TAL effectors are remote controls for gene activation

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TAL effectors are remote controls for gene activation
Heidi Scholze and Jens Boch
TAL (transcription activator-like) effectors constitute a novel
class of DNA-binding proteins with predictable specificity. They
are employed by Gram-negative plant-pathogenic bacteria of
the genus Xanthomonas which translocate a cocktail of
different effector proteins via a type III secretion system (T3SS)
into plant cells where they serve as virulence determinants.
Inside the plant cell, TALs localize to the nucleus, bind to target
promoters, and induce expression of plant genes. DNA-binding
specificity of TALs is determined by a central domain of tandem
repeats. Each repeat confers recognition of one base pair (bp)
in the DNA. Rearrangement of repeat modules allows design of
proteins with desired DNA-binding specificities. Here, we
summarize how TAL specificity is encoded, first structural data
and first data on site-specific TAL nucleases.
Address
Department of Genetics, Institute of Biology, Martin-Luther-University
Halle-Wittenberg, 06099 Halle (Saale), Germany
Corresponding author: Boch, Jens ([email protected])
typically 34 amino acids (aa) long, but also repeat types of
30–42 aa can be found ([2], Figure 2). The last repeat is
only a half repeat. Repeat-to-repeat variations are limited
to a few aa positions including two hypervariable residues
at positions 12 and 13 per repeat. Typically, TALs differ
in their number of repeats while most contain 15.5–19.5
repeats [2]. The repeat domain determines the specificity
of TALs which is mediated by selective DNA binding
[7,8]. TAL repeats constitute a novel type of DNAbinding domain [7] distinct from classical zinc finger,
helix–turn–helix, and leucine zipper motifs.
The recent understanding of the DNA-recognition specificity of TALs [9,10] has brought TAL studies to a
new level, in regard to both functional studies and applied
science. In this review we summarize the DNA-recognition code of TALs, novel structural insights, and progress in biotechnological applications. As TAL virulence
targets in plants and plant resistance against TALs were
recently reviewed [2,3,5,6] these aspects will not be
discussed here.
Current Opinion in Microbiology 2011, 14:47–53
This review comes from a themed issue on
Host-microbe interactions: bacteria
Edited by Brett Finlay and Ulla Bonas
Available online 5th January 2011
1369-5274/$ – see front matter
# 2010 Elsevier Ltd. All rights reserved.
DOI 10.1016/j.mib.2010.12.001
Introduction
Plant-pathogenic Xanthomonas bacteria translocate a
cocktail of 30–40 different effector proteins via a type
III secretion system (T3SS) into plant cells to manipulate
eukaryotic cellular pathways [1]. Members of the TAL
(transcription activator-like) effector family include
important virulence factors which function as transcription factors for target plant genes [2–6]. This is believed
to support bacterial proliferation, but the role of most
TALs in virulence is still unknown.
The N-terminal and C-terminal regions are highly conserved in TALs. The N-terminal region contains the
secretion and translocation signal for the T3SS, whereas
the C-terminal region contains nuclear localization signals
and a transcriptional activation domain, both of which are
important for protein activity ([2], Figure 1). The most
prominent feature of TALs is their central domain that
consists of tandem nearly identical repeats. Each repeat is
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TALs function as transcription factors
TAL frequency
Proteins with similarity to TALs have only been identified in the plant-pathogenic bacteria Xanthomonas spp.
and Ralstonia solanacearum. The presence, number, and
importance of TALs vary in different strains of Xanthomonas. Whereas some Xanthomonas pathovars carry none
or only few TAL genes, others contain up to 28 TAL genes
(including pseudogenes) per strain (Table 1). A few
TALs have been shown to be essential for virulence,
but the contribution of others is minor or not detectable.
It is unclear whether TALs with no effect are first,
nonfunctional, but possibly serve as recombinatory reservoir, second, only functional in specific host plants, or
third, fulfill a task in virulence that has not been detected
so far.
Many R. solanacearum strains carry homologs of Xanthomonas TAL genes (Table 1; [11,12]). However, the Nterminal and C-terminal regions of R. solanacearum TALs
show low similarity to Xanthomonas TALs, and the repeats
differ mainly in their C-terminal part (Figure 2). Because
of their similar overall repeat-architecture, it is possible
that R. solanacearum TALs bind to nucleic acids, too.
DNA-recognition specificity of TALs
TAL-specific effects are due to specific sequences localized in promoter regions of induced plant genes
[7,8,13,14,15]. Characterization of different AvrBs3induced genes in pepper revealed the presence of a
Current Opinion in Microbiology 2011, 14:47–53
48 Host-microbe interactions: bacteria
Figure 1
(a)
Repeat domain
0
NLS AD
N
C
T
12/13
34
1
LTPEQVVAIASHDGGKQALETVQRLLPVLCQAHG
(b)
Repeat type
NI HD NG IG NK NN NS
DNA specificity A
C
T
T
G
G
A
A
C
G
T
Current Opinion in Microbiology
TAL effector-DNA-binding code. (a) TALs contain nuclear localization signals (NLS, yellow) and an activation domain (AD, green) to function as
transcriptional activators. A central tandem repeat domain (red) confers DNA-binding specificity. Each 34 amino acid (aa)-repeat binds to one base pair
(bp) with specificity being determined by aa 12 and 13. One sample repeat is shown. Numbers refer to aa positions within the repeat. Repeat zero is
indicated which specifies for T. (b) Repeat types have specificity for one or several DNA bp. Only bases of the DNA leading strand are shown.
common promoter element, termed UPA (upregulated by
AvrBs3) box [7,8,16], which was essential for AvrBs3
recognition and whose function was sensitive to mutations
[7,8,17,18].
The length of the UPA box roughly matches the number
of repeats in AvrBs3, leading to a model to explain
AvrBs3 DNA-recognition specificity [9,10]. Accordingly, one TAL repeat binds to one DNA base pair (bp),
and the specificity of individual repeats is encoded in
the hypervariable residues at positions 12 and 13 in each
repeat (Figure 2; [9,10]; also termed RVD, repeatvariable diresidue). Some repeat types are specific for a
particular DNA bp whereas others recognize more than
one bp ([9,10]; Figure 1). Repeat positions other than
the hypervariable residues do not exhibit a significant
effect on repeat specificity [19]. The target DNA
elements of TALs have been termed differently, that
is, UPA box [7], UPT box (upregulated by TAL, [20])
or simply TAL box [9]. We have suggested to name
this element TAL box (e.g. AvrBs3 box, Hax3 box;
[9]), because the DNA sequence controls recognition
and binding of the TAL, but not necessarily upregulation of gene expression. TAL boxes all start with a ‘T’
indicating that the N-terminal region preceding the first
repeat (termed repeat ‘zero’) contributes to DNA binding ([9,21]; Figure 2). Furthermore, it was shown on
the basis of artificial TALs containing 1.5–16.5 repeats
that a minimum of 6.5 repeats is necessary to induce
transcription and 10.5 repeats are sufficient for full
induction [9].
The simple and modular way of how TALs bind to DNA
has far-reaching consequences. DNA-binding specificities of TALs can be predicted and repeat modules can be
Current Opinion in Microbiology 2011, 14:47–53
rearranged to generate artificial TALs with novel and
predictable DNA-binding specificities [9,22].
TAL repeat structure
PSIPRED predictions revealed a strong similarity of TAL
repeats with tetratrico peptide repeat (TPR) proteins and
pentatrico peptide repeat (PPR) proteins [23,24]. TPRs
are 34 aa long, contain two alpha helices, and mediate
protein–protein interactions in prokaryotes and eukaryotes
(e.g. 79 TPR proteins in Arabidopsis thaliana, 260 TPR
proteins in humans) [25]. TPR proteins contain 3–16
degenerated tandem repeats and are involved in diverse
cellular processes [25]. In contrast, PPR proteins carry 2–26
either degenerated tandem 35 aa-repeats or tandem alternating 31 aa-repeats, 36 aa-repeats, and 35 aa-repeats
[26,27]. PPR proteins mediate RNA binding and are
especially abundant in higher plants (e.g. >450 PPR
proteins in A. thaliana, six PPR proteins in humans) [26].
As no PPR-3D structures are known TAL repeats were
modeled onto TPR protein structures [23,24]. In such
models, the specificity-determining aa residues 12 and 13
of each TAL repeat are located next to another, oriented to
the inner face of the superhelix [23,24] which fits well to a
possible TAL–DNA interaction (Figure 2). Typically,
protein repeat units (e.g. TPR and PPR) are highly degenerate and the consensus structure only forms a scaffold to
present functional residues for interactions [25,28]. In
contrast, TAL repeats show an extraordinarily high degree
of repeat-to-repeat identity. This probably generates a
highly symmetric framework to position the two specificity-determining hypervariable residues to its highly
symmetrical binding partner, the DNA double helix.
Nuclear magnetic resonance (NMR) structural data of a
1.5 TAL repeat polypeptide showed that the TAL repeat
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TAL effector-DNA binding Scholze and Boch 49
folds into a helix–turn–helix–turn structure reminiscent
of TPRs (Figure 2; [23]). The hypervariable residues
were located at the end of the first helix. The two alpha
helices of one repeat are arranged in antiparallel orientation and likely interact with each other via hydrophobic
residues [23]. Possibly, the structure of the whole TAL
repeat domain differs, because of repeat-to-repeat interactions which could not be resolved in the short 1.5 repeat
fragment.
TAL–DNA interaction
TAL repeats specifically bind to DNA in vitro in a
sequence-dependent manner suggesting that no eukaryotic host factor is needed for DNA binding and specificity [7,8,9,17,18,21]. It is suggestive that the
hypervariable residues, which determine the specificity
of each repeat directly interact with the DNA bases.
Generally, repeat-containing proteins carry tandem arrays
of a short structural motif and the repetitive structure
typically forms an extended interaction interface to bind
diverse ligands [28]. The repetitive units can be arranged
similarly to a coil spring in a so-called solenoid structure
[29]. The vast majority of solenoids in nature are righthanded (i.e. a right-handed coil). In contrast, the Zurdo
(‘left-handed’ in Spanish) domain has recently been
described as a left-handed alpha-helical solenoid that binds
to DNA [30]. Often, solenoid units are stacked slightly
shifted to each other resulting in a twisted right-handed or
left-handed continuous superhelix [29]. Based on predictions [23,24] and to accomodate the DNA, TAL repeats
likely twist in a right-handed superhelix around the righthanded DNA helix. A manual fit of possible TAL–DNA
complexes shows that right-handed or left-handed TAL
repeat solenoids might wrap around the DNA in a sunflower-like shape (Figure 2).
TAL effectors with 17.5 repeats, for example, AvrBs3,
interact with a target DNA sequence (one repeat per bp
plus flanking sequences [9]) that corresponds to nearly
two helical turns. The predicted right-handed superhelical
TAL repeat structure can be expected to be flexible to wrap
around the DNA double helix (Figure 2). The modeled
structure of the TAL repeat region [23] is too large
(approximately twice the size) to accomplish interaction
of one repeat to one bp as required from its DNA specificity
[9,10]. Interestingly, the TAL repeats undergo conformational changes upon DNA interaction to a more compact
structure and the helical content of the repeats is decreased
upon DNA binding [23]. This suggests that TAL–DNA
complex formation is a dynamic process that involves
repeat and/or DNA conformational changes.
Biotechnology aspects
as well as endogenes in plants [9,19,22]. The position of
a TAL box defines the TAL-dependent transcriptional
start site at approximately 40–60 bp downstream of the
box [7,17,18,20]. Obviously, TAL effectors control the
transcriptional start site analogous to the TATA box
binding protein which may indicate similar functions.
In addition, different TAL boxes can be combined in a
cis-regulatory element in one promoter to render the
downstream gene inducible by more than one TAL
[20]. This has consequences for biotechnology, because
a gene of interest can be induced using different TALs
and these TALs can target DNA boxes at different places
of the promoter region.
TAL technology versus zinc finger technology
The programmable DNA-binding specificity of TALs
enables biotechnological applications comparably to the
zinc finger (ZF) technology [31]. One ZF domain binds to
3–4 DNA bp, and the specificity of ZF domains can be
modified. A tandem array of 3–6 ZFs corresponds to target
sites of 9–18 bp which is sufficient to target unique sites in
complex genomes. The ZF technology has been used to
generate artificial transcription factors, repressors, methylases, recombinases, and ZF nucleases (ZFNs) [31]. The
binding specificity of a ZF array is not completely predictable, because specificities of neighboring ZFs interdepend which results in highly laborious screening of
libraries to identify suitable candidates [32,33]. In contrast, TALs have an obvious advantage, because the
TAL–DNA-binding specificity is unambiguously predictable and TAL repeat specificity is obviously neighbor-independent [9,10].
TAL nucleases promote genome editing
Zinc finger nucleases (ZFNs) are fusion proteins of tandem ZF domains and a nonspecific endonuclease, typically the C-terminal nuclease domain of the type IIs
restriction enzyme FokI [34–37]. FokI enzymatic activity
depends on dimerization after DNA binding and, accordingly, two ZFNs are designed to bind to adjacent DNA
sequences to allow FokI dimerization and DNA cleavage
within the spacer region between both binding sites ([36];
Figure 3). DNA double-strand breaks are generally
repaired by one of two alternative mechanisms, nonhomologous end-joining (NHEJ) or homologous DNA
recombination (HDR) [36]. The first mechanism is typically accompanied by mutagenic deletions or insertions
whereas the latter can also mediate recombination between endogenous sequences and exogenously supplied
DNA fragments. Targeted cuts enable targeted DNA
integration, gene replacement or gene knockout in complex genomes [34–37]. Accordingly, the ZFN technology
has been used for genome modification of yeast, plants,
mammals, and humans [36].
TALs as transcriptional remote controls
TALs can be tailored to target specific DNA sequences
and, accordingly, specifically induce target reporter genes
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In addition to ZFNs, chimera between TALs and
the FokI nuclease have recently been constructed and
Current Opinion in Microbiology 2011, 14:47–53
50 Host-microbe interactions: bacteria
Figure 2
(a)
side view
top view
N
C
C
N
25.8 Å
12.6 Å
1
2
20 Å
10
3
36°
tw
34 Å
ist
C
9
4
r ig
left-handed
TAL-repeat solenoid
(b)
ht
8
5
-h
an
de
N
ds
up e
r h e li x
7
6
side view
36°
tw
ist
C
rig
ht
an
N
-h
right-handed
TAL-repeat solenoid
top view
de
ds
upe
rh e l i x
(c)
N
N
C
N
N
C
C
N
C
N
N
C
C
C
30 aa
33 aa
34 aa
35 aa
39 aa
40 aa
C
R. solanacearum
N
42 aa
35 aa
Current Opinion in Microbiology
Possible TAL effector repeat arrangements. (a) NMR structure of 1.5 repeats of the TAL effector PthA2 (2KQ5) forming three a-helices [23]. (b)
Cartoon of three consecutive repeats forming a predicted right-handed superhelix of repeats twisted 368 to fit the right-handed DNA helix. Manual fit of
10 individual repeats onto DNA (black). To connect individual helices, the long alpha helices would have to be kinked. Top and bottom models are
based on left-handed and right-handed solenoids (repeat twist), respectively. Repeats of the right-handed solenoids are shown tilted. a-Helical
Current Opinion in Microbiology 2011, 14:47–53
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TAL effector-DNA binding Scholze and Boch 51
Table 1
Number of TAL effectors per strain.
Host
TALs a
Reference b
Xanthomonas spp.
X. campestris pv. musacearum
X. campestris pv. vasculorum
X. campestris pv. vesicatoria
X. gardneri
X. campestris pv. campestris
X. axonopodis pv. glycines
X. axonopodis pv. manihotis
X. campestris pv. armoraciae
X. axonopodis pv. citri
X. fuscans subsp. aurantifolii
X. translucens pvs.
X. campestris pv. malvacearum
X. oryzae pv. oryzae
X. oryzae pv. oryzicola
Banana
Sugarcane
Pepper and tomato
Pepper and tomato
Brassicaceae
Soybean
Cassava
Brassicaceae
Citrus
Citrus
Cereals and grasses
Cotton
Rice
Rice
0
0
0–1
0–1
0–1
1
1 c
0–3
1–4
2–4
0–6
6–10
7–16
12–28
ACHT01000000
ACHS01000000
[42]; AM039952
[43]
[42]; AM920689; CP000050; AE008922
[44]; AY780631
[45]
[46]; www.cmr.jvci.org
[47–49]; AE008923
ACPX00000000; ACPY00000000
[50]
[51,52]
[50]; CP000967; AP008229; AE013598
[50]; AAQN01000001
Ralstonia spp.
Ralstonia solanacearum
Broad host range
0–1
[11]; AL646052
a
The number of TAL effectors per strain was determined by Southern blot or genomic sequence. Southern blots did not reveal pseudogenes and
might not have identified all alleles. Further information on Xanthomonas genomes and TALs can be found at www.xanthomonas.org and
www.cmr.jcvi.org.
b
GenBank accession numbers are given as reference for sequenced genomes and plasmids.
c
The probe for Southern analysis yielded several bands, but contained TAL and TAL-flanking sequences which precludes allele number
determination.
Figure 3
(a)
FokI
TAL
TAL nuclease
tailored DNA-binding specificity
(b)
FokI dimer
TAL nuclease “A”
DNA
TAL nuclease “B”
target sequence A
target sequence B
15-31 bp spacer
DNA
Δ
targeted deletions
DNA
targeted insertions
Current Opinion in Microbiology
TAL nucleases (TALNs) promote genome editing. (a) TALNs are fusions between TAL effectors and the FokI endonuclease domain. A tailored TAL
repeat domain controls DNA-binding specificity. (b) Two TALNs bind neighboring DNA boxes and FokI dimerization induces DNA cleavage in the
spacer region between the boxes. DNA double-strand breaks can promote nonhomologous end-joining (NHEJ) or homologous DNA recombination
(HDR) enabling targeted genome modifications like deletions or insertions.
termed TAL nucleases (TALNs or TALENs; Figure 3;
[38,39]). Different TALs were combined with a FokI
nuclease domain at the N-terminus or C-terminus.
Expression of TALN pairs that bind to adjacent DNA
boxes promoted DNA cleavage, followed by targeted
HDR in yeast with comparable efficiency as ZFNs
[38,39]. Similarly, TALNs with artificial arrangements
of repeats were designed to target a given DNA sequence
(Figure 2 Legend Continued) solenoids are most often right-handed in nature. (c) Cartoon of repeats with different lengths (aa, amino acids) occuring
in nature. The predominant 34 aa-repeat is boxed. (a)–(c) Yellow: first helix; orange: second helix; green: hypervariable residues; red: duplications,
insertions (solid) and deletions (dashed) in comparison to typical Xanthomonas 34 aa-TAL repeats; minor (1 aa) changes are indicated by a red arrow;
purple: aa sequence differs from Xanthomonas repeats.
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Current Opinion in Microbiology 2011, 14:47–53
52 Host-microbe interactions: bacteria
[38]. Surprisingly, some artificial TALNs showed no
activity, indicating that some unknown parameters still
govern efficiency of TALNs [38]. The ZFN technology
has been hampered by cytotoxicity possibly due to offtarget cleavage at multiple genomic sites [40,41]. In
contrast, TALs are highly sensitive to changes in their
target DNA boxes and three to four mutations typically
block recognition [9,19] which indicates that off-targets
might be limited.
Conclusions
Rarely has a protein in nature been identified whose
specificity can be readily predicted from its amino acid
sequence and furthermore, easily modified. The simple
structure-function encryption of the TAL–DNA-binding
specificity is both elegant and intriguing. It immediately
suggests use of TAL effectors as programmable DNAtargeting devices. First results showed that TAL
nucleases have specific activity and certainly other applications will be explored, soon. TAL proteins have the
potential to rival the existing ZF technology and establish
a game-changing variety of novel DNA sequence-specific
applications (specific gene activators, repressors, DNAprobes, gene replacement, and mutations) and hopefully
therapeutics.
Note added in proof
Recently, TAL nucleases were successfully employed to
edit human chromosomal targets and designed TALs
induced expression of endogenous human genes [53].
Acknowledgements
We thank D. Büttner, R. Koebnik, and U. Bonas for discussions and helpful
suggestions on the manuscript. Research in our laboratory is supported by a
grant from the Deutsche Forschungsgemeinschaft (SPP 1212) to J.B.
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TAL effector-DNA binding Scholze and Boch 53
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Current Opinion in Microbiology 2011, 14:47–53
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