Research SummarySenior Fellowship research summary
The inositol pyrophosphates, diphosphoinositol pentakisphosphate (PP-IP5 or IP7) and bisdiphosphoinositol tetrakisphosphate ([PP]2-IP4 or IP8), are a class of eukaryotic molecules consisting of an inositol backbone, monophosphate, and pyrophosphate moieties.
They are implicated in diverse biological functions, including growth, vesicle trafficking, apoptosis, insulin secretion and spermatogenesis. We have demonstrated that the beta phosphate group of inositol pyrophosphates can be transferred to pre-phosphorylated serine residues on proteins to form pyrophosphoserine. This novel modification, pyrophosphorylation, occurs on several proteins within the cell, including those involved in ribosome biogenesis and vesicle trafficking. IP7 is synthesised from inositol hexakisphosphate (IP6) by IP6 kinases, and IP7 kinases convert IP7 to IP8. Our research proposal outlines a comprehensive strategy to examine the biochemical links between protein pyrophosphorylation and cellular phenomena regulated by inositol pyrophosphates.
We are developing assays to measure inositol pyrophosphates, and reagents that recognise pyrophosphorylated proteins. Utilising S. cerevisiae strains and mammalian cell lines with altered levels of inositol pyrophosphates as model systems, we are performing array-based screens to understand the signalling pathways in which inositol pyrophosphates participate. We are also conducting detailed investigations of the biochemical processes whereby inositol pyrophosphates and protein pyrophosphorylation regulate particular cellular phenomena, such as vesicle trafficking and ribosome synthesis.
Figure Legend: Figure 1: Star-struck! The image depicts two migrating wild type mouse embryonic fibroblasts (MEFs) in the lower left corner, displaying numerous lamellipodial protrusions, and three IP6K1 knockout MEFs predominantly displaying filopodial protrusions, giving a distinct stellate appearance to the migrating cells. Figure 2: Protein pyrophosphorylation. The inositol pyrophosphate IP7 can transfer its beta phosphate moiety to pre-phosphorylated serine residues on proteins to generate pyrophosphoserine.