Volume 67, Issue 3, Pages e3 (August 2017)

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Volume 67, Issue 3, Pages 528-534.e3 (August 2017) Vps34 Kinase Domain Dynamics Regulate the Autophagic PI 3-Kinase Complex Goran Stjepanovic, Sulochanadevi Baskaran, Mary G. Lin, James H. Hurley Molecular Cell Volume 67, Issue 3, Pages 528-534.e3 (August 2017) DOI: 10.1016/j.molcel.2017.07.003 Copyright © 2017 Elsevier Inc. Terms and Conditions

Molecular Cell 2017 67, 528-534.e3DOI: (10.1016/j.molcel.2017.07.003) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 1 EM Analysis of the Conformational Dynamics (A) Three-dimensional reconstruction of the PI3KC3-C1 complex with the docked structures shown in a ribbon representation. (B) Representative class averages of the PI3KC3-C1 complex with the VPS34 HELCAT in range of different conformation states. (C) Percentage of well-resolved particles sorted into 2D class averages with a classical, V-shaped, WD, paddle, and dislodged VPS34 HELCAT. Schematic and representative class averages of the PI3KC3-C1 complex showing the conformations of the VPS34 HELCAT. Molecular Cell 2017 67, 528-534.e3DOI: (10.1016/j.molcel.2017.07.003) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 2 CX-MS Analysis of the Conformational Dynamics Pi3KC3-C1 was crosslinked with a lysine-specific bifunctional crosslinker, then fragmented by proteolysis, and crosslinked peptides were identified by mass spectrometry. (A) Inter-subunit crosslinks between subunits of the PI3KC3-C1 complex. (B) Overview of crosslinks observed within the PI3KC3-C1 complex corresponding to the model generated based on crystal structure of yeast complex I (PDB: 5DFZ). The crosslinks are presented in red (>38 Å) and blue (<38 Å). See also Table S1 and Movie S1. Molecular Cell 2017 67, 528-534.e3DOI: (10.1016/j.molcel.2017.07.003) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 3 Leashing of the VPS34 HELCAT to VPS15 (A) Schematic of the PI3KC3-C1 complex showing leashed and unleashed construct of the VPS34 HELCAT. (B) Percentage of well-resolved particles sorted into 2D class averages with a classical, V-shaped, WD, paddle, and dislodged VPS34 HELCAT in context of leashed and unleashed construct. (C) Quantification of PI(3)P generated by leashed and unleashed PI3KC3-C1 from PI and [γ-32 P] ATP. Samples were normalized to the activity of wild-type PI3KC3-C1 complex. (D) Pho8Δ60 assay to monitor autophagy in yeast was carried out in rich (gray) or nitrogen starvation (black) media. Samples were normalized to the activity of Vps34 in rapamycin-treated cells. (E) Quantification of PI(3)P generated by fully assembled PI3KC3-C1 and as compared to isolated full-length VPS34. Data are represented as mean of three independent experiments ± SD. See also Figures S1–S4. Molecular Cell 2017 67, 528-534.e3DOI: (10.1016/j.molcel.2017.07.003) Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 4 PI3K Complex Assembly and Activation Model Schematic of the PI3KC3-C1 complex showing the role of VPS15 in the assembly pathway and in regulating the dynamics and activity of the VPS34 HELCAT. Molecular Cell 2017 67, 528-534.e3DOI: (10.1016/j.molcel.2017.07.003) Copyright © 2017 Elsevier Inc. Terms and Conditions