binding site structure, a single conserved residue I670 of VPS34 and L2129 of PI3-K-related protein MEC1, termed the gatekeeper, controls the sensitivity to a wide range of small molecule inhibitors, inhibitor resistance id conferred by a large resiude at this position, e.g. isoleucine, whereas a small amino acid at this position like alanine, glycine, or threonine renders the enzyme sensitive for inhibition by small molecule drugs
vacuolar protein sorting 34 (Vps34) is a member of the phosphoinositide 3-kinase (PI3K) family of lipid kinases. Vps34 and its functions are highly conserved from yeast to mammals. The domain organization of Vps34 and Vps15 are highly conserved between yeast and humans
the deletion of Vps34, Vps15 or Vps30 affects both autophagy and vacuolar protein sorting. The deletion of Vps34 or Vps15 results in a reduced mRNA production from G + C-rich coding sequences (CDS). Vps34 and Vps15 can enhance the efficiency of transcription elongation based on their physical proximity to nuclear pores and transcribed chromatin
regulation by accessory proteins for Vps34 Complex I and II, and regulation of Vps34 complexes by phosphorylation during starvation, mechanisms, overview. In yeast, targeting of Vps34 to the pre-autophagosomal structure (PAS) requires Atg14 (although targeting of Vps15 to the PAS is Atg14-independent)
together with Vps34, Vps15 and Vps30 it forms the PIK3C3-Complex II, which is mainly found at endosomal membranes, modulation of PIK3C3 complex function through different subunit compositions, overview. The Vps15 kinase domain intercts with the Vps34 activation loop, which might regulate the activity of Vps34
PI3K-III (or PIK3C3) represents the most conserved PI3K class. It is the sole PI3K in yeast and plants. The catalytic subunit of the PI3K complex is Vps34, which exclusively utilizes PtdIns as substrate. It phosphorylates PtdIns at the 3-hydoxyl group of the inositol ring in order to generate PtdIns3P. Class III phosphatidylinositol 3-kinase Vps34 (vacuolar protein sorting 34) catalyzes for the formation of the signaling lipid phosphatidylinositol-3-phopsphate, which is a central factor in the regulation of autophagy, endocytic trafficking and vesicular transport. The Vps15 kinase domain interacts with the Vps34 activation loop, which might regulate the activity of Vps34. Regulation of Vps34 function by G-protein signaling. Vps34 and Vps15 act as suppressors of Gpa1 (Galpha)-mediated transcriptional responses involved in pheromone signaling. Direct link between trimeric G-proteins and Vps34p function in yeast
the Class III phosphoinositide 3-kinase Vps34 (vacuolar protein sorting 34) plays important roles in endocytic trafficking, macroautophagy, phagocytosis, cytokinesis and nutrient sensing. Vps34 acts in a complex with a probable pseudokinase, Vps15, and signals to downstream effectors through the production of phosphatidylinositol 3-phosphate (PI[3]P). This lipid supplies a binding site for proteins containing appropriate lipid-binding domains, e.g. FYVE [Fab1, YOTB, Vac1, EEA1 (early endosomal antigen 1)] and PX (Phox homology) domain. Vps34 is recruited by the binding of the WD40 domain of Vps15 to activated Rab5. Production of PI[3]P synergizes with Rab5 in the recruitment of EEA1 and Rabenosyn5 to drive endosomal tethering and fusion. Vps34-Vps15 also binds to Rab7 in late endosomess. Vps34 acts in tetrameric complexes containing Vps15, Beclin-1 and either Atg14 (Vps34 complex I) or UVRAG (Vps34 complex II). Vps34 acts by producing PI[3]P in intracellular membranes. Vps34 regulates the fusion and maturation of Rab5-positive early endosomes (EE) and their maturation into Rab7-positive late endosomes (LE). PI[3]P produced by Vps34 recruits the retromer complex, which mediates endosome to Golgi retrograde trafficking, and the ESCRT complex, which produces ILVs in multivesicular bodies (MVB). Vps34 is recruited to phagosomes after sealing to direct phagosomal maturation. It functions in the endoplasmic reticulum and in maturing autophagosomes, where it drives autophagosomal initiation and maturation. Vps34 is required for the function of the Retromer complex, which drives the retrograde trafficking of endocytic cargo to the Golgi. Mechanisms of Vps34 regulation, e.g. by phosphorylation under nutrient-replete conditions or during growth factor stimulation