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2  structures 1505  species 1  interaction 1563  sequences 6  architectures

Family: Aconitase_2_N (PF06434)

Summary: Aconitate hydratase 2 N-terminus

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Aconitate hydratase 2 N-terminus Provide feedback

This family represents the N-terminal region of several bacterial Aconitate hydratase 2 proteins and is found in conjunction with PF00330.

Literature references

  1. Jordan PA, Tang Y, Bradbury AJ, Thomson AJ, Guest JR; , Biochem J 1999;344:739-746.: Biochemical and spectroscopic characterization of Escherichia coli aconitases (AcnA and AcnB). PUBMED:10585860 EPMC:10585860


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR015929

Aconitase (aconitate hydratase; EC) is an iron-sulphur protein that contains a [4Fe-4S]-cluster and catalyses the interconversion of isocitrate and citrate via a cis-aconitate intermediate. Aconitase functions in both the TCA and glyoxylate cycles, however unlike the majority of iron-sulphur proteins that function as electron carriers, the [4Fe-4S]-cluster of aconitase reacts directly with an enzyme substrate. In eukaryotes there is a cytosolic form (cAcn) and a mitochondrial form (mAcn) of the enzyme. In bacteria there are also 2 forms, aconitase A (AcnA) and B (AcnB). Several aconitases are known to be multi-functional enzymes with a second non-catalytic, but essential function that arises when the cellular environment changes, such as when iron levels drop [PUBMED:10087914, PUBMED:15877277]. Eukaryotic cAcn and mAcn, and bacterial AcnA have the same domain organisation, consisting of three N-terminal alpha/beta/alpha domains, a linker region, followed by a C-terminal 'swivel' domain with a beta/beta/alpha structure (1-2-3-linker-4), although mAcn is small than cAcn. However, bacterial AcnB has a different organisation: it contains an N-terminal HEAT-like domain, followed by the 'swivel' domain, then the three alpha/beta/alpha domains (HEAT-4-1-2-3) [PUBMED:9020582]. Below is a description of some of the multi-functional activities associated with different aconitases.

  • Eukaryotic mAcn catalyses the second step of the mitochondrial TCA cycle, which is important for energy production, providing high energy electrons in the form of NADH and FADH2 to the mitochondrial oxidative phosphorylation pathway [PUBMED:15543948]. The TCA cycle also provides precursors for haem and amino acid production. This enzyme has a second, non-catalytic but essential role in mitochondrial DNA (mtDNA) maintenance: mAcn acts to stabilise mtDNA, forming part of mtDNA protein-DNA complexes known as nucleoids. mAcn is thought to reversibly model nucleoids to directly influence mitochondrial gene expression in response to changes in the cellular environment. Therefore, mAcn can influence the expression of components of the oxidative phosphorylation pathway encoded in mtDNA.

  • Eukaryotic cAcn enzyme balances the amount of citrate and isocitrate in the cytoplasm, which in turn creates a balance between the amount of NADPH generated from isocitrate by isocitrate dehydrogenase with the amount of acetyl-CoA generated from citrate by citrate lyase. Fatty acid synthesis requires both NADPH and acetyl-CoA, as do other metabolic processes, including the need for NADPH to combat oxidative stress. The enzymatic form of cAcn predominates when iron levels are normal, but if they drop sufficiently to cause the disassembly of the [4Fe-4S]-cluster, then cAcn undergoes a conformational change from a compact enzyme to a more open L-shaped protein known as iron regulatory protein 1 (IRP1; or IRE-binding protein 1, IREBP1) [PUBMED:17185597, PUBMED:16407072]. As IRP1, the catalytic site and the [4Fe-4S]-cluster are lost, and two new RNA-binding sites appear. IRP1 functions in the post-transcriptional regulation of genes involved in iron metabolism - it binds to mRNA iron-responsive elements (IRE), 30-nucleotide stem-loop structures at the 3' or 5' end of specific transcripts. Transcripts containing an IRE include ferritin L and H subunits (iron storage), transferrin (iron plasma chaperone), transferrin receptor (iron uptake into cells), ferroportin (iron exporter), mAcn, succinate dehydrogenase, erythroid aminolevulinic acid synthetase (tetrapyrrole biosynthesis), among others. If the IRE is in the 5'-UTR of the transcript (e.g. in ferritin mRNA), then IRP1-binding prevents its translation by blocking the transcript from binding to the ribosome. If the IRE is in the 3'-UTR of the transcript (e.g. transferrin receptor), then IRP1-binding protects it from endonuclease degradation, thereby prolonging the half-life of the transcript and enabling it to be translated [PUBMED:15604397].

  • IRP2 is another IRE-binding protein that binds to the same transcripts as IRP1. However, since IRP1 is predominantly in the enzymatic cAcn form, it is IRP2 that acts as the major metabolic regulator that maintains iron homeostasis [PUBMED:16850017]. Although IRP2 is homologous to IRP1, IRP2 lacks aconitase activity, and is known only to have a single function in the post-transcriptional regulation of iron metabolism genes [PUBMED:17513696]. In iron-replete cells, IRP2 activity is regulated primarily by iron-dependent degradation through the ubiquitin-proteasomal system.

  • Bacterial AcnB is also known to be multi-functional. In addition to its role in the TCA cycle, AcnB was shown to be a post-transcriptional regulator of gene expression in Escherichia coli and Salmonella enterica [PUBMED:15882410, PUBMED:15009904]. In S. enterica, AcnB initiates a regulatory cascade controlling flagella biosynthesis through an interaction with the ftsH transcript, an alternative RNA polymerase sigma factor. This binding lowers the intracellular concentration of FtsH protease, which in turn enhances the amount of RNA polymerase sigma32 factor (normally degraded by FtsH protease), and sigma32 then increases the synthesis of chaperone DnaK, which in turn promotes the synthesis of the flagellar protein FliC. AcnB regulates the synthesis of other proteins as well, such as superoxide dismutase (SodA) and other enzymes involved in oxidative stress.

This entry represents the N-terminal region of bacterial aconitase B (AcnB), which consists of both a HEAT-like domain and a 'swivel' domain. HEAT-like domains are usually implicated in protein-protein interactions, while the 'swivel' domain is usually a mobile unit in proteins that carry it. In AcnB, this N-terminal region was shown to be sufficient for dimerisation and for AcnB binding to mRNA. An iron-mediated dimerisation mechanism may be responsible for switching AcnB between its catalytic and regulatory roles, as dimerisation requires iron while mRNA binding is inhibited by iron.

More information about these proteins can be found at Protein of the Month: Aconitase [PUBMED:].

Gene Ontology

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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

This family is a member of clan Leu-IlvD (CL0364), which has the following description:

Superfamily includes LeuD-like, IlvD/EDD C-terminal domain-like, and AF0055-like families.

The clan contains the following 3 members:

Aconitase_2_N Aconitase_C DUF126

Alignments

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  Seed
(94)
Full
(1563)
Representative proteomes NCBI
(1212)
Meta
(908)
RP15
(74)
RP35
(178)
RP55
(263)
RP75
(323)
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  Seed
(94)
Full
(1563)
Representative proteomes NCBI
(1212)
Meta
(908)
RP15
(74)
RP35
(178)
RP55
(263)
RP75
(323)
Alignment:
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Sequence:
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  Seed
(94)
Full
(1563)
Representative proteomes NCBI
(1212)
Meta
(908)
RP15
(74)
RP35
(178)
RP55
(263)
RP75
(323)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download   Download  

You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

MyHits provides a collection of tools to handle multiple sequence alignments. For example, one can refine a seed alignment (sequence addition or removal, re-alignment or manual edition) and then search databases for remote homologs using HMMER3.

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Trees

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

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: Pfam-B_2605 (release 10.0)
Previous IDs: none
Type: Family
Author: Moxon SJ
Number in seed: 94
Number in full: 1563
Average length of the domain: 208.10 aa
Average identity of full alignment: 67 %
Average coverage of the sequence by the domain: 25.23 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 20.5 20.5
Trusted cut-off 20.5 20.5
Noise cut-off 20.4 20.4
Model length: 204
Family (HMM) version: 8
Download: download the raw HMM for this family

Species distribution

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Interactions

There is 1 interaction for this family. More...

Aconitase

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 Aconitase_2_N domain has been found. There are 2 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 seqence.

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