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4ph4

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Revision as of 09:26, 11 August 2016

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

Structural highlights

4ph4 is a 1 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Activity:	Phosphatidylinositol 3-kinase, with EC number 2.7.1.137
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.^[1] ^[2] ^[3]

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^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Volinia S, Dhand R, Vanhaesebroeck B, MacDougall LK, Stein R, Zvelebil MJ, Domin J, Panaretou C, Waterfield MD. A human phosphatidylinositol 3-kinase complex related to the yeast Vps34p-Vps15p protein sorting system. EMBO J. 1995 Jul 17;14(14):3339-48. PMID:7628435
↑ Stein MP, Feng Y, Cooper KL, Welford AM, Wandinger-Ness A. Human VPS34 and p150 are Rab7 interacting partners. Traffic. 2003 Nov;4(11):754-71. PMID:14617358
↑ Sagona AP, Nezis IP, Pedersen NM, Liestol K, Poulton J, Rusten TE, Skotheim RI, Raiborg C, Stenmark H. PtdIns(3)P controls cytokinesis through KIF13A-mediated recruitment of FYVE-CENT to the midbody. Nat Cell Biol. 2010 Apr;12(4):362-71. doi: 10.1038/ncb2036. Epub 2010 Mar 7. PMID:20208530 doi:http://dx.doi.org/10.1038/ncb2036
↑ 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. Selective VPS34 inhibitor blocks autophagy and uncovers a role for NCOA4 in ferritin degradation and iron homeostasis in vivo. Nat Cell Biol. 2014 Nov;16(11):1069-79. doi: 10.1038/ncb3053. Epub 2014 Oct 19. PMID:25327288 doi:http://dx.doi.org/10.1038/ncb3053

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4ph4"

@@ Line 1: / Line 1: @@
 ==The crystal structure of Human VPS34 in complex with PIK-III==
 <StructureSection load='4ph4' size='340' side='right' caption='[[4ph4]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
@@ Line 5: / Line 6: @@
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2UG:4-(CYCLOPROPYLMETHYL)-N~2~-(PYRIDIN-4-YL)-4,5-BIPYRIMIDINE-2,2-DIAMINE'>2UG</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Phosphatidylinositol_3-kinase Phosphatidylinositol 3-kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.137 2.7.1.137] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ph4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ph4 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ph4 RCSB], [http://www.ebi.ac.uk/pdbsum/4ph4 PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ph4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ph4 OCA], [http://pdbe.org/4ph4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ph4 RCSB], [http://www.ebi.ac.uk/pdbsum/4ph4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ph4 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 17: / Line 18: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4ph4" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Phosphoinositide 3-Kinases|Phosphoinositide 3-Kinases]]
 == References ==
 <references/>

4ph4

From Proteopedia

Revision as of 09:26, 11 August 2016

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

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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