Evolutionarily conserved structural changes in phosphatidylinositol 5-phosphate 4-kinase (PI5P4K) isoforms are responsible for differences in enzyme activity and localization
By J. Clarke, R. Irvine. 2013
62 citations recorded by the source corpus.
Mammals have genes coding for three PI5P4Ks (PtdIns5P 4-kinases), and these have different cellular localizations, tissue distributions and lipid kinase activities. We describe in the present paper a detailed molecular exploration of human PI5P4Ks α, β and γ, as well as their fly and worm homologues, to understand how and why these differences came to be. The intrinsic ATPase activities of the three isoforms are very similar, and we show that differences in their G-loop regions can account for much of their wide differences in lipid kinase activity. We have also undertaken an extensive in silico evolutionary study of the PI5P4K family, and show experimentally that the single PI5P4K homologues from Caenorhabditis elegans and Drosophila melanogaster are as widely different in activity as the most divergent mammalian isoforms. Finally we show that the close association of PI5P4Ks α and γ is a true heterodimerization, and not a higher oligomer association of homodimers. We reveal that structural modelling is consistent with this and with the apparently random heterodimerization that we had earlier observed between PI5P4Kα and PI5P4Kβ [Wang, Bond, Letcher, Richardson, Lilley, Irvine and Clarke (2010), Biochem. J. 430, 215–221]. Overall the molecular diversity of mammalian PI5P4Ks explains much of their properties and behaviour, but their physiological functionality remains elusive.
Subfields: Cell Biology, Epidemiology, Molecular Biology
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Citations in the corpus
- PIP4Ks Suppress Insulin Signaling through a Catalytic-Independent Mechanism (2018, unknown): “For instance, PIP4K α (PIP4K2A) has 1,000-fold higher activity than PIP4K γ (PIP4K2C), which is considered near-enzy-matically dead (Clarke and Irvine, 2013).”
- Inhibition of PIP4Kγ ameliorates the pathological effects of mutant huntingtin protein (2017, methodology): “PIP4Kg (1 mM, [Clarke and Irvine, 2013]) was pre-incu- bated (10 min on ice) at range of inhibitor concentrations and assayed with ATP substrate (100 mM ATP, 60 min incubation at 22˚C) in the absence of lipid substrate.”
- The lipid kinase PI5P4Kβ is an intracellular GTP sensor for metabolism and tumorigenesis (2016, unknown): “The kinase activity of PI5P4Ka is reported to be 100-fold higher than that of PI5P4Kb and 2,000-fold higher than that of PI5P4Kg; therefore, it has been considered that PI5P4Ka has a dominant role in cells and PI5P4Kb and PI5P4Kg may act as scaffolds to recruit PI5P4Ka by heterodimerization (Bultsma”