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Structural Analysis of Hippocampal Kinase Signal Transduction.

ABSTRACT: Kinases are a major clinical target for human diseases. Identifying the proteins that interact with kinases in vivo will provide information on unreported substrates and will potentially lead to more specific methods for therapeutic kinase regulation. Here, endogenous immunoprecipitations of evolutionally distinct kinases (i.e., Akt, ERK2, and CAMK2) from rodent hippocampi were analyzed by mass spectrometry to generate three highly confident kinase protein-protein interaction networks. Proteins of similar function were identified in the networks, suggesting a universal model for kinase signaling complexes. Protein interactions were observed between kinases with reported symbiotic relationships. The kinase networks were significantly enriched in genes associated with specific neurodevelopmental disorders providing novel structural connections between these disease-associated genes. To demonstrate a functional relationship between the kinases and the network, pharmacological manipulation of Akt in hippocampal slices was shown to regulate the activity of potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel(HCN1), which was identified in the Akt network. Overall, the kinase protein-protein interaction networks provide molecular insight of the spatial complexity of in vivo kinase signal transduction which is required to achieve the therapeutic potential of kinase manipulation in the brain.

SUBMITTER: McClatchy DB

PROVIDER: S-EPMC6374210 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Structural Analysis of Hippocampal Kinase Signal Transduction

Project description:Kinases are a major clinical target for human diseases. Identifying the proteins that interact with kinases in vivo will provide information on unreported substrates and will potentially lead to more specific methods for therapeutic kinase regulation. Here, endogenous immunoprecipitations of evolutionally distinct kinases (i.e. Akt, ERK2, and CAMK2) from rodent hippocampi were analyzed by mass spectrometry to generate three highly confident kinase protein-protein interaction networks. Proteins of similar function were identified in the networks, suggesting a universal model for kinase signaling complexes. Structural connections were observed between kinases with reported symbiotic relationships. The kinase networks were significantly enriched in genes associated with specific neurodevelopmental disorders providing novel structural connections between these disease-associated genes. To demonstrate a functional relationship between the kinases and its network, pharmacological manipulation of Akt in hippocampal slices was shown to regulates the activity of potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel(HCN1), which was identified in the Akt network. Overall, the kinase protein-protein interaction networks provide molecular insight of the spatial complexity of in vivo kinase signal transduction which is required to achieve the therapeutic potential of kinase manipulation in the brain.

2018-05-23 | MSV000082390 | MassIVE

Structural mechanism of signal transduction in a phytochrome histidine kinase.

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Structural Basis of Arrestin-Dependent Signal Transduction.

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Structural insight into the role of the PAS domainfor signal transduction in sensor-kinase BvgS.

Project description:The two-component system BvgAS controls the virulence regulon in Bordetella pertussis BvgS is the prototype of a family of sensor histidine-kinases harboring periplasmic Venus flytrap (VFT) domains. The VFT domains are connected to the cytoplasmic kinase moiety by helical linkers separated by a Per-ARNT-Sim (PAS) domain. Antagonism between the two linkers, as one forms a coiled coil when the other is dynamic and vice versa, regulates BvgS activity. Here we solved the structure of the intervening PAS domain by X-ray crystallography. Two forms were obtained that notably differ by the connections between the PAS core domain and the flanking helical linkers. Structure-guided mutagenesis indicated that those connections participate in the regulation of BvgS activity. The PAS domain thus appears to function as a switch-facilitator module whose conformation determines the output of the system. As many BvgS homologs have similar architectures, the mechanisms unveiled here are likely to generally apply to the regulation of sensor-histidine kinases of that family.IMPORTANCEThe whooping cough agent Bordetella pertussis colonizes the human respiratory tract using virulence factors co-regulated by the sensory transduction system BvgAS. BvgS is a model for a family of sensor-kinase proteins, some of which are found in important bacterial pathogens. BvgS functions as a kinase or a phosphatase depending on external signals, which determines if B. pertussis is virulent or avirulent. Deciphering its mode of action might thus lead to new ways of fighting infections. Here we used X-ray crystallography to solve the three-dimensional structure of the domain that precedes the enzymatic moiety and identified features that regulate BvgS activity. As many sensor-kinases of the BvgS family harbor homologous domains, the mechanism unveiled here might be of general relevance.

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Structural analysis of TIFA: Insight into TIFA-dependent signal transduction in innate immunity.

Project description:TRAF-interacting protein with a forkhead-associated (FHA) domain (TIFA), originally identified as an adaptor protein of TRAF6, has recently been shown to be involved in innate immunity, induced by a pathogen-associated molecular pattern (PAMP). ADP-?-D-manno-heptose, a newly identified PAMP, binds to alpha-kinase 1 (ALPK1) and activates its kinase activity to phosphorylate TIFA. Phosphorylation triggers TIFA oligomerisation and formation of a subsequent TIFA-TRAF6 oligomeric complex for ubiquitination of TRAF6, eventually leading to NF-?B activation. However, the structural basis of TIFA-dependent TRAF6 signalling, especially oligomer formation of the TIFA-TRAF6 complex remains unknown. In the present study, we determined the crystal structures of mouse TIFA and two TIFA mutants-Thr9 mutated to either Asp or Glu to mimic the phosphorylation state-to obtain the structural information for oligomer formation of the TIFA-TRAF6 complex. Crystal structures show the dimer formation of mouse TIFA to be similar to that of human TIFA, which was previously reported. This dimeric structure is consistent with the solution structure obtained from small angle X-ray scattering analysis. In addition to the structural analysis, we examined the molecular assembly of TIFA and the TIFA-TRAF6 complex by size-exclusion chromatography, and suggested a model for the TIFA-TRAF6 signalling complex.

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Reprogramming signal transduction through a designer receptor tyrosine kinase.

Project description:Controlling signal transduction with artificial designer receptors is a promising approach to realize future medicine for intractable diseases. Although several functional artificial receptors have been reported by domain engineering, more sophisticated engineering within domains has yet to be thoroughly investigated. Here we demonstrate motif-based engineering of a receptor tyrosine kinase for reprogramming signal transduction. We design a scaffold-less tyrosine kinase domain that does not recruit any signal transducers but retains its kinase function. The resultant scaffold-less tyrosine kinase domain is linked to a tyrosine motif that recruits a target signaling molecule upon its phosphorylation. The engineered tyrosine motif-kinase fusion protein is further connected to a small molecule- or light-dependent dimerizing domain that can switch on the kinase activity in response to an external stimulus. The resultant designer receptors attain specific chemical- or photo-activation of signaling molecules of interest in mammalian cells. Thus, our designer receptor tyrosine kinase proves the possibility of rationally reprogramming intracellular signal transduction on a motif basis. The motif-based receptor engineering may realize tailor-made functional receptors useful in the fields of biology and medicine.

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The role of the OX1 protein kinase in H2O2 signal transduction

Project description:Expression of the OX1 gene coding for a putative protein kinase was shown to be induced in Arabidopsis thaliana ecotypes Col-0, WS and RLD seedlings by treatment with H2O2 superoxidecolddroughtsalt and cellulase (elicitor). All of these treatments will ultimately lead to production of H2O2 either as a secondary effect of the applied stress through disturbance of electron transport processes or as a direct product of the plant NADPH oxidases (oxidative burst). However the sets of protective genes switched on (end-responses) will differ depending on the original stress. The induction characteristics of OX1 point to a role of this kinase in signal transduction downstream of H2O2; however it is not clear which primary signal is relayed. OX1 may function in the perception of oxidative stress caused by all/any one of the environmental stresses and/or it may be important in signalling downstream of the oxidative burst triggered by pathogen infection and wounding. An OX1 knock-out was isolated from the Wisconsin T-DNA lines with an insertion between the first and second conserved kinase domains rendering the protein product non-functional. Aim of the microarray experiment is to compare gene induction in the homozygous knock-out line to that in the wild-type (ecotype WS) following H2O2 treatment. To this end 7 day-old seedlings will be immersed in 10 mM solution for 1 h. Analysis of differences in expression of genes belonging to a certain end-response will disclose the signalling pathway which OX1 functions in. This is necessary for further planned experiments e.g. analysis of inducible OX1 antisense and constitutive lines as well as kinase activity assays.

2003-10-21 | E-NASC-5 | biostudies-arrayexpress

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