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676  structures 9088  species 0  interactions 80736  sequences 970  architectures

Family: Thioredoxin (PF00085)

Summary: Thioredoxin

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "Thioredoxin". More...

Thioredoxin Edit Wikipedia article

Thioredoxins are small proteins involved in thiol-redox processes. They contain two redox-active cysteine residues in their active sites, usually in a CXXC motif. The thioredoxins are kept in the reduced state by the flavoenzyme thioredoxin reductase, in a NADPH-dependent reaction. Thiredoxins act as electron donors to peroxidases and ribonucleotide reductase.

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This is the Wikipedia entry entitled "Thioredoxin domain". More...

Thioredoxin domain Edit Wikipedia article

Thioredoxin
Identifiers
SymbolThioredoxin
PfamPF00085
InterProIPR013766
PROSITEPDOC00172
SCOP23trx / SCOPe / SUPFAM

Thioredoxins[1][2][3][4] are small disulphide-containing redox proteins that have been found in all the kingdoms of living organisms. Thioredoxin serves as a general protein disulphide oxidoreductase. It interacts with a broad range of proteins by a redox mechanism based on reversible oxidation of 2 cysteine thiol groups to a disulphide, accompanied by the transfer of 2 electrons and 2 protons. The net result is the covalent interconversion of a disulphide and a dithiol.

<reaction>TR-S2 + NADPH + H+ -> TR-(SH)2 + NADP+ (1)</reaction>

<reaction>trx-S2 + TR-(SH)2 -> trx-(SH)2 + TR-S2 (2)</reaction>

<reaction>Protein-S2 + trx-(SH)2 -> Protein-(SH)2 + trx-S2 (3)</reaction>

In the NADPH-dependent protein disulphide reduction, thioredoxin reductase (TR) catalyses reduction of oxidised thioredoxin (trx) by NADPH using FAD and its redox-active disulphide (steps 1 and 2). Reduced thioredoxin then directly reduces the disulphide in the substrate protein (step 3)[1].

Protein disulphide isomerase (PDI), a resident foldase of the endoplasmic recticulum, is a multi-functional protein that catalyses the formation and isomerisation of disulphide bonds during protein folding[5][6]. PDI contains 2 redox active domains, near the N- and C-termini, that are similar to thioredoxin: both contribute to disulphide isomerase activity, but are functionally non-equivalent[6]. Interestingly, a mutant PDI, with all 4 of the active cysteines replaced by serine, displays a low but detectable level of disulphide isomerase activity[6]. Moreover, PDI exhibits chaperone-like activity towards proteins that contain no disulphide bonds, i.e. behaving independently of its disulphide isomerase activity[7].

A number of endoplasmic reticulum proteins that differ from the PDI major isozyme contain 2 (ERp60, ERp5) or 3 (ERp72[8]) thioredoxin domains; all of them seem to be PDIs. 3D-structures have been determined for a number of thioredoxins[9]. The molecule has a doubly-wound alternating alpha/beta fold, consisting of a 5-stranded parallel beta-sheet core, enclosed by 4 alpha-helices. The active site disulphide is located at the N-terminus of helix 2 in a short segment that is separated from the rest of the helix by a kink caused by a conserved proline. The 4-membered disulphide ring is located on the surface of the protein. A flat hydrophobic surface lies adjacent to the disulphide, which presumably facilitates interaction with other proteins.

One invariant feature of all thioredoxins is a cis-proline located in a loop preceding beta-strand 4. This residue is positioned in van der Waals contact with the active site cysteines and is important both for stability and function[9]. Thioredoxin belongs to a structural family that includes glutaredoxin, glutathione peroxidase, bacterial protein disulphide isomerase DsbA, and the N-terminal domain of glutathione transferase[4]. Thioredoxins have a beta-alpha unit preceding the motif common to all these proteins.

Human proteins containing thioredoxin domain

DNAJC10; ERP70; GLRX3; P4HB; P5; PDIA2; PDIA3; PDIA4; PDIA5; PDIA6; PDILT; PDIP; QSOX1; QSOX2; STRF8; TXN; TXN2; TXNDC1; TXNDC10; TXNDC11; TXNDC13; TXNDC14; TXNDC15; TXNDC16; TXNDC2; TXNDC3; TXNDC4; TXNDC5; TXNDC6; TXNDC8; TXNL1; TXNL3;

References

  1. ^ a b Holmgren A (1985). "Thioredoxin". Annu. Rev. Biochem. 54: 237–271. PMID 3896121.
  2. ^ Holmgren A (1989). "Thioredoxin and glutaredoxin systems". J. Biol. Chem. 264 (24): 13963–13966. PMID 2668278.
  3. ^ Holmgren A (1995). "Thioredoxin structure and mechanism: conformational changes on oxidation of the active-site sulfhydryls to a disulfide". Structure. 3 (3): 239–243. PMID 7788289.
  4. ^ a b Martin JL (1995). "Thioredoxin--a fold for all reasons". Structure. 3 (3): 245–250. PMID 7788290.
  5. ^ Puig A, Lyles MM, Noiva R, Gilbert HF (1994). "The role of the thiol/disulfide centers and peptide binding site in the chaperone and anti-chaperone activities of protein disulfide isomerase". J. Biol. Chem. 269 (29): 19128–19135. PMID 7913469.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ a b c Lyles MM, Gilbert HF (1994). "Mutations in the thioredoxin sites of protein disulfide isomerase reveal functional nonequivalence of the N- and C-terminal domains". J. Biol. Chem. 269 (49): 30946–30952. PMID 7983029.
  7. ^ Wang CC, Song JL (1995). "Chaperone-like activity of protein disulfide-isomerase in the refolding of rhodanese". Eur. J. Biochem. 231 (2): 312–316. PMID 7635143.
  8. ^ Mazzarella RA, Srinivasan M, Haugejorden SM, Green M (1990). "ERp72, an abundant luminal endoplasmic reticulum protein, contains three copies of the active site sequences of protein disulfide isomerase". J. Biol. Chem. 265 (2): 1094–1101. PMID 2295602.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ a b Gleason FK, Eklund H, Saarinen M (1995). "Crystal structure of thioredoxin-2 from Anabaena". Structure. 3 (10): 1097–1108. PMID 8590004.{{cite journal}}: CS1 maint: multiple names: authors list (link)
This article incorporates text from the public domain Pfam and InterPro: IPR013766

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This is the Wikipedia entry entitled "Thioredoxin fold". More...

Thioredoxin fold Edit Wikipedia article

The thioredoxin fold is a protein fold common to enzymes that catalyze disulfide bond formation and isomerization. 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 beta sheet sandwiched between two alpha helices.

External links

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Thioredoxin Provide feedback

Thioredoxins are small enzymes that participate in redox reactions, via the reversible oxidation of an active centre disulfide bond. Some members with only the active site are not separated from the noise.

Internal database links

External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR013766

Thioredoxins [ PUBMED:3896121 , PUBMED:2668278 , PUBMED:7788289 , PUBMED:7788290 ] are small disulphide-containing redox proteins that have been found in all the kingdoms of living organisms. Thioredoxin serves as a general protein disulphide oxidoreductase. It interacts with a broad range of proteins by a redox mechanism based on reversible oxidation of two cysteine thiol groups to a disulphide, accompanied by the transfer of two electrons and two protons. The net result is the covalent interconversion of a disulphide and a dithiol. In the NADPH-dependent protein disulphide reduction, thioredoxin reductase (TR) catalyses the reduction of oxidised thioredoxin (trx) by NADPH using FAD and its redox-active disulphide; reduced thioredoxin then directly reduces the disulphide in the substrate protein [ PUBMED:3896121 ].

Thioredoxin is present in prokaryotes and eukaryotes and the sequence around the redox-active disulphide bond is well conserved. All thioredoxins contain a cis-proline located in a loop preceding beta-strand 4, which makes contact with the active site cysteines, and is important for stability and function [ PUBMED:8590004 ]. Thioredoxin belongs to a structural family that includes glutaredoxin, glutathione peroxidase, bacterial protein disulphide isomerase DsbA, and the N-terminal domain of glutathione transferase [ PUBMED:7788290 ]. Thioredoxins have a beta-alpha unit preceding the motif common to all these proteins.

A number of eukaryotic proteins contain domains evolutionary related to thioredoxin, most of them are protein disulphide isomerases (PDI). PDI ( EC ) [ PUBMED:3371540 , PUBMED:2537773 , PUBMED:7940678 ] is an endoplasmic reticulum multi-functional enzyme that catalyses the formation and rearrangement of disulphide bonds during protein folding [ PUBMED:7913469 ]. All PDI contains two or three (ERp72) copies of the thioredoxin domain, each of which contributes to disulphide isomerase activity, but which are functionally non-equivalent [ PUBMED:7983029 ]. Moreover, PDI exhibits chaperone-like activity towards proteins that contain no disulphide bonds, i.e. behaving independently of its disulphide isomerase activity [ PUBMED:7635143 ]. The various forms of PDI which are currently known are:

  • PDI major isozyme; a multifunctional protein that also function as the beta subunit of prolyl 4-hydroxylase ( EC ), as a component of oligosaccharyl transferase ( EC ), as thyroxine deiodinase ( EC ), as glutathione-insulin transhydrogenase ( EC ) and as a thyroid hormone-binding protein
  • ERp60 (ER-60; 58 Kd microsomal protein). ERp60 was originally thought to be a phosphoinositide-specific phospholipase C isozyme and later to be a protease.
  • ERp72.
  • ERp5.

Bacterial proteins that act as thiol:disulphide interchange proteins that allows disulphide bond formation in some periplasmic proteins also contain a thioredoxin domain. These proteins include:

  • Escherichia coli DsbA (or PrfA) and its orthologs in Vibrio cholerae (TtcpG) and Haemophilus influenzae (Por).
  • E. coli DsbC (or XpRA) and its orthologues in Erwinia chrysanthemi and H. influenzae.
  • E. coli DsbD (or DipZ) and its H. influenzae orthologue.
  • E. coli DsbE (or CcmG) and orthologues in H. influenzae.
  • Rhodobacter capsulatus (Rhodopseudomonas capsulata) (HelX), Rhiziobiacae (CycY and TlpA).

This entry represents the thioredoxin domain.

Domain organisation

Below is a listing of the unique domain organisations or architectures in which this domain is found. More...

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Pfam Clan

Alignments

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  Seed
(34)
Full
(80736)
Representative proteomes UniProt
(219851)
RP15
(14392)
RP35
(37473)
RP55
(70868)
RP75
(106116)
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  Seed
(34)
Full
(80736)
Representative proteomes UniProt
(219851)
RP15
(14392)
RP35
(37473)
RP55
(70868)
RP75
(106116)
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  Seed
(34)
Full
(80736)
Representative proteomes UniProt
(219851)
RP15
(14392)
RP35
(37473)
RP55
(70868)
RP75
(106116)
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This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

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Curation and family details

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Curation View help on the curation process

Seed source: Prosite
Previous IDs: thiored;
Type: Domain
Sequence Ontology: SO:0000417
Author: Sonnhammer ELL , Eddy SR
Number in seed: 34
Number in full: 80736
Average length of the domain: 101.2 aa
Average identity of full alignment: 23 %
Average coverage of the sequence by the domain: 41.25 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 61295632 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 23.5 23.5
Trusted cut-off 23.5 23.5
Noise cut-off 23.4 23.4
Model length: 103
Family (HMM) version: 23
Download: download the raw HMM for this family

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Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Thioredoxin domain has been found. There are 676 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

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AlphaFold Structure Predictions

The list of proteins below match this family and have AlphaFold predicted structures. Click on the protein accession to view the predicted structure.

Protein Predicted structure External Information
A0A044QWT0 View 3D Structure Click here
A0A044RSH7 View 3D Structure Click here
A0A044SAZ1 View 3D Structure Click here
A0A044SLK9 View 3D Structure Click here
A0A044SVJ1 View 3D Structure Click here
A0A044SZJ8 View 3D Structure Click here
A0A044TDJ7 View 3D Structure Click here
A0A044TEQ9 View 3D Structure Click here
A0A044TJN4 View 3D Structure Click here
A0A044TWG8 View 3D Structure Click here
A0A044U124 View 3D Structure Click here
A0A044UGI6 View 3D Structure Click here
A0A044UMJ1 View 3D Structure Click here
A0A044UZ26 View 3D Structure Click here
A0A044UZW8 View 3D Structure Click here
A0A044V0A7 View 3D Structure Click here
A0A044V170 View 3D Structure Click here
A0A044V197 View 3D Structure Click here
A0A077YWL3 View 3D Structure Click here
A0A077YWN0 View 3D Structure Click here
A0A077YX42 View 3D Structure Click here
A0A077YX90 View 3D Structure Click here
A0A077Z5H0 View 3D Structure Click here
A0A077Z912 View 3D Structure Click here
A0A077Z9U6 View 3D Structure Click here
A0A077ZCK9 View 3D Structure Click here
A0A077ZDL9 View 3D Structure Click here
A0A077ZDQ6 View 3D Structure Click here
A0A077ZE04 View 3D Structure Click here
A0A077ZIA0 View 3D Structure Click here
A0A077ZIF5 View 3D Structure Click here
A0A077ZJG0 View 3D Structure Click here
A0A077ZJZ3 View 3D Structure Click here
A0A077ZKR1 View 3D Structure Click here
A0A077ZLF1 View 3D Structure Click here
A0A077ZLQ3 View 3D Structure Click here
A0A077ZLV0 View 3D Structure Click here
A0A096QB26 View 3D Structure Click here
A0A0A2V1X7 View 3D Structure Click here
A0A0B4LHC9 View 3D Structure Click here