases, a single active site catalyses 2 separate oxidation steps: oxidation of the substrate alcohol to an intermediate aldehyde; and oxidation of the aldehyde to the product acid, in this case His [
]. The reaction proceeds via a tightly- or covalently-bound inter-mediate, and requires the presence of 2 NAD molecules []. By contrast with most dehydrogenases, the substrate is bound before the NAD coenzyme []. A Cys residue has been implicated in the catalytic mechanism of the second oxidative step []. In bacteria HDH is a single chain polypeptide; in fungi it is the C-terminal domain of a multifunctional enzyme which catalyzes three different steps of histidine biosynthesis; and in plants it is expressed as nuclear encoded protein precursor which is exported to the chloroplast [].
Aldehyde dehydrogenases (
and
) are enzymes that oxidize a wide variety of aliphatic and aromatic aldehydes using NADP as a cofactor. In mammals at least four different forms of the enzyme are known [
]: class-1 (or Ald C) a tetrameric cytosolic enzyme, class-2 (or Ald M) a tetrameric mitochondrial enzyme, class- 3 (or Ald D) a dimeric cytosolic enzyme, and class IV a microsomal enzyme. Aldehyde dehydrogenases have also been sequenced from fungal and bacterial species. A number of enzymes are known to be evolutionary related to aldehyde dehydrogenases. A glutamic acid and a cysteine residue have been implicated in the catalytic activity of mammalian aldehyde dehydrogenase. These residues are conserved in all the enzymes of this entry.Some of the proteins in this entry are allergens. Allergies are hypersensitivity reactions of the immune system to specific substances called allergens (such as pollen, stings, drugs, or food) that, in most people, result in no symptoms. A nomenclature system has been established for antigens (allergens) that cause IgE-mediated atopic allergies in humans [WHO/IUIS Allergen Nomenclature Subcommittee
King T.P., Hoffmann D., Loewenstein H., Marsh D.G., Platts-Mills T.A.E.,Thomas W. Bull. World Health Organ. 72:797-806(1994)]. This nomenclature system is defined by a designation that is composed ofthe first three letters of the genus; a space; the first letter of the
species name; a space and an arabic number. In the event that two speciesnames have identical designations, they are discriminated from one another
by adding one or more letters (as necessary) to each species designation.The allergens in this family include allergens with the following designations: Alt a 10 and Cla h 3.
This superfamily represents a structural domain found at the C-terminal of aldehyde dehydrogenases [
]. These proteins contain two similar domains, each with a 3-layer alpha/beta/alpha structure, which probably arose from a duplication; this entry covers the C-terminal a/b/a domain. These enzymes bind NAD differently from other NAD(P)-dependent oxidoreductases.
Aldehyde dehydrogenases (
and
) are enzymes that oxidize a wide variety of aliphatic and aromatic aldehydes using NADP as a cofactor. In mammals at least four different forms of the enzyme are known [
]: class-1 (or Ald C) a tetrameric cytosolic enzyme, class-2 (or Ald M) a tetrameric mitochondrial enzyme, class- 3 (or Ald D) a dimeric cytosolic enzyme, and class IV a microsomal enzyme. Aldehyde dehydrogenases have also been sequenced from fungal and bacterial species. A number of enzymes are known to be evolutionary related to aldehyde dehydrogenases. A glutamic acid and a cysteine residue have been implicated in the catalytic activity of mammalian aldehyde dehydrogenase.
This domain is found mainly in plant proteins known as Casparian strip membrane proteins (CASPs). CASPs are four-membrane-span proteins that mediate the deposition of Casparian strips in the endodermis by recruiting the lignin polymerization machinery. Interestingly, the CASP first extracellular loop was found conserved in euphyllophytes but absent in plants lacking Casparian strips [
,
].
DNA topoisomerase, type IIA, subunit B, C-terminal
Type:
Homologous_superfamily
Description:
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 II topoisomerases are ATP-dependent enzymes, and can be subdivided according to their structure and reaction mechanisms: type IIA (topoisomerase II or gyrase, and topoisomerase IV) and type IIB (topoisomerase VI). These enzymes are responsible for relaxing supercoiled DNA as well as for introducing both negative and positive supercoils [
].Type IIA topoisomerases together manage chromosome integrity and topology in cells. Topoisomerase II (called gyrase in bacteria) primarily introduces negative supercoils into DNA. In bacteria, topoisomerase II consists of two polypeptide subunits, gyrA and gyrB, which form a heterotetramer: (BA)2. In most eukaryotes, topoisomerase II consists of a single polypeptide, where the N- and C-terminal regions correspond to gyrB and gyrA, respectively; this topoisomerase II forms a homodimer that is equivalent to the bacterial heterotetramer. There are four functional domains in topoisomerase II: domain 1 (N-terminal of gyrB) is an ATPase, domain 2 (C-terminal of gyrB) is responsible for subunit interactions (differs between eukaryotic and bacterial enzymes), domain 3 (N-terminal of gyrA) is responsible for the breaking-rejoining function through its capacity to form protein-DNA bridges, and domain 4 (C-terminal of gyrA) is able to non-specifically bind DNA [].Topoisomerase IV primarily decatenates DNA and relaxes positive supercoils, which is important in bacteria, where the circular chromosome becomes catenated, or linked, during replication [
]. Topoisomerase IV consists of two polypeptide subunits, parE and parC, where parC is homologous to gyrA and parE is homologous to gyrB.This superfamily represents the C-terminal domain of subunit B (gyrB and parE) of bacterial gyrase and topoisomerase IV, and the equivalent region in eukaryotic topoisomerase II composed of a single polypeptide.
