scholarly journals Activation mechanism of a small prototypic Rec-GGDEF diguanylate cyclase

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Raphael D. Teixeira ◽  
Fabian Holzschuh ◽  
Tilman Schirmer
Keyword(s):  
Sensory Input ◽  
Coiled Coil ◽  
Activation Mechanism ◽  
Diguanylate Cyclase ◽  
Histidine Kinases ◽  
Diguanylate Cyclases ◽  
Component Systems ◽  
Switch Mechanism ◽  
Two Component Systems ◽  
Ggdef Domain

AbstractDiguanylate cyclases synthesising the bacterial second messenger c-di-GMP are found to be regulated by a variety of sensory input domains that control the activity of their catalytical GGDEF domain, but how activation proceeds mechanistically is, apart from a few examples, still largely unknown. As part of two-component systems, they are activated by cognate histidine kinases that phosphorylate their Rec input domains. DgcR from Leptospira biflexa is a constitutively dimeric prototype of this class of diguanylate cyclases. Full-length crystal structures reveal that BeF3- pseudo-phosphorylation induces a relative rotation of two rigid halves in the Rec domain. This is coupled to a reorganisation of the dimeric structure with concomitant switching of the coiled-coil linker to an alternative heptad register. Finally, the activated register allows the two substrate-loaded GGDEF domains, which are linked to the end of the coiled-coil via a localised hinge, to move into a catalytically competent dimeric arrangement. Bioinformatic analyses suggest that the binary register switch mechanism is utilised by many diguanylate cyclases with N-terminal coiled-coil linkers.

scholarly journals Activation mechanism of a small prototypic Rec-GGDEF diguanylate cyclase

2020 ◽  
Author(s):  
Raphael D. Teixeira ◽  
Fabian Holzschuh ◽  
Tilman Schirmer
Keyword(s):  
Sensory Input ◽  
Coiled Coil ◽  
Activation Mechanism ◽  
Diguanylate Cyclase ◽  
Histidine Kinases ◽  
Diguanylate Cyclases ◽  
Component Systems ◽  
Switch Mechanism ◽  
Two Component Systems ◽  
Ggdef Domain

AbstractDiguanylate cyclases (DGCs) synthesising the bacterial second messenger c-di-GMP are found to be regulated by a variety of sensory input domains that control the activity of their catalytical GGDEF domain. As part of two-component systems, they are activated by cognate histidine kinases that phosphorylate their Rec input domains. DgcR from Leptospira biflexa is a constitutively dimeric prototype of this class of DGCs. Full-length crystal structures revealed that BeF3- pseudo-phosphorylation induces a relative rotation of two rigid halves in the Rec domain. This is coupled to a reorganisation of the dimeric structure with concomitant switching of the coiled-coil linker to an alternative heptad register. Finally, the activated register allows the two substrate-loaded GGDEF domains, which are linked to the end of the coiled-coil via a localised hinge, to move into a catalytically competent dimeric arrangement. Bioinformatic analyses suggest that the binary register switch mechanism is utilised by many DGCs with N-terminal coiled-coil linkers.

scholarly journals Conformational dynamics of the essential sensor histidine kinase WalK

2017 ◽  
Vol 73 (10) ◽  
pp. 793-803 ◽  
Author(s):  
Yongfei Cai ◽  
Mingyang Su ◽  
Ashfaq Ahmad ◽  
Xiaojie Hu ◽  
Jiayan Sang ◽  
...  
Keyword(s):  
Dynamic Properties ◽  
Conformational Dynamics ◽  
Bound State ◽  
Response Regulators ◽  
Histidine Kinases ◽  
Sequence Identity ◽  
Component Systems ◽  
Bacterial Signal Transduction ◽  
Two Component Systems ◽  
Intrinsic Dynamic

Two-component systems (TCSs) are key elements in bacterial signal transduction in response to environmental stresses. TCSs generally consist of sensor histidine kinases (SKs) and their cognate response regulators (RRs). Many SKs exhibit autokinase, phosphoryltransferase and phosphatase activities, which regulate RR activity through a phosphorylation and dephosphorylation cycle. However, how SKs perform different enzymatic activities is poorly understood. Here, several crystal structures of the minimal catalytic region of WalK, an essential SK fromLactobacillus plantarumthat shares 60% sequence identity with its homologue VicK fromStreptococcus mutans, are presented. WalK adopts an asymmetrical closed structure in the presence of ATP or ADP, in which one of the CA domains is positioned close to the DHp domain, thus leading both the β- and γ-phosphates of ATP/ADP to form hydrogen bonds to the ∊- but not the δ-nitrogen of the phosphorylatable histidine in the DHp domain. In addition, the DHp domain in the ATP/ADP-bound state has a 25.7° asymmetrical helical bending coordinated with the repositioning of the CA domain; these processes are mutually exclusive and alternate in response to helicity changes that are possibly regulated by upstream signals. In the absence of ATP or ADP, however, WalK adopts a completely symmetric open structure with its DHp domain centred between two outward-reaching CA domains. In summary, these structures of WalK reveal the intrinsic dynamic properties of an SK structure as a molecular basis for multifunctionality.

scholarly journals Blue Light Regulated Two-Component Systems: Enzymatic and Functional Analyses of Light-Oxygen-Voltage (LOV)-Histidine Kinases and Downstream Response Regulators

Biochemistry ◽  
2013 ◽  
Vol 52 (27) ◽  
pp. 4656-4666 ◽  
Author(s):  
Fernando Correa ◽  
Wen-Huang Ko ◽  
Victor Ocasio ◽  
Roberto A. Bogomolni ◽  
Kevin H. Gardner
Keyword(s):  
Blue Light ◽  
Response Regulators ◽  
Histidine Kinases ◽  
Component Systems ◽  
Two Component ◽  
Two Component Systems ◽  
Functional Analyses

scholarly journals A bacterial signal transduction phosphorelay in the methanogenic archaeon Methanosarcina acetivorans

2021 ◽  
Author(s):  
Nicole Frankenberg-Dinkel ◽  
Anne Sexauer
Keyword(s):  
Signal Transduction ◽  
Histidine Kinase ◽  
Environmental Changes ◽  
Methanosarcina Acetivorans ◽  
Histidine Kinases ◽  
C Terminus ◽  
Component Systems ◽  
Two Component Systems ◽  
Bacterial Type

Signal transduction via two-component systems is a powerful tool for microorganisms to respond to environmental changes. Histidine kinases originating from Bacteria are the most common signaling enzymes and are also present in Archaea, but not in all phyla. A total of 124 bacterial-type histidine kinases and/or regulators were identified in a screen of 149 Euryarchaeota genomes, but little is known about the signal transfer and molecular regulation of these systems. In this work, the hybrid kinase MA4377 from the methanogenic archaeon Methanosarcina acetivorans was investigated. MA4377 is a multidomain protein resembling a bacterial-type histidine kinase with two additional receiver domains at the C-terminus. Recombinant protein was employed to investigate the intra- and intermolecular phosphorelay in vitro. The kinase displays autophosphorylation activity of histidine residue 497. While no intramolecular phosphorelay was observed, the CheY-like receiver protein MA4376 was identified as part of the multi-component system that also seems to include the Msr-type transcription factor MA4375. This study reveals the presence and in vitro function of a bacterial-type hybrid histidine kinase integrated into an archaeal phosphorelay system.

scholarly journals Two-Component Systems of S. aureus: Signaling and Sensing Mechanisms

Genes ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 34
Author(s):  
Lisa Bleul ◽  
Patrice Francois ◽  
Christiane Wolz
Keyword(s):  
Transcriptional Activation ◽  
Drug Targets ◽  
Bacterial Survival ◽  
Histidine Kinases ◽  
Signal Perception ◽  
Signaling Mechanisms ◽  
Component Systems ◽  
Two Component ◽  
Two Component Systems ◽  
Sense And Respond

Staphylococcus aureus encodes 16 two-component systems (TCSs) that enable the bacteria to sense and respond to changing environmental conditions. Considering the function of these TCSs in bacterial survival and their potential role as drug targets, it is important to understand the exact mechanisms underlying signal perception. The differences between the sensing of appropriate signals and the transcriptional activation of the TCS system are often not well described, and the signaling mechanisms are only partially understood. Here, we review present insights into which signals are sensed by histidine kinases in S. aureus to promote appropriate gene expression in response to diverse environmental challenges.

scholarly journals Phosphatase activity of the histidine kinases ensures pathway specificity of the ChrSA and HrrSA two‐component systems in C orynebacterium glutamicum

2014 ◽  
Vol 92 (6) ◽  
pp. 1326-1342 ◽  
Author(s):  
Eva Hentschel ◽  
Christina Mack ◽  
Cornelia Gätgens ◽  
Michael Bott ◽  
Melanie Brocker ◽  
...  
Keyword(s):  
Phosphatase Activity ◽  
Histidine Kinases ◽  
Component Systems ◽  
Two Component ◽  
Two Component Systems

scholarly journals Accurate prediction of bacterial two-component signaling with a deep recurrent neural network ORAKLE

2019 ◽  
Author(s):  
Jan Balewski ◽  
Zachary F. Hallberg
Keyword(s):  
Neural Network ◽  
Amino Acid ◽  
Response Regulator ◽  
Amino Acid Sequences ◽  
Histidine Kinases ◽  
Deep Recurrent Neural Network ◽  
Component Systems ◽  
Two Component ◽  
Two Component Systems ◽  
Recommender Algorithm

AbstractTwo-component systems (2CS) are a primary method that bacteria use to detect and respond to environmental stimuli. Receptor histidine kinases (HK) detect an environmental signal, activating the appropriate response regulator (RR). Genes for such cognate HK-RR pairs are often located proximally on the chromosome, allowing easier identification of the target for a particular signal. However, almost half of all HK and RR proteins are orphans, with no nearby partner, complicating identification of the proteins that respond to a particular signal. To address this problem, we trained a neural network on the amino acid sequences of known 2CS pairs. Next, we developed a recommender algorithm that ranks a set of HKs for an arbitrary fixed RR and arbitrary species whose amino acid sequences are known. The recommender strongly favors known 2CS pairs, and correctly selects orphan pairs in Escherichia coli. We expect that use of these results will permit rapid discovery of orphan HK-RR pairs.

scholarly journals Regulation of signaling directionality revealed by 3D snapshots of a kinase:regulator complex in action

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Felipe Trajtenberg ◽  
Juan A Imelio ◽  
Matías R Machado ◽  
Nicole Larrieux ◽  
Marcelo A Marti ◽  
...  
Keyword(s):  
Bacillus Subtilis ◽  
Response Regulators ◽  
Histidine Kinases ◽  
Signaling Systems ◽  
Input Signals ◽  
Component Systems ◽  
Two Component ◽  
Two Component Systems ◽  
Conformational Rearrangements ◽  
Phosphoryl Groups

Two-component systems (TCS) are protein machineries that enable cells to respond to input signals. Histidine kinases (HK) are the sensory component, transferring information toward downstream response regulators (RR). HKs transfer phosphoryl groups to their specific RRs, but also dephosphorylate them, overall ensuring proper signaling. The mechanisms by which HKs discriminate between such disparate directions, are yet unknown. We now disclose crystal structures of the HK:RR complex DesK:DesR from Bacillus subtilis, comprising snapshots of the phosphotransfer and the dephosphorylation reactions. The HK dictates the reactional outcome through conformational rearrangements that include the reactive histidine. The phosphotransfer center is asymmetric, poised for dissociative nucleophilic substitution. The structural bases of HK phosphatase/phosphotransferase control are uncovered, and the unexpected discovery of a dissociative reactional center, sheds light on the evolution of TCS phosphotransfer reversibility. Our findings should be applicable to a broad range of signaling systems and instrumental in synthetic TCS rewiring.

scholarly journals Crystallographic snapshots of DesK and DesR: two component systems on the move

2014 ◽  
Vol 70 (a1) ◽  
pp. C1050-C1050
Author(s):  
Felipe Trajtenberg ◽  
Daniela Albanesi ◽  
Horacio Botti ◽  
Ariel Mechaly ◽  
Nicole Larrieux ◽  
...  
Keyword(s):  
Response Regulator ◽  
Full Length ◽  
Activation Mechanism ◽  
Integral Model ◽  
Allosteric Control ◽  
Receiver Domain ◽  
Activated State ◽  
Component Systems ◽  
Two Component ◽  
Two Component Systems

Two-component systems (TCSs) are key players in bacterial signaling, to better understand signal-transmission with molecular detail. The TCS DesK/DesR controls fatty acid desaturation in Bacillus subtilis in response to cold shock and other membrane-altering effectors. We had previously put forward a model of signal-dependent allosteric control of the sensor kinase catalytic activity [1,2]. We have now turned our attention to the response regulator DesR. A canonical activation pathway has been widely accepted to explain phosphorylation-mediated control of response regulator function, allosterically coupling the phosphorylation site to the α4β5α5 surface. However, the structural evidence supporting the main hypotheses is still highly fragmentary. We are now reporting the crystal structure of full-length DesR, in complex with a phosphoryl-mimetic, showing the activated state [3]. Several crystal forms of the receiver domain were determined in the active and inactive configurations, revealing molecular details of the activation switch. Comparative small angle X ray scattering of full-length constructs, structure-guided point mutagenesis, as well as in vitro and in vivo functional analyses, allow us to propose an integral model of DesR activation. The phosphorylation of the receiver domain is allosterically coupled not to one, but two exposed surfaces, independently controlling its dimerization and tetramerization. Notably, a novel surface is shown to be essential for a non-canonical dimerization and activation mechanism. Direct coupling analysis highlights this interface as a shared feature of all NarL/LuxR regulators. This surface is further involved in cognate histidine kinase binding, disclosing a novel view of response regulator allosteric control. With the data we are now reporting, the DesK/DesR signaling pathway becomes, to the best of our knowledge, one of the most thoroughly studied examples of a thermosensor TCS at the molecular and biological levels.

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