Evolutionarily conserved structural changes in phosphatidylinositol 5-phosphate 4-kinase (PI5P4K) isoforms are responsible for differences in enzyme activity and localisation

We describe here a detailed molecular exploration of human PI5P4Ks α, β and γ, as well as their fly and worm homologs, 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 homologs from C. elegans and D. 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 heterodimerisation, and not a higher oligomer association of homodimers. We reveal that structural modeling is consistent with this and with the apparently random heterodimerisation that we had earlier observed between PI5P4Kα and beta (Wang, Bond, Letcher, Richardson, Lilley, Irvine and Clarke, 2010, Biochemical Journal 430, 215-221). Overall the molecular diversity of mammalian PI5P4Ks explains much of their properties and behaviour, but their physiological functionality remains elusive.

Source: BJ Cell - June 12, 2013 Category: Biochemistry Authors: J H Clarke, R F Irvine Tags: BJ Signal Source Type: research