An evolutionary-conserved redox regulatory mechanism in human Ser/Thr protein kinases

Byrne, Dominic P.; Shrestha, Safal; Kannan, Natarajan; Eyers, Patrick A.

doi:10.1101/571844

Cited by 2 publications

(2 citation statements)

References 139 publications

(143 reference statements)

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“…This Thr residue is common amongst canonical CAMKs, and the additional P + 1 loop Thr and Tyr amino acids are also conserved in PSKH2. A Cys residue is also found two amino acids C‐terminal to the potential phosphorylated Thr in primate PSKH2; this conserved residue is present in most other CAMKs and AGC kinases , but is absent in Eph and TRIB pseudokinases. Ser241 is specific to PSKH2, since PSKH1 conserves mostly an Asn, or sometimes Glu or Cys, at this position.…”

Section: Evaluating the Underexplored And ‘Dark’ Pseudokinomementioning

confidence: 99%

Cataloguing the dead: breathing new life into pseudokinase research

et al. 2020

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Pseudoenzymes are present within many, but not all, known enzyme families and lack one or more conserved canonical amino acids that help define their catalytically active counterparts. Recent findings in the pseudokinase field confirm that evolutionary repurposing of the structurally defined bilobal protein kinase fold permits distinct biological functions to emerge, many of which rely on conformational switching, as opposed to canonical catalysis. In this analysis, we evaluate progress in evaluating several members of the 'dark' pseudokinome that are pertinent to help drive this expanding field. Initially, we discuss how adaptions in erythropoietin-producing hepatocellular carcinoma (Eph) receptor tyrosine kinase domains resulted in two vertebrate pseudokinases, EphA10 and EphB6, in which co-evolving sequences generate new motifs that are likely to be important for both nucleotide binding and catalysis-independent signalling. Secondly, we discuss how conformationally flexible Tribbles pseudokinases, which have radiated in the complex vertebrates, control fundamental aspects of cell signalling that may be targetable with covalent small molecules. Finally, we show how species-level adaptions in the duplicated canonical kinase protein serine kinase histone (PSKH)1 sequence have led to the appearance of the pseudokinase PSKH2, whose physiological role remains mysterious. In conclusion, we show how the patterns we discover are selectively conserved within specific pseudokinases, and that when they are modelled alongside closely related canonical kinases, many are found to be located in functionally important regions of the conserved kinase fold. Interrogation of these patterns will be useful for future evaluation of these, and other, members of the unstudied human kinome.

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Section: Evaluating the Underexplored And ‘Dark’ Pseudokinomementioning

confidence: 99%

Cataloguing the dead: breathing new life into pseudokinase research

et al. 2020

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“…In particular, the extended activation segment connecting the ATP and substrate binding lobes that classically controls catalytic activity through conformational changes driven by reversible phosphorylation of serine, threonine and tyrosine residues (27) is unique to ePKs and absent in small molecule kinases, including FN3Ks. An accompanying paper submitted side-by-side with this manuscript demonstrates that in addition to reversible phosphorylation, oxidation and reduction of a conserved Cys residue in the activation segment is a much more common mode of Ser/Thr protein kinase regulation than had been previously appreciated (28).…”

Section: Introductionmentioning

confidence: 79%

A novel redox-active switch in Fructosamine-3-kinases expands the regulatory repertoire of the protein kinase superfamily

Shrestha

Katiyar

Sanz-Rodriguez

et al. 2020

Preprint

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words)Aberrant regulation of metabolic kinases by altered redox homeostasis is a major contributing factor in aging and disease such as diabetes. However, the biochemical mechanisms by which metabolic kinases are regulated under oxidative stress is poorly understood. In this study, we demonstrate that the catalytic activity of a conserved family of Fructosamine-3-kinases (FN3Ks), which are evolutionarily related to eukaryotic protein kinases (ePKs), are regulated by redox active cysteines in the kinase domain. By solving the crystal structure of FN3K homolog from Arabidopsis thaliana (AtFN3K), we demonstrate that it forms an unexpected strandexchange dimer in which the ATP binding P-loop and adjoining beta strands are swapped between two chains in the dimer. This dimeric configuration is characterized by strained inter-chain disulfide bonds that stabilize the P-loop in an extended conformation and tethers the substratebinding lobes in a unique inactive conformation. Mutational analysis and solution studies confirm that the strained disulfides function as redox "switches" to reversibly regulate FN3K activity and dimerization. Consistently, we find that human FN3K, which contains an equivalent P-loop Cys, is also redox sensitive, whereas ancestral bacterial FN3K homologs, which lack a P-loop Cys, are not. Furthermore, CRISPR knockout of FN3K in human HepG2 cells results in significant upregulation of redox metabolites including glutathione. We propose that redox regulation evolved progressively in FN3Ks in response to changing cellular redox conditions. Our studies provide important new insights into the origin and evolution of redox regulation in the protein kinase superfamily and open new avenues for targeting human FN3K in diabetic complications.

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An evolutionary-conserved redox regulatory mechanism in human Ser/Thr protein kinases

Cited by 2 publications

References 139 publications

Cataloguing the dead: breathing new life into pseudokinase research

Cataloguing the dead: breathing new life into pseudokinase research

A novel redox-active switch in Fructosamine-3-kinases expands the regulatory repertoire of the protein kinase superfamily

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