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| Title | Structural pathway for allosteric activation of the autophagic PI 3-kinase complex I. |
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| Journal, issue, pages | Proc Natl Acad Sci U S A, Vol. 116, Issue 43, Page 21508-21513, Year 2019 |
| Publish date | Oct 22, 2019 |
 Authors | Lindsey N Young / Felix Goerdeler / James H Hurley /  |
| PubMed Abstract | Autophagy induction by starvation and stress involves the enzymatic activation of the class III phosphatidylinositol (PI) 3-kinase complex I (PI3KC3-C1). The inactive basal state of PI3KC3-C1 is ...Autophagy induction by starvation and stress involves the enzymatic activation of the class III phosphatidylinositol (PI) 3-kinase complex I (PI3KC3-C1). The inactive basal state of PI3KC3-C1 is maintained by inhibitory contacts between the VPS15 protein kinase and VPS34 lipid kinase domains that restrict the conformation of the VPS34 activation loop. Here, the proautophagic MIT domain-containing protein NRBF2 was used to map the structural changes leading to activation. Cryoelectron microscopy was used to visualize a 2-step PI3KC3-C1 activation pathway driven by NRFB2 MIT domain binding. Binding of a single NRBF2 MIT domain bends the helical solenoid of the VPS15 scaffold, displaces the protein kinase domain of VPS15, and releases the VPS34 kinase domain from the inhibited conformation. Binding of a second MIT stabilizes the VPS34 lipid kinase domain in an active conformation that has an unrestricted activation loop and is poised for access to membranes. |
 External links | Proc Natl Acad Sci U S A / PubMed:31591221 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 6.6 - 7.7 Å |
| Structure data |  EMDB-20387:  EMDB-20390: |
| Source |
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Homo sapiens (human)