Intrinsic Disorder in Plant Proteins and Phytopathogenic Bacterial

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Intrinsic Disorder in Plant Proteins and Phytopathogenic Bacterial Effectors Macarena Marín* and Thomas Ott* Genetics Institute, Faculty of Biology, Ludwig-Maximilians-University of Munich, Grosshaderner Strasse 2-4, 82152 Martinsried, Germany 5.4.1. AvrPto and AvrPtoB Harbor Long ID Regions and Interact with Protein Kinases 5.5. Intrinsic Disorder and Effector Evolution 6. Conclusions Author Information Corresponding Authors Author Contributions Funding Notes Biographies Acknowledgments Abbreviations References

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CONTENTS 1. Introduction 2. Intrinsic Disorder in Plant Proteins 2.1. Intrinsically Disordered Proteins Involved in Abiotic Stress Response 2.2. Intrinsic Disorder in Chloroplast Proteins 2.3. Intrinsic Disorder in Plant Signaling 3. Plant Immunity 3.1. Complexity of the Plant Immune System 3.2. PAMP-Triggered Immunity 3.3. Effector-Triggered Immunity 3.4. Effectors 4. Intrinsically Disordered Proteins in the Plant Immune System 4.1. At the Plasma Membrane 4.1.1. Pattern Recognition Receptors 4.1.2. RbohD 4.1.3. PBS1 and PBS1-like Kinases 4.1.4. RIN4 4.2. In the Cytoplasm 4.2.1. NBS-LRR 4.2.2. Hsp90 4.2.3. MAP Kinases 4.3. Nucleus 4.3.1. Transcription Factor Families in Plant Immune Response 4.3.2. WRKY 5. Effectors and Intrinsic Disorder 5.1. Intrinsic Disorder and Secretion 5.2. Activation of Effector Proteins: The Case of AvrRpt2 5.3. Intrinsic Disorder and Virulence: HopI 5.4. Interactions between Effectors and Plant Immune Proteins

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1. INTRODUCTION Plants sustain life on earth providing food and molecular oxygen. As they are sessile organisms, they have developed refined signaling systems to perceive and respond to biotic and abiotic stimuli in their ever-changing environment. One of the major challenges for plants is the discrimination between beneficial and harmful microorganisms. Lacking adaptive immune systems, plants have diversified and optimized their innate immune system. It has been estimated that about 70% of all signaling proteins harbor intrinsically disordered (ID) or unstructured regions.1 These ID regions are defined as flexible protein segments with no ordered secondary/tertiary structures under physiological conditions in vitro. They are enriched in charged, hydrophilic, and surface exposed amino acids and depleted of buried residues. Consequently, rigid, buried, neutral, order-promoting amino acids (W, C, F, I, Y, V, and L) are underrepresented in these sites. Additionally, these regions contain significantly more flexible, surface-exposed, and disorder-promoting residues (S, P, E, K). As they contain many noninteracting charged groups and few hydrophobic residues, they show lower sequence complexity and exhibit large net charges at neutral pH.2−4 The length of ID regions greatly varies between different proteins. Some harbor only short disordered segments (0.5 threshold).4,163,164 Although this method shows high confidence levels for long predictions, future studies on ID immunity proteins is essential. 4.1. At the Plasma Membrane

4.1.1. Pattern Recognition Receptors. The immune receptors flagellin-sensing 2 (FLS2) and EF-Tu receptor (EFR) perceive flagellin and the elongation factor EF-Tu, respectively. Until now, they are the best-characterized PAMP receptors in plants. Both belong to the class of leucine-rich repeat (LRR) RLKs that comprise the largest receptor family in the plant kingdom with 216 predicted members in A. thaliana.165 Both immune receptors interact with another LRR-RLK, the coreceptor BRI1 associated kinase 1 (BAK1) in a liganddependent manner.166−169 Upon ligand binding, BAK1 and 6919

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segment of the N-terminal region is not available. However, since the region surrounding the EF-hand segment has been excluded from crystallographic analyses,177,180 it can be assumed that it probably remains unstructured even in the presence of calcium. The putatively disordered N-terminal region of OsRbohB mediates the interaction with the small GTPase OsRac1.181 In AtRbohD, it comprises all in vivo phosphorylation sites.182−185 As phosphorylation and calcium binding have been shown to activate ROS production by the A. thaliana RbohD in a synergistic manner, it has been proposed that the N-terminal region could act as a regulatory domain.178 A mechanism for this synergistic effect has been postulated. There, the phosphorylated AtRbohD can undergo extended conformational changes compared to the nonphosphorylated protein.178 On the basis of this mechanism structural flexibility would be essential as, like the human NADPH oxidase NOX5, the intramolecular interaction between the regulatory N-terminal region and the catalytic C-terminal region may probably be required for activation.186 4.1.3. PBS1 and PBS1-like Kinases. The A. thaliana AvrPphB susceptible 1 (PBS1) protein is a putative serine/ threonine kinase, which belongs to the family of receptor-like cytoplasmic kinases (RLCKs). The P. syringae effector AvrPphB, a cysteine protease, cleaves PBS1 adjacent to a GDK motif, which subsequently causes activation of the NBSLRR protein RPS5.187 Interestingly such GDK motifs are present in at least 20 other A. thaliana kinases, among them BIK1, PBL1, and PBL2.188 Intrinsic disorder predictions indicate that both N- and Ctermini of PBS1 and BIK1 harbor long ID regions. PBS1 probably associates to the plasma membrane via putative myristoylation and palmitoylation sites within its disordered Nterminus.189 Furthermore the N-terminal region harbors the only known phosphorylation site at Ser-21.184 4.1.4. RIN4. The RPM1-interacting protein 4 (RIN4) is a negative regulator of plant immunity and one of the bestcharacterized host targets of type III effectors in plants.125 The fact that at least four effectors, HopF2, AvrRpt2, AvrB, and AvrRpm1, and the two R proteins, RPM1 and RPS2, target RIN4, highlights its biological importance. While AvrRpm1 and AvrB induce phosphorylation of RIN4, which leads to the subsequent activation of RPM1,190 AvrRpt2 cleaves the protein at two conserved sites,191,192 which triggers downstream RPS2 activation.193 RIN4 shows no sequence similarity to any other protein of known function, and its protein structure remains elusive. Although RIN4 is present in both monocot and dicot plants, it is overall lowly conserved at amino acid level. Exceptions to this are two short segments of ∼25 residues, which harbor the AvrRpt2 cleavage sites.191,192 These segments are predicted to be prone to folding, and one of them has been cocrystallized with the effector AvrB.194 As there is no structural data available for the remaining regions of the protein, we predicted its intrinsic disorder and secondary structure propensity and constructed ab initio models using the I-TASSER server195 (Figure 6). These in silico methods suggest that regions flanking the AvrRpt2 recognition sites are ID. The best three generated models coincide in predicting that this protein lacks a defined three-dimensional structure (Figure 6C), but differ from a previously published model that was also constructed using the I-TASSER server.196

Figure 6. Intrinsic disorder in RIN4. (A) Intrinsic disorder and secondary structure prediction of RIN4. Intrinsic disorder was predicted with the PONDR VL-XT program.4,163,164 Residues with values above the 0.5 threshold are predicted to be disordered (red line). Secondary structure predictions were performed with the Jpred webserver304 and are represented schematically on top of the PONDR prediction. Blue triangles and rectangles depict β and α structures, respectively. Yellow circles and triangles indicate experimentally determined phosphorylation sites and AvrRpt2 cleavage sites, respectively. The gray rectangle indicates the region, which has been crystallized (PDBID: 2NUD). Putative MoRFs were predicted with the MoRFPRED server and are depicted in green. (B) AvrB/RIN4142−176 complex (PDBID: 2NUD). Molecular graphics were produced with the UCSF chimera package.305 AvrB and RIN4 RIN4142−176 are represented in gray and blue, respectively. (C) Ab initio models of RIN4. Models were generated with the I-TASSER webserver.306

The numerous phosphorylation sites in RIN4 also suggest that extensive regions of this protein may be unstructured. Most of the experimentally determined phosphorylation sites (Ser-47, Ser-79, Ser-107, Ser-116, Ser-141) are indeed located in putative disordered regions (Figure 6A).183−185,197 Only Thr-21/Ser-160/Thr-166, the sites phosphorylated by the RIN4-interacting receptor-like protein kinase (RIPK), reside in the folded regions.198 Substantial functional data have been interpreted under the assumption than RIN4 is a globular protein with two domains, each of them harboring an AvrRpt2 cleavage site. However, in silico data strongly suggests that this protein probably consists of two short, folded AvrRpt2 recognition motifs surrounded and connected by largely unstructured and flexible regions. Furthermore, MoRF predictions indicate that disorder-to-order transitions can occur in segments within the ID regions (Figure 6A). Two of these MoRFs coincide with structural elements in the crystallized peptide (PDBID: 2NUD_D), suggesting that these residues can indeed undergo induced folding upon interaction with AvrB (Figure 6B). Furthermore, site-directed mutagenesis of the MoRF149−152 results in the loss of AvrRpt2 cleavage.199 The other two predicted MoRFs are located in the N- and C-termini. While there is no experimental evidence available for the short N-terminal MoRF, the C-terminal one has been analyzed. It contains three cysteine residues that are involved in plasma membrane anchoring via palmitoylation.191 Partial deletion and site-directed mutagenesis of this MoRF 6920

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resulted in a complete loss of the regulatory activity of RIN4 on RPS2 and in the abolishment of their interaction.199 On the basis of these predictions, we postulate that RIN4 may behave as a chameleon protein. Chameleon sequences are protein segments that adopt different secondary structures depending on the interacting surface.200 As a consequence, one disordered region can bind to multiple partners. A classical example for a chameleon segment is the C-terminal region of the cell cycle regulator and tumor suppressor p53.201 This region is disordered in its free form, but folds into α-helical, βstrand, or coil motifs depending on its binding to different interacting partners.202 Such property would enable RIN4 to interact with multiple and structurally unrelated binding partners like AvrRpm1, AvrB, and RPM1.

Hsp90 usually associates with cochaperones. In plants, it interacts with Rar1 and Sgt1 to form a complex that is essential for the functionality of NBS-LRRs.211 The crystal structures of the secondary complex between the N-terminal domain of Hsp90 and the C-terminal domain of Sgt1 as well as the ternary complex between these domains and a CHORD domain of Rar1 have been solved.212 A striking difference between these two structures is that Rar1 binding promotes an order-todisorder transition in the lid segment of Hsp90. This is indicated by significantly higher B-factor values and, in some crystals, by the absence of defined electron densities. This transition facilitates its displacement allowing the access of the middle domain catalytic loop.212 Superposition of the ternary complex structure on the structure of the homologous full-length protein from Saccharomyces cerevisiae in the ATP-bound conformation (PDBID: 2CG9) revealed that the charged linker region (residues 217−261) connecting the N-terminal and middle domains and a short segment within the C-terminal domain (residues 598−610) are also disordered.213 This matches the intrinsic disorder predictions for both A. thaliana and S. cerevisiae Hsp90 proteins. 4.2.3. MAP Kinases. Plant MAP kinases are organized in cascades where stimulus-dependent activation of a MAP kinase kinase kinase (MEKK) leads to phosphorylation of a MAP kinase kinase (MEK), which subsequently phosphorylates a MAP kinase.214 Some of the best-studied plant MAP kinase cascades are those that control innate immunity (i.e., MEKK1, MEK4/MEK5, and MPK3/MPK6 and MEKK1, MEK1/MEK1, and MPK4).215,216 Activation of these cascades leads to interaction and phosphorylation of transcription factors, such as WRKY33, and induction of defense genes.217 MAP kinases are serine/threonine kinases with a structured two-lobed fold domain.218 The MAP kinases, such as MPK3 and MPK6, are exclusively composed of this domain. In contrast, MEK and MEKK kinases are predicted to harbor long ID N-terminal regions (Figure 7). In the case of MEKK kinases this region is highly variable and probably corresponds to a regulatory domain.219 Deletion of this domain in MEKK1 leads to a constitutively active protein.220 The N-terminal region of MEKK2, a protein downstream the MEKK1, MEK1/MEK1, and MPK4 cascade, mediates the interaction with MPK4 and harbors most of the in vivo phosphorylation sites.221 The study of the ID structure of these regulatory regions may contribute to the understanding of the specificity of these proteins.

4.2. In the Cytoplasm

After signal perception at the plasma membrane, many of the PTI and ETI related processes occur in the cytoplasm. As structural information of cytosolic immune proteins is limited, we extended our in silico analysis to cytoplasmic components and predicted intrinsic disorder in these proteins. However, only few proteins are predicted to be unstructured in this compartment (Figure 4). 4.2.1. NBS-LRR. NBS-LRR proteins are the major class of R proteins. Even though some examples such as RPM1 and RPS2 locate to the plasma membrane, the vast majority of NBS-LRRs shuttle between the cytoplasm and the nucleus. 150,203 Structurally, these proteins harbor three distinct domains, the NBS and LRR domains common to all members of this family and a variable N-terminal domain, usually containing a toll/ interleukin-1 receptor (TIR) or a coiled-coil (CC) domain.204 The C-terminal domain is composed of multiple LRRs. On the basis of structures of mammalian LRRs, they form an α/β horseshoe fold, with each repeat unit having a β strand-turn-α helix structure.205 This domain possesses regulatory functions.206 Plant NBS domains are composed of several conserved motifs,204 which are involved in NBS-LRR function.206 It has been shown that NBS-LRR proteins are activated by a conformational change that probably occurs upon ATP binding.207,208 The N-terminal domains typically contain protein−protein interaction motifs that are probably involved in activation of downstream responses.150 Although these three domains are predicted to be folded on the basis of homology modeling, the linker regions require a certain degree of flexibility in order to allow the predicted conformational changes. Intrinsic disorder predictions indicate that several NBS-LRR proteins harbor short unstructured segments. However, since such short ID segments can be found in most proteins that undergo extensive conformational changes, we did not consider this kind of linker regions any further in this review. 4.2.2. Hsp90. Heat-shock protein 90 (Hsp90) is a molecular chaperone involved in the maturation and activation of numerous signaling proteins. Overall, Hsp90 contains a conserved N-terminal ATPase domain, a middle domain connected by a charged linker region, and a C-terminal dimerization domain.209,210 The protein undergoes large conformational changes during its functional cycle. The inactive form is in an open state. Upon ATP binding a so-called “segment-lid” in the N-terminal domain encloses the ATP molecule in the active site. Subsequently, a series of dynamic conformational changes occur that lead to a transient wrapped dimer.209,210

4.3. Nucleus

Accumulating evidence suggests that nuclear trafficking of proteins is of central importance for plant immunity, as its impairment compromises resistance of the organism.222 Furthermore, host-derived R proteins, transcription factors, and transcriptional regulators, as well as several effector proteins of pathogen origin, accumulate in this compartment.222 Consequently, plants respond to infections with significant transcriptional reprogramming, where up to 25% of A. thaliana genes show altered transcript levels under such conditions.223,224 4.3.1. Transcription Factor Families in Plant Immune Response. Multiple transcription factors control plant defense reprogramming. Some of them, such as MYC2, MYB30, and TGA3, belong to protein families, which are widespread throughout different kingdoms while others like WRKY and ERF belong to plant-specific protein families.225 In general, all 6921

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Figure 7. Intrinsic disorder predictions of MAP kinases. The Nterminal regions of MEK and MEKK kinases are enriched in intrinsic disorder. Disorder predictions of MAPK (A), MEK (B), and MEKK (C) proteins were made using the PONDR VL-XT program.4,163,164 Residues with values above the 0.5 threshold are predicted to be disordered. Gray blocks indicate the relative position of the folded MAP kinase domains.

of these transcription factors harbor small folded domains, which mediate DNA binding, and linker regions or regulatory domains that are mostly predicted to be ID (Figure 8).26 MYC2 is a central regulator of jasmonic acid-mediated defense responses as it regulates pathways that control resistance to pests and pathogens.226 As MYB30 and TGA3, MYC2 binds DNA via α-helical segments. In MYC2 these regions are composed of a canonical basic helix−loop−helix (bHLH) DNA binding motif (Figure 8). This is composed of two α-helices connected by a loop and basic residues that facilitate DNA binding.227 Members of this family usually dimerize and bind the palindromic E-box consensus sequence, CANNTG.228 In the case of TGA transcription factors, a basic region/leucine zipper (bZIP) motif confers direct interaction with the nucleotides. Functionally, TGAs interacts with NPR1, a central regulator of pathogenesis-related gene expression.229 Both bHLH and bZIP transcription factors harbor long regions of intrinsic disorder, which fold upon dimerization.230,231 While in MYB30, a positive regulator of the hypersensitive response in A. thaliana232 and the target of the bacterial effector XopD, the

Figure 8. Intrinsic disorder in transcription factors. The DNA binding domains of transcription factors are mostly folded, whereas the regulatory domains are often ID. PONDR VL-XT predictions support this statement. Residues with values above the 0.5 threshold are predicted to be disordered. Long ID regions are depicted in red. Gray blocks indicate the relative position of the folded DNA binding domains. Adjacent to each disorder plot are the molecular graphic representations of the respective folded domains. Graphics were generated using the UCSF chimera package.305 PDBID: 3GCC, 1DH3, 2AYD, 2QL2.

predicted unstructured regions are restricted to shorter segments (Figure 8).233 Long ID regions are also present in most WRKY proteins and members of the ERF/AP2 protein family of ethylene response factors that all bind DNA via β-stranded motifs. It has been shown that a wide spectrum of transcription factors such as HvNAC013, AtMYB91, and AtbHLH011 also interact via ID regions with radical-induced cell death 1 (RCD1). The RCD1 6922

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cytoplasm via the TTSS. Additionally, this process already requires unfolding prior to insertion into the narrow channel formed by the secretion machinery.248 We have recently postulated that intrinsic disorder may also be essential for evasion of immune recognition and may resemble eukaryotic signaling proteins. A proteome-wide analysis of plant-associated bacteria revealed that effectors are enriched in long ID regions and supports this hypothesis.249 In this section we will discuss some examples of unstructured effector proteins that nicely illustrate how this property could contribute to effector function.

protein functions as a regulator of stress responses and development in A. thaliana.61,234 Interestingly, RCD1 also interacts with at least one member of the WRKY family, namely AtWRKY47.234 This suggests that intrinsic disorder is a common feature of the interaction between RCD1 and unrelated transcription factors.26 4.3.2. WRKY. The WRKY superfamily is an especially interesting case study as it is involved in a plethora of defenserelated processes. With more than 70 members in A. thaliana, WRKYs comprise one of the major transcription factor classes.235 This family was named after its DNA-binding WRKY domain, which contains the conserved WRKYGQK sequence and a zinc finger motif. Usually, it binds to the consensus W box (C/TTGACT/C).236 Multiple WRKY transcription factors act both as positive and negative regulators in plant defense responses.236 For example, RRS1 (AtWRKY52) combines the WRKY domain with an NBS-LRR structure and confers resistance toward Ralstonia solanacearum.237 Similarly, Arabidopsis wrky53 mutant plants show delayed symptom development upon R. solanacearum infestation, but increased susceptibility toward P. syringae.238,239 In barley, the NBS-LRR MLA protein confers resistance to the powdery mildew fungus Blumeria graminis. This protein interacts with HvWRKY1/2 in the nucleus, thereby interfering with their function as repressors of PTI.240 These examples highlight the importance of this family in plant immune response. To date, three structures of WRKY domains have been solved: the NMR solution structure of the C-terminal WRKY domain of AtWRKY4 alone (PDBID: 1WJ2) and in complex with a promoter element (PDBID: 2LEX) and the crystal structure of the WRKY domain of AtWRKY1 (PDBID: 2AYD). 241,242 The solution structure bound to DNA demonstrated that the WRKY domain contacts the major DNA groove with a four-stranded β-sheet that is almost perpendicular to the DNA helical axis and that residues in the conserved WRKYGQK motif contact the thymine methyl groups mainly through apolar interactions (Figure 8).243 Structural analyses of the full-length AtWRKY1 and AtWRKY4 indicated that both proteins have a great tendency to be ID, with the exception of both WRKY domains. This has been experimentally confirmed for residues 266−292 of AtWRKY1, which were absent from the electron density.242 Furthermore, folding of the C-terminal WRKY domain of AtWRKY4 is zinc-dependent, as titration with EDTA induced its unfolding.241 The function of these putative disordered regions in WRKYcontaining proteins remains currently unknown. However, it has been postulated that long flexible linker regions connect the folded globular zinc finger motifs and that they are essential for regulating the spacing between them and thus their activity.244,245 Alternatively, this disordered segments may constitute regulatory domains, as such domains are often ID.

5.1. Intrinsic Disorder and Secretion

The secretion specificity via the TTSS is probably ensured by the presence of an N-terminal secretion signal and the formation of a protein complex between the effector and cognate ATP-independent chaperones.156 It has been estimated that both the secretion signal as well as the chaperone recognition sites are encoded within the first 100 N-terminal residues of the effector protein.250−256 TTSS signals are short 15−20 residue-long segments located at the N-terminus of effector proteins. These signal peptides are highly variable at the sequence level, but show conserved amphipathicity and are enriched in serine residues. In accordance with these features, it has been experimentally shown that these segments are often ID.257 This led to the hypothesis that the lack of a defined structure is the actual secretion signal.156,257,258 Prior to host−pathogen contact and protein secretion, the majority of effector proteins are stored in complex with cognate chaperones in the microbial cytoplasm. These serve protective functions as several effectors aggregate or get rapidly degraded in the absence of their cognate chaperones.259−262 This hypothesis is further supported by several crystal structures that demonstrated the association of the chaperones with partially unfolded effector proteins.263−265 For example, the Nterminal region of the human pathogenic Yersinia pseudotuberculosis YopE effector is ID and undergoes partial folding upon association with its cognate chaperone SycE.266 Disorder may therefore be an inherent advantage, as it would spare the active unfolding of already disordered domains. Once they are secreted into the host cytoplasm, they may remain disordered or only fold upon activation or interaction with partner proteins. 5.2. Activation of Effector Proteins: The Case of AvrRpt2

Effectors such as AvrB or AvrRpt2 become active only after entrance into the host cell. For example, AvrB is activated by nucleotide binding and subsequent phosphorylation.194,267 Keeping these proteins in an unfolded and inactive state is likely to represent a protective mechanism for the pathogen itself to prevent detrimental intracellular activities prior to secretion. AvrRpt2 encodes a cysteine protease that promotes bacterial growth and virulence in susceptible A. thaliana lines, but behaves as an avirulence factor in lines expressing its cognate R protein RPS2. Upon entrance into the plant cell AvrRpt2 becomes activated and cleaves RIN4. Its disappearance induces activation of RPS2.193,267,268 AvrRpt2 is delivered into plant cells in the form of an inactive protease.269 Its activation is mediated by ROC1, a singledomain cyclophilin peptidyl-prolyl cis/trans isomerase.267 The two-dimensional NMR spectrum of AvrRpt2 in its apo state shows only a few backbone amide peaks, and these peaks show chemical shifts from 7.9 to 8.5 ppm in the random coil region (Figure 9B).270 Upon interaction with ROC1, AvrRpt2 folds at

5. EFFECTORS AND INTRINSIC DISORDER It has been estimated that on average 20% of a given eukaryotic proteome contains long (>50 residues) ID segments. In contrast, such regions are significantly underrepresented in bacterial proteins (99%) to the N-terminal region of Wiskott−Aldrich syndrome proteins (WASP), which are cytoskeletal scaffolds involved in signal transduction.276 Hsp70 proteins are essential for protein folding and translocation as they bind unfolded peptides or folding intermediates. The interaction of these proteins with the J domain containing Hsp40 cochaperones is essential for their function, as Hsp40s stimulate Hsp70 ATPase activity and stabilize interactions with substrate proteins.277 Although the J domain of HopI is active and mediates interaction with Hsp70, the virulence function of the effector is encoded in the ID P/Qrich region. It is likely that the ID region of HopI interferes with Hsp70 activity and/or substrate specificity and therefore with the folding or translocation into the chloroplast of SAbiosynthesis or transport components.161

least partially and undergoes self-processing by cleaving its 71 N-terminal residues, which are mostly disordered and encode the TTSS secretion signal (Figure 9A). The remaining residues encode the catalytically active cysteine protease domain with the canonical catalytic triad Cys-His-Asp.271 This example nicely illustrates how activation of effectors can depend on disorder-to-order transitions upon entrance into the host cytoplasm. 5.3. Intrinsic Disorder and Virulence: HopI

HopI is a widespread effector among different P. syringae pathovars.272 After secretion into the plant cell, HopI translocates into chloroplasts, where it suppresses the accumulation of the defense-signaling phytohormone salicylic acid (SA).160 It comprises three regions: a conserved Nterminal region of unknown function, a middle region with a variable number of P/Q-rich repeats, and a conserved Cterminal J domain (Figure 10A).160 J domains are also present in cochaperones such as Hsp40 and Hsp40-like, where they mediate the interaction with the partner chaperone Hsp70 and regulate its function.273 Various Hsp70 isoforms are upregulated upon pathogen infection.274,275 In planta, HopI interacts with different isoforms of Hsp70 proteins via its J domain and recruits Hsp70 into chloroplasts.161 The P/Q-rich 6924

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5.4. Interactions between Effectors and Plant Immune Proteins

A key feature of plant effector proteins is their specificity to target and interact with host proteins, especially with interconnected cellular hubs that converge into a reduced number of pathways.278 Thereby, pathogens can efficiently manipulate host defense responses and improve their own fitness. For example, the type IV effector CagA of the human pathogen Helicobacter pylori harbors an ID C-terminal region that mediates interactions with multiple proteins, is involved in intramolecular interactions, undergoes induced folding, and thereby potentiates the CagA scaffold/hub function.279 In this section we analyzed examples of effectors from plant-associated bacteria, which are involved in complex protein interaction networks and contain long ID regions. 5.4.1. AvrPto and AvrPtoB Harbor Long ID Regions and Interact with Protein Kinases. In Solanum lycopersicum (tomato), Pto confers resistance toward pathogenic strains of P. syringae pathovar tomato expressing either the AvrPto or the AvrPtoB effector.280 These effectors not only interact with this serine/threonine-kinase but also with the cytoplasmic domains of the RLKs BAK1 and FLS2. These interactions are specific as AvrPto does not interact with Fen, a closely related kinase that shares >80% sequence identity with Pto.281−285 The structure of AvrPto has been solved in solution for the apo state (PDBID: 1R5E) and crystallographically for the complex with the Pto kinase (PDBID: 2QKW) (Figure 11). The overall structure of AvrPto consists of a core composed of a three-helix bundle motif. This core is flanked by the ID N- and C-termini, as shown by NMR spectroscopy (Figure 11).286,287 The ∼30 residue long ID N-terminal region harbors the secretion signal and a myristoylation site responsible for plasma membrane localization. Furthermore, it mediates the interaction with Api1, a protein of unknown function.159,287,288 The unstructured C-terminal region comprises multiple phosphorylation sites, of which at least Ser-147 and Ser-149 contribute to virulence and avirulence.288 Furthermore, an uncharacterized tobacco R protein recognizes these structural features and the phosphorylation status of this region.159,289 According to the solution structure, the protein core exists in a dynamic equilibrium between folded and unfolded ensembles, which at pH 6.1 exhibits slow folding and unfolding rates.287,290 The crystal structure of AvrPto in complex with Pto shows that the interaction between these proteins is mediated by hydrophobic and van der Waals contacts and relies mainly in two interfaces (Figure 11D). The AvrPto structure in complex with Pto is basically identical to the folded solution structure with the exception of having a more ordered GINP motif, which has been shown to be essential for the interaction with Pto (Figure 11B,C). This suggests a stabilization of the folded state upon interaction (Figure 11C).286 The second effector that interacts with Pto is AvrPtoB. It belongs to the HopAB effector family. AvrPtoB is truly modular. It contains an N-terminal region with a Pto-binding domain (PID) and a BAK1-binding domain (BID), and a Cterminal region that comprises an E3 ligase domain (Figure 12).172,291,292 Regions that are predicted to be ID connect these at least partially folded modules. The crystal structures of the PID (AvrPtoBPID: 121−205) alone (PDBID: 3HGL) and in complex with Pto (PDBID: 3HGK) have been solved and show that it is mostly folded (Figure 12a). AvrPtoBPID mainly forms a globular four-helix bundle composed of four short α-helices. Additionally, it

Figure 11. AvrPto structure. (A) Intrinsic disorder prediction. Intrinsic disorder was predicted with the PONDR VL-XT program.4,163,164 Residues with values above the 0.5 threshold are predicted to be disordered (red line). The gray block indicates the relative position of the folded domain, whereas regions where disorder has been experimentally demonstrated are depicted in red. Green lines indicate putative MoRFs. The asterisk marks the flexible GINP motif. (B) 1 H−15N HSQC spectrum of full-length AvrPto. Peaks, which correspond to the mobile N- and C-terminal regions are highlighted in red. The plot was reprinted with permission from ref 287. Copyright 2004 Elsevier. (C) Comparison between the apo and that in complex structures of AvrPto. The solution structure in apo state of AvrPto exhibits a highly flexible GINP motif highlighted in orange (PDBID: 1R5E). In contrast, this motif is fixed in the crystal structure of AvrPto in complex with Pto (PDBID: 2QKW). (D) AvrPto/Pto protein complex. Zoom representation of the interaction surface between AvrPto and Pto. The interaction between these proteins is mediated by hydrophobic residues. Molecular graphics were created with the UCSF chimera package.305 Hydrophobic and hydrophilic surfaces are depicted in cyan and blue, respectively.

contains a long rigid loop with a shorter α-helix that significantly differs from the AvrPto structure. AvrPtoBPID and Pto form a stable complex in solution. Like in the AvrPto-Pto complex, the interaction between Pto and AvrPtoBPID results from two interfaces, which make extensive hydrophobic contacts and hydrogen bonds.291 In contrast, the BID (AvrPtoBBID: 250−359) shows a high tendency to be unstructured. The crystal structure of AvrPtoBBID (PDBID: 3TL8) has been solved exclusively in complex with the BAK1 kinase domain (BAK1-KD) (Figure 12). These proteins form a stable complex in solution. Despite low sequence conservation (∼20% identity), the structure of AvrPtoBBID bound to the BAK1-KD with its globular helix bundle and the extended rigid loop is remarkably similar to the AvrPtoBPID structure. The main difference is the length of one helix of AvrPtoBBID that is much longer compared to the corresponding one in AvrPtoBPID. This causes both domains to interact with their respective kinases in different orientations.172 The C-terminal domain of AvrPtoB (AvrPtoBE3: 436−553) is resistant to limited proteolysis, and in silico predictions suggest that it is mostly folded. The crystal structure of AvrPtoBE3 (PDBID: 2FDA) reveals the presence of a fold that is 6925

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Figure 12. Intrinsic disorder of the HopAB effector family. (A) Domain structure and intrinsic disorder profile of AvrPtoB. Long disordered regions connect folded domains. The structures are located on top of their respective domains. Green lines indicate putative MoRFs. (B) Domain structure and disorder profile of HopPmaL. Red lines in schematic domain representation indicate regions, where disorder has been experimentally verified. (C) The AvrPtoB/BAK1 complex. To illustrate intrinsic disorder in the complex, we overlaid the NMR structure of HopPmalBID (PDBID: 2LF3) onto the crystal structure of the AvrPtoBID/BAK1 complex (PDBID: 3TL8). The folded HopPmalBID and AvrPtoBID are depicted as ribbon representations in light blue and cyan, respectively, whereas BAK1 surface is depicted in light gray. Disordered segments in HopPmalBID are colored in orange. Molecular graphics were generated with the UCSF chimera package.305

138 residues of HopPmaL, the first 90 residues of HopAB1Pph1448A, and the region in HopPmaL between the two folded domains (residues 218− 307) also lack a defined 3D structure.297 All available structural data indicate that, beside the two folded kinase interacting domains and the E3 ligase domain, members of the HopAB family are mostly ID. This flexibility is probably essential for the simultaneous interaction with multiple binding partners and could confer substrate specificity.

structurally similar to the RING-finger and U-box folds, which are present in E3 ubiquitin ligases (AtPUB14rmsd: 1.1 Å).292 The core of AvrPtoBE3 is folded, but a large and partially disordered N-terminal segment (residues 436−475) is loosely packed against it (Figure 12a). Functionally, the E3 ligase activity of AvrPtoBE3 is essential for its role in suppression of plant cell death and in promotion of P. syringae virulence.292 To add an extra level of complexity, AvrPtoB interacts with other host kinases besides Pto and BAK1. AvrPtoBPID interacts with Bti9/CERK1 in A. thaliana,157,293,294 but does not recognize the highly similar Fen kinase.291 The exact interaction domain responsible for the recognition of Fen and FLS2 remains unknown.295,296 Prediction of putative MoRFs using the MoRFPRED server16 indicated the presence of such elements in AvrPtoB. Interestingly, one of them (MoRFA: SGAYFVGHTD) is located outside the domains described to be involved in protein interaction (Figure 12a). This suggests that the interaction repertoire of AvrPtoB may even be wider. Structural information regarding the regions connecting the folded domains is not available for AvrPtoB, but it is for other member of the HopAB effector family, HopPmaL. HopPmaL is produced by P. syringae pathovar maculicola and lacks the Cterminal E3 ligase domain. X-ray crystallography and solution NMR revealed that HopPmaL harbors two domains that are structurally equivalent to AvrPtoBPID and AvrPtoBBID and which we denominate as HopPmaLPID (residues 140−217) and HopPmaLBID (residues 300−385), respectively (Figure 12b).297 Like in AvrPtoBPID, the interaction surface of HopPmaLPID (PDBID: 3TJY, 3SVI) is mostly composed of hydrophobic residues. Segments upstream and downstream of HopPmaLPID (residues 57−138 and 218−273) have been shown to be susceptible to proteolytic cleavage and are therefore most probably unstructured. The solution structures of the Cterminal region of HopPmaL (HopPmaLC: 281−385; PDBID: 2LF3) and the related P. syringae pathovar phaseolicola HopAB1Pph1448A (HopAB1C: 220−320; PDBID: 2LF6) show a well-ordered core highly similar to AvrPtoBBID. NMR signals obtained for residues 281−299 were typical of a flexible random coil region.297 The four C-terminal residues of the HopPmaLC fragment also appear to be disordered. Furthermore, the first

5.5. Intrinsic Disorder and Effector Evolution

Plant immune responsiveness is a complex continuum of coevolution. While pathogenic microbes constantly diversify their effector repertoire, plants evolve their perception and guard systems. This is the evolutionary basis for a continuous selection of novel pathogen isolates that can overcome immunity and new plant genotypes that can reconstitute it.125 ID proteins perfectly match these requirements as they often acquire more deletions, insertions, and repeat expansions and exhibit different single nucleotide polymorphism patterns.298 Therefore, they generally evolve faster and exhibit enhanced positive selection compared to ordered proteins.298,299 Furthermore, It has been proposed that disordered proteins exhibit less structural constrains, as they are less restricted with respect to intramolecular interactions.300 It is noteworthy that, despite these high rates of sequence evolution, some disordered proteins maintain their structural flexibility under physiological conditions indicating that even though mutations may be nonsynonymous a bias toward disorder-promoting residues can be observed.298 Such diversifying selection may be beneficial in the context of evasion of immune recognition or adaptation to new alleles of the host target. However, the extent of the diversifying selection on effector encoding genes might be constrained by the structure of the effector, which determines its function.

6. CONCLUSIONS Plants exhibit high phenotypic plasticity, which enables them to face variable environmental conditions. It has been estimated that intrinsic disorder is enriched in processes that underlie 6926

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phenotypic plasticity, such as signaling.34 Intrinsic disorder probably constitutes an additional aspect of this complex trait and its detailed investigation may help understanding the dynamics of phenotypic plasticity at a molecular level. One of the most intriguing systems, the interaction between plants and microbes, which is tightly controlled by a plethora of ID proteins has so far been neglected with respect to this structural feature. Plants are continuously exposed to a variety of beneficial and hazardous microbes, and they need to adapt their responses to these variable and complex stimuli. Structural flexibility of innate immune signaling proteins may therefore contribute to this adaptation at a molecular level. This is supported by in silico predictions of intrinsic disorder components of the plant immune system. Structural information on these proteins is comparably rare and mostly limited to folded regions. Disordered regions, however, often mediate protein−protein interactions and recently have been shown to allosterically modulate protein function.301,302 They may be key to understanding how signaling cascades can be fine-tuned at a molecular level and contribute to phenotypic plasticity from two angles: the pathogenic microbes and the host plant.

Thomas Ott studied Biology at the University of Gö ttingen (Germany). He did his Ph.D. at the Max-Planck-Institute of Molecular Plant Physiology in Golm (Germany) in the group of Professor Michael Udvardi (now Samuel Roberts Noble Foundation, Ardmore, OK, United States) on functional genomics of nodulins in the model legume Lotus japonicus. For his postdoc time he obtained a MarieCurie Intra-European Fellowship of the European Union to study the function of a remorin protein during root-nodule symbiosis at the INRA-CNRS institute “Laboratoire des Interactions Plantes Microorganismes (LIPM)” in Toulouse (France). He was then appointed to the University of Munich (LMU) as principal investigator. Since 2009 he has been the head of an independent research group funded by the Emmy-Noether programme of the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG).

AUTHOR INFORMATION Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

ACKNOWLEDGMENTS We would like to thank Dagmar Hann for critically reading the manuscript. Financial support was provided by the Collaborative Research Center (Sonderforschungsbereich) SFB924 and the Emmy Noether program (Grant OT423/2-1) funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG).

Funding Notes

The authors declare no competing financial interest. Biographies

ABBREVIATIONS BAK1 BRI1 associated kinase 1 bHLH basic helix−loop−helix bZIP basic region/leucine zipper CC coiled-coil CD circular dichroism COR cold regulated cpSRP43 chloroplast signal recognition particle CRY1 cryptochrome-1 EFR EF-Tu receptor ETI effector-triggered immunity ETS effector-triggered susceptibility FLS2 flagellin-sensing 2 FT-IR Fourier transform infrared spectroscopy GAPDH glyceraldehyde-3-phosphate dehydrogenase GRAS gibberellic acid insensitive (GAI), repressor of GAI (RGA) and scarecrow (SCR) HR hypersensitive response Hsp90 heat-shock protein 90 HY5 long hypocotyl 5 ID intrinsicaly disordered LEA late embryogenesis abundant MAMPs microbe-associated molecular patterns MAP mitogen activated protein MAPK MAP kinase

Macarena Marı ́n obtained her Ph.D. from the Technical University Braunschweig (Germany) in 2009 for her work in structural aspects of the catabolism of aromatic compounds under the supervision of Dr. Dietmar Pieper. She then moved to the Ludwig-Maximilians University in Munich for postdoctoral training in the group of Dr. Thomas Ott. Since then she has been developing a new research line studying intrinsic disorder in plant proteins and proteins from plantassociated bacteria. During her Ph.D. she received a scholarship from the international research training group “Pseudomonas: pathogenicity and biotechnology”. 6927

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MAP kinase kinase MAP kinase kinase kinase molecular recognition features manganese stabilizing protein nucleotide binding site leucine-rich repeat nuclear magnetic resonance pathogen-associated molecular patterns protein database pattern recognition receptors PAMP triggered immunity respiratory burst oxidase homologue radical-induced cell death 1 RPM1-interacting protein 4 RIN4-interacting receptor-like protein kinase receptor-like cytoplasmic kinases receptor-like kinase reactive oxygen species resistance proteins systemic acquired resistance short linear motifs teosinte branched1, cycloidea, proliferating cell nuclear factor 2,2,2-trifluoroethanol toll/interleukin-1 receptor type III secretion system

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dx.doi.org/10.1021/cr400488d | Chem. Rev. 2014, 114, 6912−6932