Cataloguing the dead: breathing new life into pseudokinase research

Abstract

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.

The dead phosphatases society: a review of the emerging roles of pseudophosphatases

“…Understanding the origin of pseudophosphatases is more complicated than of pseudokinases [7]. The catalytic domains of protein kinases consist mostly of a single protein structural fold implying that they originated from an ancestral kinase [8].…”

Approaches to Manipulate Ephrin-A:EphA Forward Signaling Pathway

“…EphA10 diverges from the other member of the EphA family since it lacks kinase and docking properties. EphA10 is overexpressed in some cancer cells and its precise role in EphA signaling is still unclear [65,66].…”

Nucleotide binding, evolutionary insights and interaction partners of the pseudokinase Unc-51-like kinase 4

“…Pseudokinases are present in all major groups of the human kinome and across diverse species (Kwon et al, 2019). The structural features of pseudokinases are accordingly diverse, sharing many regulatory mechanisms observed in canonical kinases (Ha and Boggon, 2018;Jura et al, 2009;Patel et al, 2017;Scheeff et al, 2009;Shrestha et al, 2020;Zeqiraj et al, 2009b).…”