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| Open AccessC9orf72-catalyzed GTP loading of Rab39A enables HOPS-mediated membrane tethering and fusion in mammalian autophagy
The HOPS complex mediates membrane tethering and autophagosome-lysosome fusion. Here, the authors biochemically reconstitute the mammalian HOPS in protoliposomes and propose a model of complex assembly that depends on Rab2 and Rab39A.
- Shen Zhang
- , Mindan Tong
- & Qing Zhong
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Article
| Open AccessMembranes prime the RapGEF EPAC1 to transduce cAMP signaling
EPAC1 is a cAMP-activated guanine nucleotide exchange factor (GEF) for Rap GTPases and a major transducer of cAMP signaling. Here, the authors show anionic membranes can activate EPAC1 independently of cAMP, increase its affinity for cAMP by two orders of magnitude, and synergize with cAMP to yield maximal GEF activity.
- Candice Sartre
- , François Peurois
- & Jacqueline Cherfils
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Article
| Open AccessrRNA methylation by Spb1 regulates the GTPase activity of Nog2 during 60S ribosomal subunit assembly
Regulation of 60S biogenesis remains poorly understood. Using cryo-EM, the authors show that failure of Spb1 to methylate the A-loop nucleotide G2922 prematurely activates the GTPase Nog2, suggesting that Spb1 and Nog2 form a kinetic checkpoint during ribosome maturation.
- Kamil Sekulski
- , Victor Emmanuel Cruz
- & Jan P. Erzberger
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Article
| Open AccessStructure of the Sec14 domain of Kalirin reveals a distinct class of lipid-binding module in RhoGEFs
A subset of Sec14 domain proteins use their gated hydrophobic pocket to bind and transport lipids. Here the authors provide structural and biochemical data revealing how the Sec14-fold of a Rho-GEF forms a surface groove that interacts with lysolipids.
- Yunfeng Li
- , Yulia Pustovalova
- & Bing Hao
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Article
| Open AccessConstruction of a synthetic methodology-based library and its application in identifying a GIT/PIX protein–protein interaction inhibitor
Chemical libraries with skeleton diversity are important for drug discovery. Here, the authors establish a synthetic methodology-based compound library (SMBL), and apply it to identify a small-molecule inhibitor to interrupt a challenging target: the protein–protein interaction (PPI) of GIT1/β-Pix.
- Jing Gu
- , Rui-Kun Peng
- & Qin Ouyang
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Article
| Open AccessSH3 domain regulation of RhoGAP activity: Crosstalk between p120RasGAP and DLC1 RhoGAP
Inhibition of DLC1 RhoGAP by p120RasGAP allows for crosstalk between the Rho and Ras pathways. Here, Chau et al. present the co-crystal structure of DLC1 RhoGAP domain and p120RasGAP SH3 domain and probe the interaction with biochemical studies.
- Jocelyn E. Chau
- , Kimberly J. Vish
- & Amy L. Stiegler
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Article
| Open AccessAfadin couples RAS GTPases to the polarity rheostat Scribble
Goudreault et al. investigate the role of Afadin downstream of RAS GTPases, substantiating this cell adhesion protein as a true RAS effector that couples its activation to cell polarity through the Scribble protein.
- Marilyn Goudreault
- , Valérie Gagné
- & Matthew J. Smith
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Article
| Open AccessCompact IF2 allows initiator tRNA accommodation into the P site and gates the ribosome to elongation
Initiation factor 2 (IF2) guides the ribosome to the elongation phase of protein synthesis. Here, Basu et al. provide structural insights into how compact IF2-GDP makes way for initiator tRNA accommodation into the peptidyl (P) site of the ribosome.
- Ritwika S. Basu
- , Michael B. Sherman
- & Matthieu G. Gagnon
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Article
| Open AccessStructure of the class C orphan GPCR GPR158 in complex with RGS7-Gβ5
The orphan GPR158 receptor belongs to the class C GPCR family and interacts with the regulator of G protein signaling 7 (RGS7)-Gβ5 complex. Here, the authors present the cryo-EM structure of human GPR158, which reveals that the extracellular domain contains a PAS domain, and they also determine the structures of GPR158 in complex with either one or two RGS7-Gβ5 heterodimers and discuss implications for the signaling mechanism.
- Eunyoung Jeong
- , Yoojoong Kim
- & Yunje Cho
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Article
| Open AccessStructural asymmetry governs the assembly and GTPase activity of McrBC restriction complexes
The bacterial defense system McrBC is a two-component motor-driven nuclease complex that cleaves foreign DNA. Here, the authors present the structures of the GTP-specific AAA + motor protein McrB and two McrBC complexes and discuss the molecular mechanism of how McrC binding stimulates McrB GTP hydrolysis.
- Yiming Niu
- , Hiroshi Suzuki
- & Joshua S. Chappie
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Article
| Open AccessStructure of the G protein chaperone and guanine nucleotide exchange factor Ric-8A bound to Gαi1
Ric-8A is guanine nucleotide exchange factor (GEF) that also acts as a folding chaperone for its Gα subunit. Here, the authors present the structure of Ric-8A bound to nucleotide-free Gαi1, revealing the mechanism by which Ric-8A exerts both GEF and chaperone activity.
- Levi J. McClelland
- , Kaiming Zhang
- & Stephen R. Sprang
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Article
| Open AccessStructural underpinnings of Ric8A function as a G-protein α-subunit chaperone and guanine-nucleotide exchange factor
Ric8A regulates G protein α-subunits (Gα) by acting as a guanine nucleotide exchange factor (GEF) and a Gα chaperone. Here, the authors solve the crystal structures of free and Gα fragment bound Ric8A, and provide insights into the structural basis for Ric8A’s GEF and chaperone functions.
- Dhiraj Srivastava
- , Lokesh Gakhar
- & Nikolai O. Artemyev
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Article
| Open AccessStructural basis for the inhibition of translation through eIF2α phosphorylation
During stress, protein synthesis is inhibited through phosphorylation of the initiation factor eIF2 on its alpha subunit and its interaction with eIF2B. Here the authors describe a structure of the yeast eIF2B in complex with its substrate - the GDP-bound phosphorylated eIF2, providing insights into how phosphorylation results in a tighter interaction with eIF2B.
- Yuliya Gordiyenko
- , José Luis Llácer
- & V. Ramakrishnan
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Article
| Open AccessStructural determinants of Rab11 activation by the guanine nucleotide exchange factor SH3BP5
Rab11 GTPases are involved in various cellular processes but their activation by guanine nucleotide exchange factors (GEFs) is not fully understood. Here, the authors present a structural and biochemical analysis of Rab11 bound to the GEF SH3BP5, providing insights how Rab-GEF specificity is achieved.
- Meredith L. Jenkins
- , Jean Piero Margaria
- & John E. Burke
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Article
| Open AccessThe protease GtgE from Salmonella exclusively targets inactive Rab GTPases
The bacterial protease GtgE is involved in the establishment of Salmonellosis. Here the authors provide a structural and biochemical analysis of GtgE that sheds light on the molecular mechanisms of reprogramming infected host cells via site-specific proteolytic cleavage of the vesicular trafficking regulator Rab32.
- Rudolf Wachtel
- , Bastian Bräuning
- & Aymelt Itzen
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Article
| Open AccessA conformational switch in initiation factor 2 controls the fidelity of translation initiation in bacteria
The GTP-bound form of initiation factor 2 (IF2) promotes translation initiation by accelerating 50S ribosomal subunit joining the 30S ribosomal initiation complex (30S IC). Here the authors use single-molecule FRET and ensemble rapid kinetic methods to uncover the mechanism behind IF2-mediated subunit joining.
- Kelvin Caban
- , Michael Pavlov
- & Ruben L. Gonzalez Jr
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Article
| Open AccessMechanism of SOS PR-domain autoinhibition revealed by single-molecule assays on native protein from lysate
The guanine nucleotide exchange factor SOS is a critical intermediary that transduces receptor tyrosine kinase stimulation into Ras activation. Here the authors develop a single molecule assay in which SOS is captured from raw lysates using Ras-functionalized membrane microarrays and uncover an autoinhibitory mechanism of SOS regulation.
- Young Kwang Lee
- , Shalini T. Low-Nam
- & Jay T. Groves
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Article
| Open AccessBidirectional regulation of synaptic transmission by BRAG1/IQSEC2 and its requirement in long-term depression
BRAG1 mutations are linked to synaptic deficits and X-chromosome linked intellectual disability. Here, the authors show that BRAG1 mediates activity-dependent removal of synaptic AMPA receptors via Arf-GEF activity and PDZ interactions, and is required for maintaining AMPAR-mediated synaptic transmission.
- Joshua C. Brown
- , Amber Petersen
- & Nashaat Z. Gerges
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Article
| Open AccessEmerging roles of ARHGAP33 in intracellular trafficking of TrkB and pathophysiology of neuropsychiatric disorders
The molecular mechanisms of neurotrophin receptor trafficking are only partially understood. Here the authors show that ARHGAP33 interacts with SORT1 to regulate TrkB trafficking, the dysfunction of which impairs synapse development and leads to schizophrenia-related behavioural abnormalities in mice.
- Takanobu Nakazawa
- , Ryota Hashimoto
- & Masanobu Kano
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Rheb activation disrupts spine synapse formation through accumulation of syntenin in tuberous sclerosis complex
Tuberous sclerosis complex (TSC) arises from mutations in an activator of the small GTPase Rheb. Here the authors show that syntenin binds to GDP-bound Rheb, and loss of this interaction in TSC leads to increased syntenin expression and downstream signalling defects leading to aberrant spine synapse morphogenesis.
- Hiroko Sugiura
- , Shin Yasuda
- & Kanato Yamagata
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Article |
P-Rex1 is required for efficient melanoblast migration and melanoma metastasis
The processes that regulate melanoblast migration during development are also thought to be involved in melanoma metastasis. Here, Prex1 null mice are shown to have a melanoblast migration defect and, when crossed to a mouse model of melanoma, are resistant to metastasis, suggesting a role for Prex1 in metastatic melanoma.
- Colin R. Lindsay
- , Samuel Lawn
- & Owen J. Sansom
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Article |
G-protein β2 subunit interacts with mitofusin 1 to regulate mitochondrial fusion
Little is known about the regulation of mitofusin proteins that are involved in the fusion of mitochondrial membranes. In this study, the authors report that a heterotrimeric G protein, Gβ-subunit 2, can interact with mitofusin 1, and is involved in the regulation of mitochondrial fusion.
- Juan Zhang
- , Weihua Liu
- & Quan Chen