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J Lipid Res. 2018 Nov 5. pii: jlr.R089490. doi: 10.1194/jlr.R089490. [Epub ahead of print]

VPS34 complexes from a structural perspective.

Author information

1
MRC Laboratory of Molecular Biology, United Kingdom.
2
MRC Laboratory of Molecular Biology, United Kingdom rlw@mrc-lmb.cam.ac.uk.

Abstract

VPS34 phosphorylates phosphatidylinositol to produce PtdIns3P and is the progenitor of the 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 ATG14L, 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 complexes I and II subunits. Lipid kinase activities of the complexes are also influenced by post-translational modifications (PTMs). Mapping PTMs and somatic mutations on three-dimensional models of the complexes suggests mechanisms for how these affect VPS34 activity.

KEYWORDS:

Autophagy; Electron microscopy; Endocytic sorting; Endocytosis; Lipid Kinases; Phosphatidylinositol 3-kinase; Phosphoinositides; Structural biology; VPS34; X-ray crystallography

PMID:
30397185
DOI:
10.1194/jlr.R089490
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