4ph4

The crystal structure of Human VPS34 in complex with PIK-III

spinqualitylabelsall models 4ph4, resolution 2.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4ph4 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.8Å Ligands: 2UG, GOL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PK3C3_HUMAN Catalytic subunit of the PI3K complex that mediates formation of phosphatidylinositol 3-phosphate which plays a key role in initiation and maturation of autophagosomes. Involved in the transport of lysosomal enzyme precursors to lysosomes. Required for the abcission step in cytokinesis. Required for transport from early to late endosomes. Publication Abstract from PubMed Cells rely on autophagy to clear misfolded proteins and damaged organelles to maintain cellular homeostasis. In this study we use the new autophagy inhibitor PIK-III to screen for autophagy substrates. PIK-III is a selective inhibitor of VPS34 that binds a unique hydrophobic pocket not present in related kinases such as PI(3)Kalpha. PIK-III acutely inhibits autophagy and de novo lipidation of LC3, and leads to the stabilization of autophagy substrates. By performing ubiquitin-affinity proteomics on PIK-III-treated cells we identified substrates including NCOA4, which accumulates in ATG7-deficient cells and co-localizes with autolysosomes. NCOA4 directly binds ferritin heavy chain-1 (FTH1) to target the iron-binding ferritin complex with a relative molecular mass of 450,000 to autolysosomes following starvation or iron depletion. Interestingly, Ncoa4(-/-) mice exhibit a profound accumulation of iron in splenic macrophages, which are critical for the reutilization of iron from engulfed red blood cells. Taken together, the results of this study provide a new mechanism for selective autophagy of ferritin and reveal a previously unappreciated role for autophagy and NCOA4 in the control of iron homeostasis in vivo. Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo.,Dowdle WE, Nyfeler B, Nagel J, Elling RA, Liu S, Triantafellow E, Menon S, Wang Z, Honda A, Pardee G, Cantwell J, Luu C, Cornella-Taracido I, Harrington E, Fekkes P, Lei H, Fang Q, Digan ME, Burdick D, Powers AF, Helliwell SB, D'Aquin S, Bastien J, Wang H, Wiederschain D, Kuerth J, Bergman P, Schwalb D, Thomas J, Ugwonali S, Harbinski F, Tallarico J, Wilson CJ, Myer VE, Porter JA, Bussiere DE, Finan PM, Labow MA, Mao X, Hamann LG, Manning BD, Valdez RA, Nicholson T, Schirle M, Knapp MS, Keaney EP, Murphy LO Nat Cell Biol. 2014 Nov;16(11):1069-79. doi: 10.1038/ncb3053. Epub 2014 Oct 19. PMID:25327288 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Phosphoinositide 3-kinase 3D structures

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