Notation: Let Fur stand for ferric uptake regulation.
"The Fur protein [...] acts as a transcriptional repressor of iron-regulated promoters by virtue of its Fe2+-dependent DNA binding activity (5, 25, 32, 33)."
Aggregatibacter actinomycetemcomitans (previously Actinobacillus actinomycetemcomitans) is a gram-negative, facultative anaerobe, non-motile bacterium that is often found in association with localized aggressive periodontitis, a severe infection of the periodontium, also suspected to be involved in chronic periodontitis.
The species has attracted attention because of its association with localized aggressive periodontitis.
There is a phylogenetic similarity of A. actinomycetemcomitans and Haemophilus aphrophilus, H. paraphrophilus, and H. segnis, which suggests the new genus Aggregatibacter for them.
It is one of the bacteria that might be implicated in destructive periodontal disease, although it has been found more frequently in localized aggressive periodontitis. It has also been isolated from actinomycotic lesions (mixed infection with certain Actinomyces species, in particular A. israelii), possesses certain virulence factors that enable it to invade tissues, such as the pore-forming toxin leukotoxin A (LtxA), isolated from women with bacterial vaginosis and as an etiologic agent in endocarditis. The pore-forming toxin LtxA of A. actinomycetemcomitans may be a trigger of the autoimmune disease rheumatoid arthritis due to its ability to stimulate protein citrullination, a post-translational protein modification targeted by autoantibodies in this disease.
Small non-coding RNAs
Four small non-coding RNAs containing a ferric uptake regulator (fur), or Fur box-like sequence identified by bioinformatics analysis in Aggregatibacter actinomycetemcomitans HK1651 called JA01-JA04 where the transcription of sRNAs was confirmed by Northern blot with fur binding demonstrated to each sRNA promoter, transcription of the sRNAs decreased in the presence of iron, increased by iron limitation anf JA03 may have the ability to regulate biofilm formation. JA01 is conserved only among A. actinomycetemcomitans. JA02 is present in both A. actinomycetemcomitans and P. multocida. JA03 and JA04 are most widely conserved and have orthologues across many Pasteurellaceae. HrrF RNA is another Fur-regulated sRNA conserved among the Pasteurcellaceae.
"In high G + C Gram-positive bacteria, the control of the expression of genes involved in iron metabolism is exerted by a DmdR [divalent (bivalent) metal-dependent regulatory] protein, previously named DtxR (diphtheria toxin repressor), in the presence of Fe2+ or other bivalent ions. This system was first reported in Corynebacterium diphtheriae, and controls the expression of the diphtheriae toxin (tox) gene . Expression of the tox gene, located in the integrated corynephage β DNA, is controlled by the DtxR protein in presence of Fe2+. The tox gene promoter region contains a 27 bp palindrome, which overlaps the − 10 region of the promoter [2–4]. The minimal consensus sequence for binding of the DtxR protein was confirmed by Tao and Murphy  by the CAST (cyclic amplification and selection of targets) technique."
"An analysis of the 28 kDa DtxR protein  showed that it binds to the tox palindromic sequence as a dimer (56 kDa form) [6,7], which was confirmed by cross-linking studies . A bivalent metal (Fe2+, Co2+, Ni2+ or Cd2+) is required for binding of the DtxR protein to the palindrome sequence in the DNA [5,6,9]."
"The nucleotide sequence of iron boxes of the desA and tox promoters have 14 nt in common, including the inverted repeat."
"Electrophoretic mobility-shift assays showed that both [divalent (bivalent) metal-dependent regulatory protein] DmdR1 and DmdR2 bind to the 19-nt tox and desA iron boxes forming two different complexes in each case."
"Ten different iron boxes were found in a search for iron boxes in the genome of S. coelicolor. Most of them correspond to putative genes involved in siderophore biosynthesis. [The] nucleotide sequence of these ten boxes is identical (or slightly different)".
"Iron box sequences (CD1–CD10) found in the genome of S. coelicolor by searching with the desA box of S. pilosus (TTAGGTTAGGCTCACCTAA).
- CD 1 TTAGGTTAGGCTCACCTAA 63 nt ATG pyridoxyl-dependent decarboxylase
- CD 2 TTAGGTTAGGCTCACCTAA 20 nt GTG antibiotic hydrolase (ABP) / 45 nt ATG ABC transporter ATP-binding protein
- CD 3 TTAGGTTAGGCTCgCCTAA 48 nt ATG esterase (cchJ) / 19 nt ATG hypothetical protein
- CD 4 TgAGGgTAGGCTtACCTcA 33 nt ATG iron-siderophore binding lipoprotein (cchF)
- CD 5 cTcGaTTAGGCTCgCCTtA 8 nt GTG iron-siderophore ABC transporter ATP-binding protein (cchE)
- CD 6 TTAGcTTAGGCTCACCTAA 131 nt ATG formyltransferase (cchA) / 24 nt ATG peptide monoxygenase (cchB)
- CD 7 TTAGGTaAGGCTCACCTAA 21 nt ATG hypothetical protein
- CD 8 TTAGGTTAGGCTaACCTtc 5 nt GTG ABC-transport protein ATP-binding component
- CD 9 TcAGGTTAGGCTCACCTct 1 nt GTG hypothetical protein
- CD 10 actcGTTAGGCTCACCTAA 69 nt ATG integral membrane protein
DmdR consense t 9 t 7 a 8 g 9 g 8 t 9 t 9 A 10 G 10 G 10 C 10 T 10 c 8 a 8 C 10 C 10 T 10 a 7 a 8
The distance in nucleotides of the iron boxes to the ATG-translation start codon is indicated. The consensus iron box sequence and the percentage of conservation is indicated in the [number next to the nucleotide]. Capital letters indicate full conservation of the nucleotides [10, conservation in the ten CD sequences (100 %); 9, 90 % conservation; 8, 80 % conservation; 7, 70 % conservation]. The designation of the genes and the putative proteins encoded by them are indicated on the right-hand side [...]."
"Several putative iron boxes were found upstream of ten different open reading frames in the genome of S. coelicolor. This allowed us to define a consensus iron box for Streptomyces species (TTAGGTTAGGCTCACCTAA; see the above table)."
"Under iron-rich conditions Fur binds the divalent ion, acquires a configuration able to bind target DNA sequences (generally known as Fur boxes or iron boxes, [...]), and inhibits transcription from virtually all the genes and operons repressed by the metal."
Def. Any "medium-sized molecule that has a high specificity for binding or chelating iron; they are employed by microorganisms to obtain iron from the environment" is called a siderophore.
When "iron is scarce, the equilibrium is displaced to release Fe2+, the RNA polymerase accesses cognate promoters, and the genes for the biosynthesis of siderophores and other iron-related functions are expressed (41, 55)."
The "sequence 5′-GATAATGATAATCATTATC-3′ [is] the functional target of the Fur protein."
Many "iron-regulated promoters appear to have not just one Fur box but multiple, sometimes overlapping, boxes (42, 53, 87)"
The "same 19-bp sequence [5′-GATAATGATAATCATTATC-3′] can be viewed as a combination of three adjacent repeats, 5′-NATA/TAT-3′."
- Lucía Escolar, Jose Pérez-Martín, and Víctor de Lorenzo (October 1999). "Opening the Iron Box: Transcriptional Metalloregulation by the Fur Protein". Journal of Bacteriology 181 (20): 6223-9. http://jb.asm.org/content/181/20/6223.short. Retrieved 2017-04-04.
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- "Reclassification of Actinobacillus actinomycetemcomitans, Haemophilus aphrophilus, Haemophilus paraphrophilus and Haemophilus segnis as Aggregatibacter actinomycetemcomitans gen. nov., comb. nov., Aggregatibacter aphrophilus comb. nov. and Aggregatibacter segnis comb. nov., and emended description of Aggregatibacter aphrophilus to include V factor-dependent and V factor-independent isolates". International Journal of Systematic and Evolutionary Microbiology 56 (Pt 9): 2135–46. September 2006. doi:10.1099/ijs.0.64207-0. PMID 16957111.
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- "Aggregatibacter actinomycetemcomitans-induced hypercitrullination links periodontal infection to autoimmunity in rheumatoid arthritis". Science Translational Medicine 8 (369): 369ra176. December 2016. doi:10.1126/scitranslmed.aaj1921. PMID 27974664. PMC 5384717. //www.ncbi.nlm.nih.gov/pmc/articles/PMC5384717/.
- "To Prevent Rheumatoid Arthritis, Look Past the Joints to the Gums". JAMA 317 (12): 1201–1202. March 2017. doi:10.1001/jama.2017.0764. PMID 28273301.
- Amarasinghe, J. J.; Connell, T. D.; Scannapieco, F. A.; Haase, E. M. (2012-10-01). "Novel iron-regulated and Fur-regulated small regulatory RNAs in Aggregatibacter actinomycetemcomitans". Molecular Oral Microbiology 27 (5): 327–349. doi:10.1111/j.2041-1014.2012.00645.x. ISSN 2041-1014. PMID 22958383. PMC 3442931. //www.ncbi.nlm.nih.gov/pmc/articles/PMC3442931/.
- Santana, Estevan A.; Harrison, Alistair; Zhang, Xinjun; Baker, Beth D.; Kelly, Benjamin J.; White, Peter; Liu, Yunlong; Munson, Robert S. (2014-01-01). "HrrF is the Fur-regulated small RNA in nontypeable Haemophilus influenzae". PLoS One 9 (8): e105644. doi:10.1371/journal.pone.0105644. ISSN 1932-6203. PMID 25157846. PMC 4144887. //www.ncbi.nlm.nih.gov/pmc/articles/PMC4144887/.
- Francisco J. Flores and Juan F. Martín (1 June 2004). "Iron-regulatory proteins DmdR1 and DmdR2 of Streptomyces coelicolor form two different DNA–protein complexes with iron boxes". Biochemical Journal 380 (2): 497–503. doi:10.1042/bj20031945. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1224170/pdf/14960152.pdf. Retrieved 7 November 2018.
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