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Article ; Online: Longin domain GAP complexes in nutrient signalling, membrane traffic and neurodegeneration.

Jansen, Rachel M / Hurley, James H

2022 Volume 597, Issue 6, Page(s) 750–761

Abstract: Small GTPases act as molecular switches and control numerous cellular processes by their binding and hydrolysis of guanosine triphosphate (GTP). The activity of small GTPases is coordinated by guanine nucleotide exchange factors (GEFs) and GTPase ... ...

Abstract	Small GTPases act as molecular switches and control numerous cellular processes by their binding and hydrolysis of guanosine triphosphate (GTP). The activity of small GTPases is coordinated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). Recent structural and functional studies have characterized a subset of GAPs whose catalytic units consist of longin domains. Longin domain containing GAPs regulate small GTPases that facilitate nutrient signalling, autophagy, vesicular trafficking and lysosome homeostasis. All known examples in this GAP family function as part of larger multiprotein complexes. The three characterized mammalian protein complexes in this class are FLCN:FNIP, GATOR1 and C9orf72:SMCR8. Each complex carries out a unique cellular function by regulating distinct small GTPases. In this article, we explore the roles of longin domain GAPs in nutrient sensing, membrane dynamic, vesicular trafficking and disease. Through a structural lens, we examine the mechanism of each longin domain GAP and highlight potential therapeutic applications.
MeSH term(s)	Animals ; Signal Transduction ; Monomeric GTP-Binding Proteins/metabolism ; GTPase-Activating Proteins/metabolism ; Protein Transport ; Nutrients ; Mammals/metabolism
Chemical Substances	Monomeric GTP-Binding Proteins (EC 3.6.5.2) ; GTPase-Activating Proteins
Language	English
Publishing date	2022-11-22
Publishing country	England
Document type	Journal Article ; Review ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	212746-5
ISSN	1873-3468 ; 0014-5793
ISSN (online)	1873-3468
ISSN	0014-5793
DOI	10.1002/1873-3468.14538
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Article ; Online: Dynamics of upstream ESCRT organization at the HIV-1 budding site.

Hudait, Arpa / Hurley, James H / Voth, Gregory A

Biophysical journal

2023 Volume 122, Issue 13, Page(s) 2655–2674

Abstract: In the late stages of the HIV-1 life cycle, membrane localization and self-assembly of Gag polyproteins induce membrane deformation and budding. Release of the virion requires direct interaction between immature Gag lattice and upstream ESCRT machinery ... ...

Abstract	In the late stages of the HIV-1 life cycle, membrane localization and self-assembly of Gag polyproteins induce membrane deformation and budding. Release of the virion requires direct interaction between immature Gag lattice and upstream ESCRT machinery at the viral budding site, followed by assembly of downstream ESCRT-III factors, culminating in membrane scission. However, molecular details of upstream ESCRT assembly dynamics at the viral budding site remain unclear. In this work, using coarse-grained (CG) molecular dynamics (MD) simulations, we investigated the interactions between Gag, ESCRT-I, ESCRT-II, and membrane to delineate the dynamical mechanisms by which upstream ESCRTs assemble templated by late-stage immature Gag lattice. We first systematically derived "bottom-up" CG molecular models and interactions of upstream ESCRT proteins from experimental structural data and extensive all-atom MD simulations. Using these molecular models, we performed CG MD simulations of ESCRT-I oligomerization and ESCRT-I/II supercomplex formation at the neck of the budding virion. Our simulations demonstrate that ESCRT-I can effectively oligomerize to higher-order complexes templated by the immature Gag lattice both in the absence of ESCRT-II and when multiple copies of ESCRT-II are localized at the bud neck. The ESCRT-I/II supercomplexes formed in our simulations exhibit predominantly columnar structures, which has important implications for the nucleation pathway of downstream ESCRT-III polymers. Importantly, ESCRT-I/II supercomplexes bound to Gag initiate membrane neck constriction by pulling the inner edge of the bud neck closer to the ESCRT-I headpiece ring. Our findings serve to elucidate a network of interactions between upstream ESCRT machinery, immature Gag lattice, and membrane neck that regulate protein assembly dynamics at the HIV-1 budding site.
MeSH term(s)	HIV-1/metabolism ; Gene Products, gag/genetics ; Gene Products, gag/metabolism ; Molecular Dynamics Simulation ; Cell Division ; Endosomal Sorting Complexes Required for Transport/metabolism
Chemical Substances	Gene Products, gag ; Endosomal Sorting Complexes Required for Transport
Language	English
Publishing date	2023-05-22
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	218078-9
ISSN	1542-0086 ; 0006-3495
ISSN (online)	1542-0086
ISSN	0006-3495
DOI	10.1016/j.bpj.2023.05.020
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Article ; Online: Toward a standard model for autophagosome biogenesis.

Cook, Annan S I / Hurley, James H

The Journal of cell biology

2023 Volume 222, Issue 7

Abstract: Two papers in this issue resolve a long-standing obstacle to a "standard model" for autophagosome biogenesis in mammals. The first, Olivas et al. (2023. J. Cell Biol. https://doi.org/10.1083/jcb.202208088), uses biochemistry to confirm that the lipid ... ...

Abstract	Two papers in this issue resolve a long-standing obstacle to a "standard model" for autophagosome biogenesis in mammals. The first, Olivas et al. (2023. J. Cell Biol. https://doi.org/10.1083/jcb.202208088), uses biochemistry to confirm that the lipid scramblase ATG9A is a bona fide autophagosome component, while the second, Broadbent et al. (2023. J. Cell Biol. https://doi.org/10.1083/jcb.202210078), uses particle tracking to show that the dynamics of autophagy proteins are consistent with the concept.
MeSH term(s)	Animals ; Autophagosomes ; Autophagy ; Macroautophagy ; Mammals ; Autophagy-Related Proteins
Chemical Substances	Autophagy-Related Proteins
Language	English
Publishing date	2023-06-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	218154-x
ISSN	1540-8140 ; 0021-9525
ISSN (online)	1540-8140
ISSN	0021-9525
DOI	10.1083/jcb.202304011
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Article ; Online: Longin domain GAP complexes in nutrient signalling, membrane traffic and neurodegeneration

Jansen, Rachel M. / Hurley, James H.

FEBS Letters. 2023 Mar., v. 597, no. 6 p.750-761

2023

Abstract	Small GTPases act as molecular switches and control numerous cellular processes by their binding and hydrolysis of guanosine triphosphate (GTP). The activity of small GTPases is coordinated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). Recent structural and functional studies have characterized a subset of GAPs whose catalytic units consist of longin domains. Longin domain containing GAPs regulate small GTPases that facilitate nutrient signalling, autophagy, vesicular trafficking and lysosome homeostasis. All known examples in this GAP family function as part of larger multiprotein complexes. The three characterized mammalian protein complexes in this class are FLCN:FNIP, GATOR1 and C9orf72:SMCR8. Each complex carries out a unique cellular function by regulating distinct small GTPases. In this article, we explore the roles of longin domain GAPs in nutrient sensing, membrane dynamic, vesicular trafficking and disease. Through a structural lens, we examine the mechanism of each longin domain GAP and highlight potential therapeutic applications.
Keywords	autophagy ; guanosine triphosphate ; guanosinetriphosphatase ; homeostasis ; hydrolysis ; lysosomes ; mammals ; neurodegenerative diseases ; physiological transport ; therapeutics
Language	English
Dates of publication	2023-03
Size	p. 750-761.
Publishing place	John Wiley & Sons, Ltd
Document type	Article ; Online
Note	REVIEW
ZDB-ID	212746-5
ISSN	1873-3468 ; 0014-5793
ISSN (online)	1873-3468
ISSN	0014-5793
DOI	10.1002/1873-3468.14538
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Article: Crystallographic molecular replacement using an

Flower, Thomas G / Hurley, James H

bioRxiv : the preprint server for biology

2021

Abstract: The majority of crystal structures are determined by the method of molecular replacement (MR). The range of application of MR is limited mainly by the need for an accurate search model. In most cases, pre-existing experimentally determined structures are ...

Abstract	The majority of crystal structures are determined by the method of molecular replacement (MR). The range of application of MR is limited mainly by the need for an accurate search model. In most cases, pre-existing experimentally determined structures are used as search models. In favorable cases,
Language	English
Publishing date	2021-01-05
Publishing country	United States
Document type	Preprint
DOI	10.1101/2021.01.05.425441
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Article ; Online: Crystallographic molecular replacement using an in silico-generated search model of SARS-CoV-2 ORF8.

Flower, Thomas G / Hurley, James H

Protein science : a publication of the Protein Society

2021 Volume 30, Issue 4, Page(s) 728–734

Abstract	The majority of crystal structures are determined by the method of molecular replacement (MR). The range of application of MR is limited mainly by the need for an accurate search model. In most cases, pre-existing experimentally determined structures are used as search models. In favorable cases, ab initio predicted structures have yielded search models adequate for MR. The ORF8 protein of SARS-CoV-2 represents a challenging case for MR using an ab initio prediction because ORF8 has an all β-sheet fold and few orthologs. We previously determined experimentally the structure of ORF8 using the single anomalous dispersion (SAD) phasing method, having been unable to find an MR solution to the crystallographic phase problem. Following a report of an accurate prediction of the ORF8 structure, we assessed whether the predicted model would have succeeded as an MR search model. A phase problem solution was found, and the resulting structure was refined, yielding structural parameters equivalent to the original experimental solution.
MeSH term(s)	COVID-19/virology ; Crystallography, X-Ray ; Humans ; Models, Molecular ; Protein Conformation ; SARS-CoV-2/chemistry ; Viral Proteins/chemistry
Chemical Substances	ORF8 protein, SARS-CoV-2 ; Viral Proteins
Language	English
Publishing date	2021-03-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1106283-6
ISSN	1469-896X ; 0961-8368
ISSN (online)	1469-896X
ISSN	0961-8368
DOI	10.1002/pro.4050
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Article ; Online: Amino acid sensing and lysosomal signaling complexes.

Cui, Zhicheng / Joiner, Aaron M N / Jansen, Rachel M / Hurley, James H

Current opinion in structural biology

2023 Volume 79, Page(s) 102544

Abstract: Amino acid pools in the cell are monitored by dedicated sensors, whose structures are now coming into view. The lysosomal Rag GTPases are central to this pathway, and the regulation of their GAP complexes, FLCN-FNIP and GATOR1, have been worked out in ... ...

Abstract	Amino acid pools in the cell are monitored by dedicated sensors, whose structures are now coming into view. The lysosomal Rag GTPases are central to this pathway, and the regulation of their GAP complexes, FLCN-FNIP and GATOR1, have been worked out in detail. For FLCN-FNIP, the entire chain of events from the arginine transporter SLC38A9 to substrate-specific mTORC1 activation has been visualized. The structure GATOR2 has been determined, hinting at an ordering of amino acid signaling across a larger size scale than anticipated. The centerpiece of lysosomal signaling, mTORC1, has been revealed to recognize its substrates by more nuanced and substrate-specific mechanisms than previous appreciated. Beyond the well-studied Rag GTPase and mTORC1 machinery, another lysosomal amino acid sensor/effector system, that of PQLC2 and the C9orf72-containing CSW complex, is coming into structural view. These developments hold promise for further insights into lysosomal physiology and lysosome-centric therapeutics.
MeSH term(s)	Amino Acids/metabolism ; Monomeric GTP-Binding Proteins/metabolism ; Signal Transduction ; Mechanistic Target of Rapamycin Complex 1/metabolism ; Lysosomes/metabolism
Chemical Substances	Amino Acids ; Monomeric GTP-Binding Proteins (EC 3.6.5.2) ; Mechanistic Target of Rapamycin Complex 1 (EC 2.7.11.1)
Language	English
Publishing date	2023-02-16
Publishing country	England
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1068353-7
ISSN	1879-033X ; 0959-440X
ISSN (online)	1879-033X
ISSN	0959-440X
DOI	10.1016/j.sbi.2023.102544
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Article ; Online: A firehose for phospholipids.

Prinz, William A / Hurley, James H

The Journal of cell biology

2020 Volume 219, Issue 5

Abstract: All lipid transport proteins in eukaryotes are thought to shuttle lipids between cellular membranes. In this issue, Li et al. (2020. J. Cell Biol.https://doi.org/10.1083/jcb.202001161) show that Vps13 has a channel-like domain that may allow lipids to ... ...

Abstract	All lipid transport proteins in eukaryotes are thought to shuttle lipids between cellular membranes. In this issue, Li et al. (2020. J. Cell Biol.https://doi.org/10.1083/jcb.202001161) show that Vps13 has a channel-like domain that may allow lipids to flow between closely apposed membranes at contact sites.
MeSH term(s)	Cell Membrane ; Cryoelectron Microscopy ; Membranes ; Mitochondrial Membranes ; Phospholipids
Chemical Substances	Phospholipids
Language	English
Publishing date	2020-04-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	218154-x
ISSN	1540-8140 ; 0021-9525
ISSN (online)	1540-8140
ISSN	0021-9525
DOI	10.1083/jcb.202003132
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Article ; Online: Editorial Overview: Molecular Mechanisms of Autophagy-Part A.

Hurley, James H

Journal of molecular biology

2016 Volume 428, Issue 9 Pt A, Page(s) 1657–1658

MeSH term(s)	Animals ; Autophagosomes/metabolism ; Autophagy ; Humans
Language	English
Publishing date	2016--08
Publishing country	England
Document type	Editorial ; Introductory Journal Article
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2016.03.019
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Article ; Online: Three-step docking by WIPI2, ATG16L1, and ATG3 delivers LC3 to the phagophore.

Rao, Shanlin / Skulsuppaisarn, Marvin / Strong, Lisa M / Ren, Xuefeng / Lazarou, Michael / Hurley, James H / Hummer, Gerhard

Science advances

2024 Volume 10, Issue 6, Page(s) eadj8027

Abstract: The covalent attachment of ubiquitin-like LC3 proteins (microtubule-associated proteins 1A/1B light chain 3) prepares the autophagic membrane for cargo recruitment. We resolve key steps in LC3 lipidation by combining molecular dynamics simulations and ... ...

Abstract	The covalent attachment of ubiquitin-like LC3 proteins (microtubule-associated proteins 1A/1B light chain 3) prepares the autophagic membrane for cargo recruitment. We resolve key steps in LC3 lipidation by combining molecular dynamics simulations and experiments in vitro and in cellulo. We show how the E3-like ligaseautophagy-related 12 (ATG12)-ATG5-ATG16L1 in complex with the E2-like conjugase ATG3 docks LC3 onto the membrane in three steps by (i) the phosphatidylinositol 3-phosphate effector protein WD repeat domain phosphoinositide-interacting protein 2 (WIPI2), (ii) helix α2 of ATG16L1, and (iii) a membrane-interacting surface of ATG3. Phosphatidylethanolamine (PE) lipids concentrate in a region around the thioester bond between ATG3 and LC3, highlighting residues with a possible role in the catalytic transfer of LC3 to PE, including two conserved histidines. In a near-complete pathway from the initial membrane recruitment to the LC3 lipidation reaction, the three-step targeting of the ATG12-ATG5-ATG16L1 machinery establishes a high level of regulatory control.
MeSH term(s)	Autophagy-Related Proteins/genetics ; Autophagy-Related Proteins/metabolism ; Autophagosomes/metabolism ; Microtubule-Associated Proteins/metabolism ; Phagocytosis ; Autophagy
Chemical Substances	Autophagy-Related Proteins ; Microtubule-Associated Proteins
Language	English
Publishing date	2024-02-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.adj8027
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