Redefining pseudokinases: A look at the untapped enzymatic potential of pseudokinases

Pon, Alex D.; Osinski, Adam; Sreelatha, Anju

doi:10.1002/iub.2698

Cited by 3 publications

(2 citation statements)

References 53 publications

(119 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The discovery of pseudokinases presents another layer of complexity in identifying effector kinases and their substrates, due to these effectors being characterized as catalytically inactive in protein phosphorylation, but with structural or sequence homology to known kinases (Poh et al, 2008). For example, Pseudomonas syringae SelO shares structural and folding homology with eukaryotic kinases, but has been shown to catalyze AMPylation (Sreelatha et al, 2018;Pon et al, 2023). SidJ and SelO, among other microbial proteins, demonstrate that sequence or structural homology is not sufficient to categorize effectors as kinases, and their biochemical activity must be experimentally tested.…”

Section: Discussionmentioning

confidence: 99%

Bacterial effector kinases and strategies to identify their target host substrates

Louis

Quagliato²,

Lee³

2023

Front. Microbiol.

View full text Add to dashboard Cite

Post-translational modifications (PTMs) are critical in regulating protein function by altering chemical characteristics of proteins. Phosphorylation is an integral PTM, catalyzed by kinases and reversibly removed by phosphatases, that modulates many cellular processes in response to stimuli in all living organisms. Consequently, bacterial pathogens have evolved to secrete effectors capable of manipulating host phosphorylation pathways as a common infection strategy. Given the importance of protein phosphorylation in infection, recent advances in sequence and structural homology search have significantly expanded the discovery of a multitude of bacterial effectors with kinase activity in pathogenic bacteria. Although challenges exist due to complexity of phosphorylation networks in host cells and transient interactions between kinases and substrates, approaches are continuously being developed and applied to identify bacterial effector kinases and their host substrates. In this review, we illustrate the importance of exploiting phosphorylation in host cells by bacterial pathogens via the action of effector kinases and how these effector kinases contribute to virulence through the manipulation of diverse host signaling pathways. We also highlight recent developments in the identification of bacterial effector kinases and a variety of techniques to characterize kinase-substrate interactions in host cells. Identification of host substrates provides new insights for regulation of host signaling during microbial infection and may serve as foundation for developing interventions to treat infection by blocking the activity of secreted effector kinases.

show abstract

Section: Discussionmentioning

confidence: 99%

Bacterial effector kinases and strategies to identify their target host substrates

Louis

Quagliato²,

Lee³

2023

Front. Microbiol.

View full text Add to dashboard Cite

show abstract

“…Notably, the NIRAN domain of coronavirus protein nsp12, which harbors sequence similarity to SelO, catalyzes RNAylation [ 35–37 ]. These alternative transferase activities have been extensively reviewed in [ 38 ]. As demonstrated in the above studies, intact mass analysis of the substrates is a powerful technique for identifying unexpected and novel post-translational modifications catalyzed by pseudoenzymes.…”

Section: Pseudokinasesmentioning

confidence: 99%

Emerging functions of pseudoenzymes

Goldberg

Sreelatha

2023

Biochemical Journal

Self Cite

View full text Add to dashboard Cite

As sequence and structural databases grow along with powerful analysis tools, the prevalence and diversity of pseudoenzymes have become increasingly evident. Pseudoenzymes are present across the tree of life in a large number of enzyme families. Pseudoenzymes are defined as proteins that lack conserved catalytic motifs based on sequence analysis. However, some pseudoenzymes may have migrated amino acids necessary for catalysis, allowing them to catalyze enzymatic reactions. Furthermore, pseudoenzymes retain several non-enzymatic functions such as allosteric regulation, signal integration, scaffolding, and competitive inhibition. In this review, we provide examples of each mode of action using the pseudokinase, pseudophosphatase, and pseudo ADP-ribosyltransferase families. We highlight the methodologies that facilitate the biochemical and functional characterization of pseudoenzymes to encourage further investigation in this burgeoning field.

show abstract