Structural basis for the conserved roles of PI4KA and its regulatory partners and their misregulation in disease

Abstract

The type III Phosphatidylinositol 4-kinase alpha (PI4KA) is an essential lipid kinase that is a master regulator of phosphoinositide signalling at the plasma membrane (PM). It produces the predominant pool of phosphatidylinositol 4-phosphate (PI4P) at the PM, with this being essential in lipid transport and in regulating the PLC and PI3K signalling pathways. PI4KA is essential and is highly conserved in all eukaryotes. In yeast, the PI4KA ortholog stt4 predominantly exists as a heterodimer with its regulatory partner ypp1. In higher eukaryotes, PI4KA instead primarily forms a heterotrimer with a TTC7 subunit (ortholog of ypp1) and a FAM126 subunit. In all eukaryotes PI4KA is recruited to the plasma membrane by the protein EFR3, which does not directly bind PI4KA, but instead binds to the TTC7/ypp1 regulatory partner. Misregulation in PI4KA or its regulatory partners is involved in myriad human diseases, including loss of function mutations in neurodevelopmental and inflammatory intestinal disorders and gain of function in human cancers. This review describes an in-depth analysis of the structure function of PI4KA and its regulatory partners, with a major focus on comparing and contrasting the differences in regulation of PI4KA throughout evolution.