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Recent Work
- Mechanistic target of rapamycin complex 1 (mTORC1), which consists of mTOR, Raptor, and mLST8, receives signaling inputs from growth factor signals and nutrients. These signals are mediated by the Rheb and Rag small GTPases, respectively, which activate mTORC1 on the cytosolic face of the lysosome membrane. We biochemically reconstituted the […]
- Selective autophagy is a lysosomal degradation pathway that is critical for maintaining cellular homeostasis by disposing of harmful cellular material. While the mechanisms by which soluble cargo receptors recruit the autophagy machinery are becoming increasingly clear, the principles governing how organelle-localized transmembrane cargo receptors initiate selective autophagy remain poorly understood. […]
- Rough endoplasmic reticulum (ER) sheets are a fundamental domain of the ER and the gateway into the secretory pathway. Although reticulon proteins stabilize high-curvature ER tubules, it is unclear whether other proteins scaffold the flat membranes of rough ER sheets. Through a proteomics screen using ER sheet-localized RNA-binding proteins as […]
- The prion-like spread of protein aggregates is a leading hypothesis for the propagation of neurofibrillary lesions in the brain, including the spread of tau inclusions associated with Alzheimer's disease. The mechanisms of cellular uptake of tau seeds and subsequent nucleated polymerization of cytosolic tau are major questions in the field, […]
- Activation of PINK1 and Parkin in response to mitochondrial damage initiates a response that includes phosphorylation of RAB7A at Ser72. Rubicon is a RAB7A binding negative regulator of autophagy. The structure of the Rubicon:RAB7A complex suggests that phosphorylation of RAB7A at Ser72 would block Rubicon binding. Indeed, in vitro phosphorylation […]
2020
Fromm SA, Lawrence RE, Hurley JH. Structural mechanism for amino acid-dependent Rag GTPase nucleotide state switching by SLC38A9. Nat Struct Mol Biol. 2020 Aug 31. doi: 10.1038/s41594-020-0490-9. Epub ahead of print. PMID: 32868926.
Su MY, Fromm SA, Zoncu R, Hurley JH. Structure of the C9orf72 ARF GAP complex that is haploinsufficient in ALS and FTD. Nature. 2020 Sep;585(7824):251-255. doi: 10.1038/s41586-020-2633-x. Epub 2020 Aug 26. PMID: 32848248.
Shi X, Chang C, Yokom AL, Jensen LE, Hurley JH. The autophagy adaptor NDP52 and the FIP200 coiled-coil allosterically activate ULK1 complex membrane recruitment. Elife. 2020 Aug 10;9:e59099. doi: 10.7554/eLife.59099. PMID: 32773036; PMCID: PMC7447430.
Bhargava HK, Tabata K, Byck JM, Hamasaki M, Farrell DP, Anishchenko I, DiMaio F, Im YJ, Yoshimori T, Hurley JH. Structural basis for autophagy inhibition by the human Rubicon-Rab7 complex. Proc Natl Acad Sci U S A. 2020 Jul 21;117(29):17003-17010. doi: 10.1073/pnas.2008030117. Epub 2020 Jul 6. PMID: 32632011; PMCID: PMC7382272.
Shi, X., Yokom, A. L., Wang, C., Young, L. N., Youle, R. J., & Hurley, J. H. (2020). ULK complex organization in autophagy by a C-shaped FIP200 N-terminal domain dimer. The Journal of cell biology, 219(7), e201911047. https://doi.org/10.1083/jcb.201911047
Fracchiolla, D., Chang, C., Hurley, J. H., & Martens, S. (2020). A PI3K-WIPI2 positive feedback loop allosterically activates LC3 lipidation in autophagy. The Journal of cell biology, 219(7), e201912098. https://doi.org/10.1083/jcb.201912098
Flower, T. G., Takahashi, Y., Hudait, A., Rose, K., Tjahjono, N., Pak, A. J., Yokom, A. L., Liang, X., Wang, H. G., Bouamr, F., Voth, G. A., & Hurley, J. H. (2020). A helical assembly of human ESCRT-I scaffolds reverse-topology membrane scission. Nature structural & molecular biology, 27(6), 570–580. https://doi.org/10.1038/s41594-020-0426-4
Prinz, W. A., & Hurley, J. H. (2020). A firehose for phospholipids. The Journal of cell biology, 219(5), e202003132. https://doi.org/10.1083/jcb.202003132
2019
Lawrence, R. E., Fromm, S. A., Fu, Y., Yokom, A. L., Kim, D. J., Thelen, A. M., Young, L. N., Lim, C. Y., Samelson, A. J., Hurley, J. H., & Zoncu, R. (2019). Structural mechanism of a Rag GTPase activation checkpoint by the lysosomal folliculin complex. Science (New York, N.Y.), 366(6468), 971–977. https://doi.org/10.1126/science.aax0364
Young, L. N., Goerdeler, F., & Hurley, J. H. (2019). Structural pathway for allosteric activation of the autophagic PI 3-kinase complex I. Proceedings of the National Academy of Sciences of the United States of America, 116(43), 21508–21513. https://doi.org/10.1073/pnas.1911612116
Buffalo, C. Z., Iwamoto, Y., Hurley, J. H., & Ren, X. (2019). How HIV Nef Proteins Hijack Membrane Traffic To Promote Infection. Journal of virology, 93(24), e01322-19. https://doi.org/10.1128/JVI.01322-19
Horst, B. G., Yokom, A. L., Rosenberg, D. J., Morris, K. L., Hammel, M., Hurley, J. H., & Marletta, M. A. (2019). Allosteric activation of the nitric oxide receptor soluble guanylate cyclase mapped by cryo-electron microscopy. eLife, 8, e50634. https://doi.org/10.7554/eLife.50634
Buffalo, C. Z., Stürzel, C. M., Heusinger, E., Kmiec, D., Kirchhoff, F., Hurley, J. H., & Ren, X. (2019). Structural Basis for Tetherin Antagonism as a Barrier to Zoonotic Lentiviral Transmission. Cell host & microbe, 26(3), 359–368.e8. https://doi.org/10.1016/j.chom.2019.08.002
Turco, E., Witt, M., Abert, C., Bock-Bierbaum, T., Su, M. Y., Trapannone, R., Sztacho, M., Danieli, A., Shi, X., Zaffagnini, G., Gamper, A., Schuschnig, M., Fracchiolla, D., Bernklau, D., Romanov, J., Hartl, M., Hurley, J. H., Daumke, O., & Martens, S. (2019). How RB1CC1/FIP200 claws its way to autophagic engulfment of SQSTM1/p62-ubiquitin condensates. Autophagy, 15(8), 1475–1477. https://doi.org/10.1080/15548627.2019.1615306
Chang, C., Young, L. N., & Hurley, J. H. (2019). The BARA necessities of PtdIns 3-kinase activation in autophagy. Autophagy, 15(6), 1122–1123. https://doi.org/10.1080/15548627.2019.1596501
Turco, E., Witt, M., Abert, C., Bock-Bierbaum, T., Su, M. Y., Trapannone, R., Sztacho, M., Danieli, A., Shi, X., Zaffagnini, G., Gamper, A., Schuschnig, M., Fracchiolla, D., Bernklau, D., Romanov, J., Hartl, M., Hurley, J. H., Daumke, O., & Martens, S. (2019). FIP200 Claw Domain Binding to p62 Promotes Autophagosome Formation at Ubiquitin Condensates. Molecular cell, 74(2), 330–346.e11. https://doi.org/10.1016/j.molcel.2019.01.035
Brier, L. W., Ge, L., Stjepanovic, G., Thelen, A. M., Hurley, J. H., & Schekman, R. (2019). Regulation of LC3 lipidation by the autophagy-specific class III phosphatidylinositol-3 kinase complex. Molecular biology of the cell, 30(9), 1098–1107. https://doi.org/10.1091/mbc.E18-11-0743
Hurley, J. H., & Johannes, L. (2019). Retro Styles for Vesicle Coats. Biochemistry, 58(6), 433–434. https://doi.org/10.1021/acs.biochem.8b01271
Chang, C., Young, L. N., Morris, K. L., von Bülow, S., Schöneberg, J., Yamamoto-Imoto, H., Oe, Y., Yamamoto, K., Nakamura, S., Stjepanovic, G., Hummer, G., Yoshimori, T., & Hurley, J. H. (2019). Bidirectional Control of Autophagy by BECN1 BARA Domain Dynamics. Molecular cell, 73(2), 339–353.e6. https://doi.org/10.1016/j.molcel.2018.10.035
2018
Schöneberg, J., Pavlin, M. R., Yan, S., Righini, M., Lee, I. H., Carlson, L. A., Bahrami, A. H., Goldman, D. H., Ren, X., Hummer, G., Bustamante, C., & Hurley, J. H. (2018). ATP-dependent force generation and membrane scission by ESCRT-III and Vps4. Science (New York, N.Y.), 362(6421), 1423–1428. https://doi.org/10.1126/science.aat1839
Schulze-Gahmen, U., & Hurley, J. H. (2018). Structural mechanism for HIV-1 TAR loop recognition by Tat and the super elongation complex. Proceedings of the National Academy of Sciences of the United States of America, 115(51), 12973–12978. https://doi.org/10.1073/pnas.1806438115
Hurley, J. H., & Cada, A. K. (2018). Inside job: how the ESCRTs release HIV-1 from infected cells. Biochemical Society transactions, 46(5), 1029–1036. https://doi.org/10.1042/BST20180019
Lawrence, R. E., Cho, K. F., Rappold, R., Thrun, A., Tofaute, M., Kim, D. J., Moldavski, O., Hurley, J. H., & Zoncu, R. (2018). A nutrient-induced affinity switch controls mTORC1 activation by its Rag GTPase-Ragulator lysosomal scaffold. Nature cell biology, 20(9), 1052–1063. https://doi.org/10.1038/s41556-018-0148-6
Morris, K. L., Buffalo, C. Z., Stürzel, C. M., Heusinger, E., Kirchhoff, F., Ren, X., & Hurley, J. H. (2018). HIV-1 Nefs Are Cargo-Sensitive AP-1 Trimerization Switches in Tetherin Downregulation. Cell, 174(3), 659–671.e14. https://doi.org/10.1016/j.cell.2018.07.004
Lin, M. G., Schöneberg, J., Davies, C. W., Ren, X., & Hurley, J. H. (2018). The dynamic Atg13-free conformation of the Atg1 EAT domain is required for phagophore expansion. Molecular biology of the cell, 29(10), 1228–1237. https://doi.org/10.1091/mbc.E17-04-0258
Gardner, B. M., Castanzo, D. T., Chowdhury, S., Stjepanovic, G., Stefely, M. S., Hurley, J. H., Lander, G. C., & Martin, A. (2018). The peroxisomal AAA-ATPase Pex1/Pex6 unfolds substrates by processive threading. Nature communications, 9(1), 135. https://doi.org/10.1038/s41467-017-02474-4
2017
Stjepanovic, G., Baskaran, S., Lin, M. G., & Hurley, J. H. (2017). Unveiling the role of VPS34 kinase domain dynamics in regulation of the autophagic PI3K complex. Molecular & cellular oncology, 4(6), e1367873. https://doi.org/10.1080/23723556.2017.1367873
Su, M. Y., Morris, K. L., Kim, D. J., Fu, Y., Lawrence, R., Stjepanovic, G., Zoncu, R., & Hurley, J. H. (2017). Hybrid Structure of the RagA/C-Ragulator mTORC1 Activation Complex. Molecular cell, 68(5), 835–846.e3. https://doi.org/10.1016/j.molcel.2017.10.016
Bahrami, A. H., Lin, M. G., Ren, X., Hurley, J. H., & Hummer, G. (2017). Scaffolding the cup-shaped double membrane in autophagy. PLoS computational biology, 13(10), e1005817. https://doi.org/10.1371/journal.pcbi.1005817
Stjepanovic, G., Baskaran, S., Lin, M. G., & Hurley, J. H. (2017). Vps34 Kinase Domain Dynamics Regulate the Autophagic PI 3-Kinase Complex. Molecular cell, 67(3), 528–534.e3. https://doi.org/10.1016/j.molcel.2017.07.003
Mandadapu, K. K., & Hurley, J. H. (2017). Friction at the BAR Leads to Membrane Breakup. Cell, 170(1), 14–16. https://doi.org/10.1016/j.cell.2017.06.027
Hurley, J. H., & Young, L. N. (2017). Mechanisms of Autophagy Initiation. Annual review of biochemistry, 86, 225–244. https://doi.org/10.1146/annurev-biochem-061516-044820
Qi, S., Li, Z., Schulze-Gahmen, U., Stjepanovic, G., Zhou, Q., & Hurley, J. H. (2017). Structural basis for ELL2 and AFF4 activation of HIV-1 proviral transcription. Nature communications, 8, 14076. https://doi.org/10.1038/ncomms14076
Tooze, S. A., & Hurley, J. H. (2017). Molecular Mechanisms of Autophagy-Part B. Journal of molecular biology, 429(4), 455–456. https://doi.org/10.1016/j.jmb.2017.01.009
Schöneberg, J., Lee, I. H., Iwasa, J. H., & Hurley, J. H. (2017). Reverse-topology membrane scission by the ESCRT proteins. Nature reviews. Molecular cell biology, 18(1), 5–17. https://doi.org/10.1038/nrm.2016.121
2016
Schulze-Gahmen U, Echeverria I, Stjepanovic G, Bai Y, Lu H, Schneidman-Duhovny D, Doudna JA, Zhou Q, Sali A, Hurley JH. Insights into HIV-1 proviral transcription from integrative structure and dynamics of the Tat:AFF4:P-TEFb:TAR complex. Elife. 2016 Oct 12;5:e15910. doi: 10.7554/eLife.15910. PMID: 27731797; PMCID: PMC5072841.
Hurley JH, Nogales E. Next-generation electron microscopy in autophagy research. Curr Opin Struct Biol. 2016 Dec;41:211-216. doi: 10.1016/j.sbi.2016.08.006. Epub 2016 Sep 8. PMID: 27614295; PMCID: PMC5154772.
Young LN, Cho K, Lawrence R, Zoncu R, Hurley JH. Dynamics and architecture of the NRBF2-containing phosphatidylinositol 3-kinase complex I of autophagy. Proc Natl Acad Sci U S A. 2016 Jul 19;113(29):8224-9. doi: 10.1073/pnas.1603650113. Epub 2016 Jul 6. PMID: 27385829; PMCID: PMC4961193.