Abstract
VPS34 phosphorylates phosphatidylinositol to produce PtdIns3P and is the progenitor of the phosphoinositide 3-kinase (PI3K) family. VPS34 has a simpler domain organization than class I PI3Ks, which belies the complexity of its quaternary organization, with the enzyme always functioning within larger assemblies. PtdIns3P recruits specific recognition modules that are common in protein-sorting pathways, such as autophagy and endocytic sorting. It is best characterized in two heterotetramers, complexes I and II. Complex I is composed of VPS34, VPS15, Beclin 1, and autophagy-related gene (ATG)14L, whereas complex II replaces ATG14L with UVRAG. Because VPS34 can form a component of several distinct complexes, it enables independent regulation of various pathways that are controlled by PtdIns3P. Complexes I and II are critical for early events in autophagy and endocytic sorting, respectively. Autophagy has a complex association with cancer. In early stages, it inhibits tumorigenesis, but in later stages, it acts as a survival factor for tumors. Recently, various disease-associated somatic mutations were found in genes encoding complex I and II subunits. Lipid kinase activities of the complexes are also influenced by posttranslational modifications (PTMs). Mapping PTMs and somatic mutations on three-dimensional models of the complexes suggests mechanisms for how these affect VPS34 activity.
Highlights
CORE ARCHITECTURE OF COMPLEXES I AND IIComplexes I and II are 1:1:1:1 heterotetramers, as shown by multi-angle light scattering, the X-ray crystal structure of complex II, and the cryo-EM structures of complexes I and II [2, 3, 17, 18]
VPS34 phosphorylates phosphatidylinositol to produce PtdIns3P and is the progenitor of the phosphoinositide 3-kinase (PI3K) family
Complex I is composed of VPS34 (PIK3C3), VPS15 (p150, PIK3R4), Beclin 1, and ATG14L, whereas complex II has UV irradiation resistance-associated gene (UVRAG) instead of ATG14L (Fig. 1A)
Summary
Complexes I and II are 1:1:1:1 heterotetramers, as shown by multi-angle light scattering, the X-ray crystal structure of complex II, and the cryo-EM structures of complexes I and II [2, 3, 17, 18]. A study of the human complexes I and II by HDX-MS and electron microscopy suggested that the VPS34 kinase domain does not tightly associate with the VPS15 pseudokinase domain when the enzyme is active [5]. A cryo-EM analysis of the orientations of complexes I and II on lipid monolayers suggested that what the authors referred to as the VPS34 C-terminal domain (which was a module consisting of most of the helical domain and the kinase domain) determines the orientation of the complex on lipid membranes, but contributes little to the affinity for membranes Understanding this mutation will require a definitive analysis of the orientation of the enzyme on intact lipid bilayers. The active site of VPS34 is somewhat narrower than the class IA PI3Ks [1] These compounds target the hydrophobic region of the kinase domain ATP binding pocket (Fig. 3B, C).
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