4PH4

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

Summary for 4PH4

• Entry DOI: 10.2210/pdb4ph4/pdb
• Descriptor: Phosphatidylinositol 3-kinase catalytic subunit type 3, GLYCEROL, 4'-(cyclopropylmethyl)-N~2~-(pyridin-4-yl)-4,5'-bipyrimidine-2,2'-diamine, ... (4 entities in total)
• Functional Keywords: vps34, autophagy, class iii, phosphatidylinositol-3-kinase, pik3c3, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Midbody: Q8NEB9
• Total number of polymer chains: 1
• Total formula weight: 72256.51

Authors

Knapp, M.S.,Elling, R.A. (deposition date: 2014-05-04, release date: 2014-10-29, Last modification date: 2023-12-27)

Primary citation

Dowdle, W.E.,Nyfeler, B.,Nagel, J.,Elling, R.A.,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, M.E.,Burdick, D.,Powers, A.F.,Helliwell, S.B.,D'Aquin, S.,Bastien, J.,Wang, H.,Wiederschain, D.,Kuerth, J.,Bergman, P.,Schwalb, D.,Thomas, J.,Ugwonali, S.,Harbinski, F.,Tallarico, J.,Wilson, C.J.,Myer, V.E.,Porter, J.A.,Bussiere, D.E.,Finan, P.M.,Labow, M.A.,Mao, X.,Hamann, L.G.,Manning, B.D.,Valdez, R.A.,Nicholson, T.,Schirle, M.,Knapp, M.S.,Keaney, E.P.,Murphy, L.O.
Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo.
Nat.Cell Biol., 16:1069-1079, 2014

PubMed Abstract: 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)Kα. 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.

PubMed: 25327288
DOI: 10.1038/ncb3053

Experimental method

X-RAY DIFFRACTION (2.8 Å)