Biology:Transcription activator-like effector

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180-TALEffectors 3ugm.png
TAL effector (PDB: 3ugm​), spacefill by David Goodsell. Stripes are repeat domains.
Identifiers
OrganismXanthomonas oryzae
SymbolpthXo1
RefSeq (Prot)WP_041182630.1
UniProtB2SU53
Other data
ChromosomeGenomic: 1.65 - 1.65 Mb

TAL (transcription activator-like) effectors (often referred to as TALEs, but not to be confused with the three amino acid loop extension homeobox class of proteins) are proteins secreted by some β- and γ-proteobacteria.[1] Most of these are Xanthomonads. Plant pathogenic Xanthomonas bacteria are especially known for TALEs, produced via their type III secretion system. These proteins can bind promoter sequences in the host plant and activate the expression of plant genes that aid bacterial infection. The TALE domain responsible for binding to DNA is known to have 1.5 to 33.5 short sequences that are repeated multiple times (tandem repeats).[2] Each of these repeats was found to be specific for a certain base pair of the DNA.[2] These repeats also have repeat variable residues (RVD) that can detect specific DNA base pairs.[2] They recognize plant DNA sequences through a central repeat domain consisting of a variable number of ~34 amino acid repeats. There appears to be a one-to-one correspondence between the identity of two critical amino acids in each repeat and each DNA base in the target sequence. These proteins are interesting to researchers both for their role in disease of important crop species and the relative ease of retargeting them to bind new DNA sequences. Similar proteins can be found in the pathogenic bacterium Ralstonia solanacearum[3][4][1] and Burkholderia rhizoxinica,[5][1] as well as yet unidentified marine microorganisms.[6] The term TALE-likes is used to refer to the putative protein family encompassing the TALEs and these related proteins.

Function in plant pathogenesis

Xanthomonas

Xanthomonas are Gram-negative bacteria that can infect a wide variety of plant species including pepper/capsicum, rice, citrus, cotton, tomato, and soybeans.[7] Some types of Xanthomonas cause localized leaf spot or leaf streak while others spread systemically and cause black rot or leaf blight disease. They inject a number of effector proteins, including TAL effectors, into the plant via their type III secretion system. TAL effectors have several motifs normally associated with eukaryotes including multiple nuclear localization signals and an acidic activation domain. When injected into plants, these proteins can enter the nucleus of the plant cell, bind plant promoter sequences, and activate transcription of plant genes that aid in bacterial infection.[7] Plants have developed a defense mechanism against type III effectors that includes R (resistance) genes triggered by these effectors. Some of these R genes appear to have evolved to contain TAL-effector binding sites similar to site in the intended target gene. This competition between pathogenic bacteria and the host plant has been hypothesized to account for the apparently malleable nature of the TAL effector DNA binding domain.[8]

Examples of Xanthomonas-crop pathosystems involving TALEs[1]
X. species victim crop
X. campestris pv. musacerum, X. vasicola pv. musacerum banana and ensete
X. axonopodis pv. phaseoli, X. axonopodis pv. glycines common bean and soybean
X. axonopodis pv. vignicola cowpea
X. campestris pv. campestris, X. campestris pv. armoracieae all Brassicas
X. axonopodis pv. manihotis cassava
X. translucens pv. translucens barley, rye, wheat, triticale
X. axonopodis pv. citri, X. citri, X. citri pv. aurantifolii citrus
X. campestris pv. malvacearum cotton
X. euvesicatoria, X. gardneri pepper/capsicum
X. oryzae pv. oryzae rice
X. arboricola pv. pruni plum, peach, nectarine
X. perforans, X. campestris pv. vesicatoria tomato
X. campestris pv. mangiferaindicae mango
X. arboricola pv. juglandis walnut

Non-Xanthomonas

R. solanacearum, B. rhizoxinica, and banana blood disease (a bacterium not yet definitively identified, in the R. solanacearum species group).[1]

DNA recognition

The most distinctive characteristic of TAL effectors is a central repeat domain containing between 1.5 and 33.5 repeats that are usually 34 residues in length (the C-terminal repeat is generally shorter and referred to as a “half repeat”).[7] A typical repeat sequence is LTPEQVVAIASHDGGKQALETVQRLLPVLCQAHG, but the residues at the 12th and 13th positions are hypervariable (these two amino acids are also known as the repeat variable diresidue or RVD). There is a simple relationship between the identity of these two residues in sequential repeats and sequential DNA bases in the TAL effector's target site.[8] The crystal structure of a TAL effector bound to DNA indicates that each repeat comprises two alpha helices and a short RVD-containing loop where the second residue of the RVD makes sequence-specific DNA contacts while the first residue of the RVD stabilizes the RVD-containing loop.[10][11] Target sites of TAL effectors also tend to include a thymine flanking the 5’ base targeted by the first repeat; this appears to be due to a contact between this T and a conserved tryptophan in the region N-terminal of the central repeat domain.[10] However, this "zero" position does not always contain a thymine, as some scaffolds are more permissive.[12]

The TAL-DNA code was broken by two separate groups in 2010.[8] The first group, headed by Adam Bogdanove, broke this code computationally by searching for patterns in protein sequence alignments and DNA sequences of target promoters derived from a database of genes upregulated by TALEs.[13] The second group (Boch) deduced the code through molecular analysis of the TAL effector AvrBs3 and its target DNA sequence in the promoter of a pepper gene activated by AvrBs3.[14] The experimentally validated code between RVD sequence and target DNA base can be expressed as follows:

TAL base recognition
Residue Base Notes References
NI A [14]
HD C Not 5-methyl-C [14]
NG T, 5mC [14][15]
NN R Purine: G or A [14]
NS N Any [14]
NK G Reduced TALEN activity if used exclusively [16][17]
NH G [9]

Target genes

TAL effectors can induce susceptibility genes that are members of the NODULIN3 (N3) gene family. These genes are essential for the development of the disease. In rice two genes, Os-8N3 and Os-11N3, are induced by TAL effectors. Os-8N3 is induced by PthXo1 and Os-11N3 is induced by PthXo3 and AvrXa7. Two hypotheses exist about possible functions for N3 proteins:

  • They are involved in copper transport, resulting in detoxification of the environment for bacteria. The reduction in copper level facilitates bacterial growth.
  • They are involved in glucose transport, facilitating glucose flow. This mechanism provides nutrients to bacteria and stimulates pathogen growth and virulence [citation needed]

Engineering TAL effectors

This simple correspondence between amino acids in TAL effectors and DNA bases in their target sites makes them useful for protein engineering applications. Numerous groups have designed artificial TAL effectors capable of recognizing new DNA sequences in a variety of experimental systems.[14][16][17][18][19][20] Such engineered TAL effectors have been used to create artificial transcription factors that can be used to target and activate or repress endogenous genes in tomato,[16] Arabidopsis thaliana,[16] and human cells.[17][19][9][21]

Genetic constructs to encode TAL effector-based proteins can be made using either conventional gene synthesis or modular assembly.[19][21][22][23][24][25][26][27] A plasmid kit for assembling custom TALEN and other TAL effector constructs is available through the public, not-for-profit repository Addgene. Webpages providing access to public software, protocols, and other resources for TAL effector-DNA targeting applications include the TAL Effector-Nucleotide Targeter and taleffectors.com.

Applications

Engineered TAL effectors can also be fused to the cleavage domain of FokI to create TAL effector nucleases (TALEN) or to meganucleases (nucleases with longer recognition sites) to create "megaTALs."[28] Such fusions share some properties with zinc finger nucleases and may be useful for genetic engineering and gene therapy applications.[29]

TALEN-based approaches are used in the emerging fields of gene editing and genome engineering. TALEN fusions show activity in a yeast-based assay,[18][30] at endogenous yeast genes,[22] in a plant reporter assay,[20] at an endogenous plant gene,[23] at endogenous zebrafish genes,[31][32] at an endogenous rat gene,[33] and at endogenous human genes.[17][23][34] The human HPRT1 gene has been targeted at detectable, but unquantified levels.[23] In addition, TALEN constructs containing the FokI cleavage domain fused to a smaller portion of the TAL effector still containing the DNA binding domain have been used to target the endogenous NTF3 and CCR5 genes in human cells with efficiencies of up to 25%.[17] TAL effector nucleases have also been used to engineer human embryonic stem cells and induced pluripotent stem cells (IPSCs)[34] and to knock out the endogenous ben-1 gene in C. elegans.[35]

TALE-induced non-homologous end joining modification has been used to produce novel disease resistance in rice.[1]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 "Engineering plant disease resistance based on TAL effectors". Annual Review of Phytopathology (Annual Reviews) 51 (1): 383–406. 2013-08-04. doi:10.1146/annurev-phyto-082712-102255. PMID 23725472. 
  2. ↑ 2.0 2.1 2.2 Deng, Dong; Yan, Chuangye; Pan, Xiaojing; Mahfouz, Magdy; Wang, Jiawei; Zhu, Jian-Kang; Shi, Yigong; Yan, Nieng (2012-02-10). "Structural basis for sequence-specific recognition of DNA by TAL effectors". Science 335 (6069): 720–723. doi:10.1126/science.1215670. ISSN 1095-9203. PMID 22223738. Bibcode: 2012Sci...335..720D. 
  3. ↑ "Repeat domain diversity of avrBs3-like genes in Ralstonia solanacearum strains and association with host preferences in the field". Applied and Environmental Microbiology 73 (13): 4379–84. July 2007. doi:10.1128/AEM.00367-07. PMID 17468277. Bibcode: 2007ApEnM..73.4379H. 
  4. ↑ "Characterization and DNA-binding specificities of Ralstonia TAL-like effectors". Molecular Plant 6 (4): 1318–30. July 2013. doi:10.1093/mp/sst006. PMID 23300258. 
  5. ↑ "Programmable DNA-binding proteins from Burkholderia provide a fresh perspective on the TALE-like repeat domain". Nucleic Acids Research 42 (11): 7436–49. June 2014. doi:10.1093/nar/gku329. PMID 24792163. 
  6. ↑ "DNA-binding proteins from marine bacteria expand the known sequence diversity of TALE-like repeats". Nucleic Acids Research 43 (20): 10065–80. November 2015. doi:10.1093/nar/gkv1053. PMID 26481363. 
  7. ↑ 7.0 7.1 7.2 "Xanthomonas AvrBs3 family-type III effectors: discovery and function". Annual Review of Phytopathology 48: 419–36. September 2010. doi:10.1146/annurev-phyto-080508-081936. PMID 19400638. 
  8. ↑ 8.0 8.1 8.2 "Plant science. DNA binding made easy". Science 326 (5959): 1491–2. December 2009. doi:10.1126/science.1183604. PMID 20007890. Bibcode: 2009Sci...326.1491V. 
  9. ↑ 9.0 9.1 9.2 "Comprehensive interrogation of natural TALE DNA-binding modules and transcriptional repressor domains". Nature Communications. 968 3 (7): 968. July 2012. doi:10.1038/ncomms1962. PMID 22828628. Bibcode: 2012NatCo...3..968C. 
  10. ↑ 10.0 10.1 "The crystal structure of TAL effector PthXo1 bound to its DNA target". Science 335 (6069): 716–9. February 2012. doi:10.1126/science.1216211. PMID 22223736. Bibcode: 2012Sci...335..716M. 
  11. ↑ "Structural basis for sequence-specific recognition of DNA by TAL effectors". Science 335 (6069): 720–3. February 2012. doi:10.1126/science.1215670. PMID 22223738. Bibcode: 2012Sci...335..720D. 
  12. ↑ "Structure of the AvrBs3-DNA complex provides new insights into the initial thymine-recognition mechanism". Acta Crystallographica. Section D, Biological Crystallography 69 (Pt 9): 1707–16. September 2013. doi:10.1107/S0907444913016429. PMID 23999294. Bibcode: 2013AcCrD..69.1707S. 
  13. ↑ "A simple cipher governs DNA recognition by TAL effectors". Science 326 (5959): 1501. December 2009. doi:10.1126/science.1178817. PMID 19933106. Bibcode: 2009Sci...326.1501M. 
  14. ↑ 14.0 14.1 14.2 14.3 14.4 14.5 14.6 "Breaking the code of DNA binding specificity of TAL-type III effectors". Science 326 (5959): 1509–12. December 2009. doi:10.1126/science.1178811. PMID 19933107. Bibcode: 2009Sci...326.1509B. 
  15. ↑ "Recognition of methylated DNA by TAL effectors". Cell Research 22 (10): 1502–4. October 2012. doi:10.1038/cr.2012.127. PMID 22945353. 
  16. ↑ 16.0 16.1 16.2 16.3 "Regulation of selected genome loci using de novo-engineered transcription activator-like effector (TALE)-type transcription factors". Proceedings of the National Academy of Sciences of the United States of America 107 (50): 21617–22. December 2010. doi:10.1073/pnas.1013133107. PMID 21106758. Bibcode: 2010PNAS..10721617M. 
  17. ↑ 17.0 17.1 17.2 17.3 17.4 "A TALE nuclease architecture for efficient genome editing". Nature Biotechnology 29 (2): 143–8. February 2011. doi:10.1038/nbt.1755. PMID 21179091. 
  18. ↑ 18.0 18.1 "Targeting DNA double-strand breaks with TAL effector nucleases". Genetics 186 (2): 757–61. October 2010. doi:10.1534/genetics.110.120717. PMID 20660643. 
  19. ↑ 19.0 19.1 19.2 "Efficient construction of sequence-specific TAL effectors for modulating mammalian transcription". Nature Biotechnology 29 (2): 149–53. February 2011. doi:10.1038/nbt.1775. PMID 21248753. 
  20. ↑ 20.0 20.1 "De novo-engineered transcription activator-like effector (TALE) hybrid nuclease with novel DNA binding specificity creates double-strand breaks". Proceedings of the National Academy of Sciences of the United States of America 108 (6): 2623–8. February 2011. doi:10.1073/pnas.1019533108. PMID 21262818. Bibcode: 2011PNAS..108.2623M. 
  21. ↑ 21.0 21.1 Shiu, Shin-Han, ed (2011). "Transcriptional activators of human genes with programmable DNA-specificity". PLOS ONE 6 (5): e19509. doi:10.1371/journal.pone.0019509. PMID 21625585. Bibcode: 2011PLoSO...619509G. 
  22. ↑ 22.0 22.1 "Modularly assembled designer TAL effector nucleases for targeted gene knockout and gene replacement in eukaryotes". Nucleic Acids Research 39 (14): 6315–25. August 2011. doi:10.1093/nar/gkr188. PMID 21459844. 
  23. ↑ 23.0 23.1 23.2 23.3 "Efficient design and assembly of custom TALEN and other TAL effector-based constructs for DNA targeting". Nucleic Acids Research 39 (12): e82. July 2011. doi:10.1093/nar/gkr218. PMID 21493687. 
  24. ↑ "Assembly of custom TALE-type DNA binding domains by modular cloning". Nucleic Acids Research 39 (13): 5790–9. July 2011. doi:10.1093/nar/gkr151. PMID 21421566. 
  25. ↑ Bendahmane, Mohammed, ed (2011). "Assembly of designer TAL effectors by Golden Gate cloning". PLOS ONE 6 (5): e19722. doi:10.1371/journal.pone.0019722. PMID 21625552. Bibcode: 2011PLoSO...619722W. 
  26. ↑ "A transcription activator-like effector toolbox for genome engineering". Nature Protocols 7 (1): 171–92. January 2012. doi:10.1038/nprot.2011.431. PMID 22222791. 
  27. ↑ "Iterative capped assembly: rapid and scalable synthesis of repeat-module DNA such as TAL effectors from individual monomers". Nucleic Acids Research 40 (15): e117. August 2012. doi:10.1093/nar/gks624. PMID 22740649. 
  28. ↑ "megaTALs: a rare-cleaving nuclease architecture for therapeutic genome engineering". Nucleic Acids Research 42 (4): 2591–601. February 2014. doi:10.1093/nar/gkt1224. PMID 24285304. 
  29. ↑ "Move over ZFNs". Nature Biotechnology 29 (8): 681–4. August 2011. doi:10.1038/nbt.1935. PMID 21822235. 
  30. ↑ "TAL nucleases (TALNs): hybrid proteins composed of TAL effectors and FokI DNA-cleavage domain". Nucleic Acids Research 39 (1): 359–72. January 2011. doi:10.1093/nar/gkq704. PMID 20699274. 
  31. ↑ "Heritable gene targeting in zebrafish using customized TALENs". Nature Biotechnology 29 (8): 699–700. August 2011. doi:10.1038/nbt.1939. PMID 21822242. 
  32. ↑ "Targeted gene disruption in somatic zebrafish cells using engineered TALENs". Nature Biotechnology 29 (8): 697–8. August 2011. doi:10.1038/nbt.1934. PMID 21822241. 
  33. ↑ "Knockout rats generated by embryo microinjection of TALENs". Nature Biotechnology 29 (8): 695–6. August 2011. doi:10.1038/nbt.1940. PMID 21822240. 
  34. ↑ 34.0 34.1 "Genetic engineering of human pluripotent cells using TALE nucleases". Nature Biotechnology 29 (8): 731–4. July 2011. doi:10.1038/nbt.1927. PMID 21738127. 
  35. ↑ "Targeted genome editing across species using ZFNs and TALENs". Science 333 (6040): 307. July 2011. doi:10.1126/science.1207773. PMID 21700836. Bibcode: 2011Sci...333..307W. 

Further reading

External links



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