The PI(3,5)P2 regulatory complex regulates both the synthesis and turnover of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2). It catalyzes the phosphorylation of phosphatidylinositol 3-phosphate on the fifth hydroxyl of the myo-inositol ring, to form phosphatidylinositol 3,5-bisphosphate. The dynamic interconversion of PI3P and PI(3,5)P2 is regulated by a protein complex which is conserved from yeast to mammals. It includes at least five proteins in yeast, located in the vacuole membrane: the lipid kinase Fab1p, lipid phosphatase Fig4p, the Fab1p activator Vac7p, the Fab1p inhibitor Atg18p, and Vac14p. Homologues of Fab1p, Vac14p and Fig4p are found in all eukaryotes which in mammalian cells, are known as Fab1/PIKfyve/PIP5K3, Fig4/Sac3, and Vac14/ArPIKfyve, located on early and late endosomes. Fab1, Vac14, and Fig4 form a ternary complex where Fab1 lipid kinase and Fig4 lipid phosphatase bind to opposite ends of Vac14. A conformational change of Vac14 allows a quick effect on kinase and phosphatase activities. This complex is required for endocytic-vacuolar pathway and nuclear migration. It plays a role in the biogenesis of endosome carrier vesicles (ECV)/ multivesicular bodies (MVB) transport intermediates from early endosomes in mammals, being essential for nervous tissue function. It has been shown that alterations in this complex leads to reduced intracellular levels of PI(3,5)P2, cytoplasmic vacuolisation and neurodegeneration [, ].This entry represents the 1-phosphatidylinositol-3phosphate-5-kinase (PIKfyve) found in eukaryotes.
PIKfyve catalyzes the phosphorylation of phosphatidylinositol 3-phosphate on the fifth hydroxyl of the myo-inositol ring, to form phosphatidylinositol 3,5-bisphosphate []. It is part of the PI(3,5)P2 regulatory complex that regulates both the synthesis and turnover of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2) []. PIKfyve contains N-terminal Fyve finger and DEP domains, a central chaperonin-like domain and a C-terminal PIPK (phosphatidylinositol phosphate kinase) domain.
Vac14 is a component of the PI(3,5)P2 regulatory complex, which regulates both the synthesis and turnover of phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) []. This complex is composed of Atg18, Fig4, Fab1, Vac14 and Vac7 in yeast. In mammals it consists of PIKfyve, FIG4 and VAC14. Fab1/PIKfyve (Fab1 in yeast and PIKfyve in mammals) is a kinase that converts PI(3)P into PI(3,5)P2 by phosphorylation at the 5-position; conversely Fig4 dephosphorylates PI(3,5)P2 back to PI(3)P. Vac14 is a scaffolding adaptor protein whose multimerisation is a prerequisite step for PI(3,5)P2 complex assembly and function [].
This entry represents the C-terminal catalytic lipid kinase domain related to PtdInsP kinases (PIPKc domain) found in PIKfyve and related proteins.1-phosphatidylinositol-3-phosphate 5-kinase (), also called FYVE finger-containing phosphoinositide kinase (PIKfyve), forms a complex with its regulators, the scaffolding protein Vac14 and the lipid phosphatase Fig4. The complex synthesises phosphatidylinositol 3,5-bisphosphate [PtdIns(3,5)P2]through the phosphorylation of phosphatidylinositol 3-phosphate (PtdIns3P or PI3P) on the fifth hydroxyl of the myo-inositol ring. Then phosphatidylinositol-5-phosphate (PtdIns5P) is generated directly from PtdIns(3,5)P2. PtdIns(3,5)P2 and PtdIns5P regulate endosomal trafficking and responses to extracellular stimuli []. It is vital in early embryonic development and plays a role in different pathways, such as receptor tyrosine kinase (RTK) or EGFR degradation, regulation of the glutamate transporters EAAT2, EAAT3 and EAAT4 and the cystic fibrosis transmembrane conductance regulator (CFTR). It is also essential for systemic glucose homeostasis and insulin-regulated glucose uptake/GLUT4 translocation in skeletal muscle [, , ].The yeast orthologue of human PIKfyve, Fab1, is required for endocytic-vacuolar pathway and nuclear migration [, ]. The plant orthologues such as FAB1A-D from Arabidopsis are important for the maintenance of endomembrane homeostasis and for development of viable pollen [, ].PIKfyve and its orthologues share a similar architecture consisting of a N-terminal FYVE domain, a middle region related to the CCT/TCP-1/Cpn60 chaperonins that are involved in productive folding of actin and tubulin, a second middle domain that contains a number of conserved cysteine residues (CCR) unique to these proteins, and a C-terminal catalytic lipid kinase domain related to PtdInsP kinases (or the PIPKc domain).
