Thioredoxin fold
Encyclopedia
The thioredoxin fold is a protein
fold
common to enzyme
s that catalyze disulfide bond
formation and isomer
ization. The fold is named for the canonical example thioredoxin
and is found in both prokaryotic
and eukaryotic
proteins. It is an example of an alpha/beta protein fold that has oxidoreductase
activity. The fold's spatial topology consists of a four-stranded antiparallel beta sheet
sandwiched between two alpha helices
. The strand topology is 2134 with 3 antiparallel to the rest.
sequence with two reactive cysteine
residues: Cys-X-Y-Cys, where X and Y are often but not necessarily hydrophobic amino acid
s. The reduced form of the protein contains two free thiol
groups at the cysteine residues, whereas the oxidized form contains a disulfide bond between them.
of their free thiols, which derives from the ability of the overall protein structure to stabilize the activated thiolate. Although the structure is fairly consistent among proteins containing the thioredoxin fold, the pKa is extremely sensitive to small variations in structure, especially in the placement of protein backbone
atoms near the first cysteine.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
fold
Tertiary structure
In biochemistry and molecular biology, the tertiary structure of a protein or any other macromolecule is its three-dimensional structure, as defined by the atomic coordinates.-Relationship to primary structure:...
common to enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
s that catalyze disulfide bond
Disulfide bond
In chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...
formation and isomer
Isomer
In chemistry, isomers are compounds with the same molecular formula but different structural formulas. Isomers do not necessarily share similar properties, unless they also have the same functional groups. There are many different classes of isomers, like stereoisomers, enantiomers, geometrical...
ization. The fold is named for the canonical example thioredoxin
Thioredoxin
Thioredoxin is a class of small redox proteins known to be present in all organisms. It plays a role in many important biological processes. In humans, it is encoded by the TXN gene. Loss-of-function mutation of either of the two human thioredoxin genes is lethal at the four-cell stage of the...
and is found in both prokaryotic
Prokaryote
The prokaryotes are a group of organisms that lack a cell nucleus , or any other membrane-bound organelles. The organisms that have a cell nucleus are called eukaryotes. Most prokaryotes are unicellular, but a few such as myxobacteria have multicellular stages in their life cycles...
and eukaryotic
Eukaryote
A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...
proteins. It is an example of an alpha/beta protein fold that has oxidoreductase
Oxidoreductase
In biochemistry, an oxidoreductase is an enzyme that catalyzes the transfer of electrons from one molecule to another...
activity. The fold's spatial topology consists of a four-stranded antiparallel beta sheet
Beta sheet
The β sheet is the second form of regular secondary structure in proteins, only somewhat less common than the alpha helix. Beta sheets consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet...
sandwiched between two alpha helices
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
. The strand topology is 2134 with 3 antiparallel to the rest.
Sequence conservation
Despite sequence variability in many regions of the fold, thioredoxin proteins share a common active siteActive site
In biology the active site is part of an enzyme where substrates bind and undergo a chemical reaction. The majority of enzymes are proteins but RNA enzymes called ribozymes also exist. The active site of an enzyme is usually found in a cleft or pocket that is lined by amino acid residues that...
sequence with two reactive cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
residues: Cys-X-Y-Cys, where X and Y are often but not necessarily hydrophobic amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s. The reduced form of the protein contains two free thiol
Thiol
In organic chemistry, a thiol is an organosulfur compound that contains a carbon-bonded sulfhydryl group...
groups at the cysteine residues, whereas the oxidized form contains a disulfide bond between them.
Disulfide bond formation
Different thioredoxin fold-containing proteins vary greatly in their reactivity and in the pKaPKA
PKA, pKa, or other similar variations may stand for:* pKa, the symbol for the acid dissociation constant at logarithmic scale* Protein kinase A, a class of cAMP-dependent enzymes* Pi Kappa Alpha, the North-American social fraternity...
of their free thiols, which derives from the ability of the overall protein structure to stabilize the activated thiolate. Although the structure is fairly consistent among proteins containing the thioredoxin fold, the pKa is extremely sensitive to small variations in structure, especially in the placement of protein backbone
Peptide bond
This article is about the peptide link found within biological molecules, such as proteins. A similar article for synthetic molecules is being created...
atoms near the first cysteine.
Examples
Human proteins containing this domain include:- DNAJC10DNAJC10DnaJ homolog subfamily C member 10 is a protein that in humans is encoded by the DNAJC10 gene.-Further reading:...
- ERP70
- GLRX3GLRX3Glutaredoxin-3 is a protein that in humans is encoded by the GLRX3 gene.-Further reading:...
- P4HBP4HBProtein disulfide-isomerase is an enzyme that in humans is encoded by the P4HB gene.-Interactions:P4HB has been shown to interact with UBQLN1, ERO1LB and ERO1L.-Further reading:...
; P5; PDIA2; PDIA3PDIA3Protein disulfide isomerase family A, member 3 also known as glucose-regulated protein, 58-kD is an isomerase enzyme.-Function:The PDIA3 protein has protein disulfide isomerase activity...
; PDIA4; PDIA5; PDIA6; PDILT - QSOX1QSOX1Sulfhydryl oxidase 1 is an enzyme that in humans is encoded by the QSOX1 gene.-Further reading:...
; QSOX2 - STRF8
- TXNThioredoxinThioredoxin is a class of small redox proteins known to be present in all organisms. It plays a role in many important biological processes. In humans, it is encoded by the TXN gene. Loss-of-function mutation of either of the two human thioredoxin genes is lethal at the four-cell stage of the...
; TXN2TXN2Thioredoxin, mitochondrial is a protein that in humans is encoded by the TXN2 gene.-Further reading:...
; TXNDC1TXNDC1Thioredoxin-related transmembrane protein 1 is a protein that in humans is encoded by the TMX1 gene.-Further reading:...
; TXNDC10TXNDC10Protein disulfide-isomerase TMX3 is an enzyme that in humans is encoded by the TMX3 gene.-Further reading:...
; TXNDC11; TXNDC13TXNDC13Thioredoxin-related transmembrane protein 4 also known as thioredoxin domain-containing protein 13 is a protein that in humans is encoded by the TMX4 gene....
; TXNDC14; TXNDC15; TXNDC16; TXNDC2TXNDC2Thioredoxin domain-containing protein 2 is a protein that in humans is encoded by the TXNDC2 gene.-Further reading:...
; TXNDC3TXNDC3Thioredoxin domain-containing protein 3 , also known as spermatid-specific thioredoxin-2 , is a protein that in humans is encoded by the TXNDC3 gene.- Function :...
; TXNDC4TXNDC4Endoplasmic reticulum resident protein 44 also known as thioredoxin domain-containing protein 4 is a protein that in humans is encoded by the ERP44 gene....
; TXNDC5TXNDC5Thioredoxin domain-containing protein 5 is a protein that in humans is encoded by the TXNDC5 gene.- Function :This gene encodes a protein disulfide-isomerase. Its expression is induced by hypoxia and its role may be to protect hypoxic cells from apoptosis. This gene can be co-transcribed with the...
; TXNDC6; TXNDC8; TXNL1TXNL1Thioredoxin-like protein 1 is a protein that in humans is encoded by the TXNL1 gene.-Further reading:...
; TXNL3