Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.3.5.1 (succinate dehydrogenase)
 8,177 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The family of phosphatidylinositols (PtdIns) plays essential roles in membrane identity and intracellular trafficking events. In animals and yeast, PtdIn-3-phosphate, which is particularly important for endosomal sorting, lysosomal/vacuolar transport and autophagy, is assembled by two conserved kinase complexes comprised of the catalytic VACUOLAR PROTEIN SORTING (VPS)-34 subunit, along with VPS15, AUTOPHAGY-RELATED (ATG)-6, and either ATG14 (complex I) or VPS38 (complex II). Here, we describe the Arabidopsis ortholog of VPS38 and show by interaction assays that it assembles into a tetrameric PtdIn-3 kinase complex II. Plants missing VPS38 are viable but have dampened pollen germination and heightened seed abortion, and display a dwarf rosette phenotype, with defects in leaf and vascular development and sucrose sensing. vps38 seeds accumulate irregular protein storage vesicles and suppress processing of storage proteins into their mature forms. Consistent with a role for PtdIn-3-phosphate in autophagy, vps38 mutants are hypersensitive to nitrogen and fixed-carbon starvation and show reduced autophagic transport of cargo into vacuoles. vps38 seedlings also have dampened root gravitropism, which is underpinned by aberrant vectoral auxin transport likely caused by defects in plasma membrane/endosome cycling of the PIN-FORMED family of auxin transporters necessary for asymmetric cell elongation. Collectively, this study places VPS38 and its class-III PtdIn-3 kinase complex at the nexus of numerous endosomal trafficking events important to plant growth and development.
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PMID:The Vacuolar Protein Sorting-38 Subunit of the Arabidopsis Phosphatidylinositol-3-Kinase Complex Plays Critical Roles in Autophagy, Endosome Sorting, and Gravitropism. 3218 Jul 88

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.
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PMID:VPS34 complexes from a structural perspective. 3039 85

The PIK3C3/VPS34-containing phosphatidylinositol 3-kinase (PtdIns3K) initiation complex (complex I) is necessary for macroautophagy/autophagy initiation and is comprised of PIK3R4/VPS15-PIK3C3/VPS34-BECN1-ATG14, while the endosomal trafficking complex (complex II) is necessary for vesicle trafficking and is comprised of PIK3R4/VPS15-PIK3C3/VPS34-BECN1-UVRAG. This composition difference was exploited to identify novel and specific autophagy inhibitors that disrupted the BECN1-ATG14 protein-protein interaction, without affecting vesicle trafficking. A cellular NanoBRET assay was implemented to identify these inhibitors, and one compound was able to successfully disrupt the BECN1-ATG14 interaction and inhibit autophagy, with limited impact on vesicle trafficking. These results reveal the first protein-protein interaction inhibitor targeting the autophagy initiation machinery and demonstrate the viability of targeting protein-protein interactions for the discovery of autophagy-specific modulators.
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PMID:Selective autophagy inhibition through disruption of the PIK3C3-containing complex I. 3261 30