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| Open AccessThe prion-like domain of Drosophila Imp promotes axonal transport of RNP granules in vivo
The physiological role of prion-like domains (PLDs) within RNA-binding proteins is not well understood. Here, authors show in Drosophila that the PLD in the protein Imp is required for localization of ribonucleoprotein granules to axons and axonal remodelling.
- Jeshlee Vijayakumar
- , Charlène Perrois
- & Florence Besse
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Article
| Open AccessThe structural basis for release-factor activation during translation termination revealed by time-resolved cryogenic electron microscopy
Translation termination is under strong selection pressure for high speed and accuracy. Here the authors provide a 3D view of the dynamics of a translating bacterial ribosome as it recruits a class-1 release factor (RF1 or RF2) upon encountering a stop codon, and propose a structure-based kinetic model for the early steps in bacterial translation termination.
- Ziao Fu
- , Gabriele Indrisiunaite
- & Joachim Frank
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Article
| Open AccessElectric field dynamics in the brain during multi-electrode transcranial electric stimulation
Transcranial alternating current stimulation (TACS) of the brain is widely used in neuroscience, but the electric fields produced when multiple stimulation electrodes are used are not well understood. Here, the authors directly record electric fields in primate brains during multi-electrode TACS.
- Ivan Alekseichuk
- , Arnaud Y. Falchier
- & Alexander Opitz
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Article
| Open AccessDiffusing wave paradox of phototactic particles in traveling light pulses
The amoebae Dictyostelium have previously been observed to migrate counter to the direction of a traveling chemical wave. Here the authors demonstrate that light-activated phototactic synthetic particles move counter to the pulse direction in a way which is reminiscent of the amoebae’s behavior.
- Celia Lozano
- & Clemens Bechinger
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Article
| Open AccessSelective recruitment of different Ca2+-dependent transcription factors by STIM1-Orai1 channel clusters
Endoplasmic reticulum Ca2+ sensing STIM proteins and plasma membrane Orai1 channels together regulate Ca2+ influx in eukaryotic cells. Here authors show that two Ca2+-dependent transcription factors, NFAT1 and c-fos, have different requirements for the number of STIM1-Orai1 clusters and on the Ca2+ flux through the clusters.
- Yu-Ping Lin
- , Daniel Bakowski
- & Anant B. Parekh
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Article
| Open AccessTau local structure shields an amyloid-forming motif and controls aggregation propensity
The biophysical mechanisms of how disease-associated tau mutations drive amyloid formation are not well understood. Here the authors use biophysical approaches, cell models and MD simulations and find that the intrinsically disordered repeat domain of tau encodes a metastable local structure and perturbations through mutations and proline isomerization cause an aggregation phenotype in vitro and in cells.
- Dailu Chen
- , Kenneth W. Drombosky
- & Lukasz A. Joachimiak
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Article
| Open AccessAuto-encoding NMR chemical shifts from their native vector space to a residue-level biophysical index
NMR chemical shift information is highly valuable in the investigation of small molecule and protein structure. Here, the authors developed a neural network approach to unify protein chemical shifts and their changes in response to changes in protein sequence, structure, and dimerization interactions.
- Gabriele Orlando
- , Daniele Raimondi
- & Wim F. Vranken
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Article
| Open AccessDisordered RNA chaperones can enhance nucleic acid folding via local charge screening
RNA chaperones, such as the hepatitic C virus (HCV) core protein, are proteins that aid in the folding of nucleic acids. Here authors use single‐molecule spectroscopy and simulation to show that the HCV core protein acts as a flexible macromolecular counterion which facilitates nucleic acid folding.
- Erik D. Holmstrom
- , Zhaowei Liu
- & Benjamin Schuler
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Article
| Open AccessInvariance properties of bacterial random walks in complex structures
It has been previously shown theoretically that the average path length of random walks inside a closed domain is invariant. Here the authors demonstrate that this invariance property can be used to predict the mean residence time of swimming bacteria exploring structured micro-environments.
- Giacomo Frangipane
- , Gaszton Vizsnyiczai
- & Roberto Di Leonardo
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Article
| Open AccessA mechanism for reversible mesoscopic aggregation in liquid solutions
Solutions of proteins and other molecules can host puzzling, solute-rich inclusions of mesoscopic dimensions. Here the authors report a mechanism by which mesoscopic clusters can nucleate and ripen, requiring that the solute form long-lived complexes, with implications for biologically and industrially relevant systems.
- Ho Yin Chan
- & Vassiliy Lubchenko
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Perspective
| Open AccessAre microtubules tension sensors?
Cellular mechanical stress is a key determinant of cell shape and function, but how the cell senses stress direction is unclear. In this Perspective the authors propose that microtubules autonomously sense stress directions in plant cells, where tensile stresses are higher than in animal cells.
- Olivier Hamant
- , Daisuke Inoue
- & Eric Mjolsness
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Article
| Open AccessThe origin of heterogeneous nanoparticle uptake by cells
Cellular uptake of nanoparticles is highly variable between individual cells in a population. Here, the authors show that this heterogeneity is a result of varying numbers of nanoparticle-containing endosomes while the nanoparticle dose per endosome remains constant.
- Paul Rees
- , John W. Wills
- & Huw D. Summers
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Article
| Open AccessDirect imaging of the circular chromosome in a live bacterium
Bacterial chromosomes are tightly packed, limiting structural analysis by imaging techniques. Here, by quantitative time-lapse single-cell imaging of widened Escherichia coli cells, Wu and Japaridze et al. show that the chromosome exhibits a ring-like torus topology and a dynamic domain structure.
- Fabai Wu
- , Aleksandre Japaridze
- & Cees Dekker
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Article
| Open AccessMolecular basis for heat desensitization of TRPV1 ion channels
The heat-sensitive ion channel TRPV1 is essential to temperature sensing in mammals and other animals. Here the authors find that the platypus form of TRPV1 does not desensitize, identify the mechanism underlying this property, and show that knock-in of this form of the receptor in mice leads to deficits in heat sensitivity.
- Lei Luo
- , Yunfei Wang
- & Ren Lai
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Article
| Open AccessControlling CRISPR-Cas9 with ligand-activated and ligand-deactivated sgRNAs
Control of CRISPR-Cas9 activity allows for fine-tuning of editing and gene expression. Here the authors use gRNAs modified with RNA aptamers to enable small molecule control in bacterial systems.
- Kale Kundert
- , James E. Lucas
- & Tanja Kortemme
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Article
| Open AccessInitial state of DNA-Dye complex sets the stage for protein induced fluorescence modulation
Protein-induced fluorescence enhancement (PIFE) is a popular tool for characterizing protein-DNA interactions. Here, authors provide a perspective on understanding the general phenomenon of induced fluorescence modulation
- Fahad Rashid
- , Vlad-Stefan Raducanu
- & Samir M. Hamdan
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Article
| Open AccessSingle-molecule kinetics of pore assembly by the membrane attack complex
The membrane attack complex (MAC) is a hetero-oligomeric protein assembly that kills pathogens by perforating their cell envelopes. Here, the authors use atomic force microscopy to show that MAC proteins oligomerize within the membrane, allowing them to identify the kinetic bottleneck of MAC formation.
- Edward S. Parsons
- , George J. Stanley
- & Bart W. Hoogenboom
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Article
| Open AccessBacterial hopping and trapping in porous media
Many bacteria swim with run-and-tumble motion in unconfined fluid. Here the authors report that confinement of these bacteria in a 3D porous medium changes this motion into hopping and trapping, in which the cells are intermittently and transiently trapped as they navigate the pore space.
- Tapomoy Bhattacharjee
- & Sujit S. Datta
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Article
| Open AccessSide chain to main chain hydrogen bonds stabilize a polyglutamine helix in a transcription factor
Polyglutamine (polyQ) tracts are low-complexity regions and their expansion is linked to certain neurodegenerative diseases. Here the authors combine experimental and computational approaches to find that the length of the androgen receptor polyQ tract correlates with its helicity and show that the polyQ helical structure is stabilized by hydrogen bonds between the Gln side chains and main chain carbonyl groups.
- Albert Escobedo
- , Busra Topal
- & Xavier Salvatella
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Article
| Open AccessA binding cooperativity switch driven by synergistic structural swelling of an osmo-regulatory protein pair
The bacterial protein Cnu together with the transcription repressor H-NS regulate expression of virulence factors in an osmo-sensitive manner. Here authors show that the structure of Cnu swells with decreasing ionic strength driving the oligomerization of H-NS and regulating osmo-sensory response.
- Abhishek Narayan
- , Soundhararajan Gopi
- & Athi N. Naganathan
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Article
| Open AccessRed-shifting mutation of light-driven sodium-pump rhodopsin
Microbial rhodopsins are photoreceptive and widely used in optogenetics for which they should preferable function with longer-wavelength light. Here, authors achieve a 40-nm red-shift in the absorption wavelength of a sodium-pump rhodopsin (KR2) by altering the distribution of the retinal chromophore.
- Keiichi Inoue
- , María del Carmen Marín
- & Hideki Kandori
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Article
| Open AccessA calcium/cAMP signaling loop at the ORAI1 mouth drives channel inactivation to shape NFAT induction
ORAI1 constitutes the store-operated Ca2+ release-activated Ca2+ (CRAC) channel, but how this channel is turned off through Ca2+-dependent inactivation (CDI) remained unclear. Here the authors identify a spatially-restricted Ca2+/cAMP signaling crosstalk critical for mediating CDI which in turn regulates cellular Ca2+ signals and NFAT activation.
- Xuexin Zhang
- , Trayambak Pathak
- & Mohamed Trebak
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Article
| Open AccessCeramides bind VDAC2 to trigger mitochondrial apoptosis
Ceramides are lipids that act directly on mitochondria to trigger apoptosis, but the underlying mechanism remains largely unclear. Here authors use a photoactivatable ceramide probe combined with a computation approach and functional studies to identify the voltage-dependent anion channel VDAC2 as a direct effector of ceramide-mediated cell death.
- Shashank Dadsena
- , Svenja Bockelmann
- & Joost C. M. Holthuis
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Article
| Open AccessAn inner activation gate controls TMEM16F phospholipid scrambling
TMEM16F is an enigmatic Ca2 + -activated phospholipid scramblase (CaPLSase) that passively transports phospholipids. Here authors identify an inner activation gate and its disruption profoundly alters TMEM16F phospholipid permeation.
- Trieu Le
- , Zhiguang Jia
- & Huanghe Yang
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Article
| Open AccessRNA G-quadruplex is resolved by repetitive and ATP-dependent mechanism of DHX36
DHX36 is a G-quadruplex (G4) resolving helicase that targets both DNA-G4 and RNA-G4. Here the authors use single molecule FRET measurements and show that DHX36 resolves RNA-G4 structures by a mechanism involving an ATP-dependent, highly repetitive and stepwise refolding of RNA-G4 that differs from its DNA-G4 structures resolving mechanism.
- Ramreddy Tippana
- , Michael C. Chen
- & Sua Myong
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Article
| Open AccessThe dynamic and structural properties of axonemal tubulins support the high length stability of cilia
The axoneme in cilia and flagella has exceptionally high stability despite being composed of microtubules that are known to be highly dynamic. Here authors extract tubulin from different components of Chlamydomonas reinhardtii axonemes and characterize their properties.
- Ron Orbach
- & Jonathon Howard
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Article
| Open AccessDynamic fibroblast contractions attract remote macrophages in fibrillar collagen matrix
Macrophages play an important role in wound healing but the guidance cues driving macrophages to sites of repair are still not clear. Here the authors discover that macrophages are attracted to contracting fibroblasts by responding to locally sensed displacements of collagen fibres.
- Pardis Pakshir
- , Moien Alizadehgiashi
- & Boris Hinz
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Article
| Open AccessSmall molecule electro-optical binding assay using nanopores
Nanopore detection of small molecules can be improved using molecular carriers, but separating a small analyte from the carrier signal can be challenging. Here the authors address this challenge using simultaneous electrical and optical readout in nanopore sensing to detect small molecules and quantify binding affinities.
- Shenglin Cai
- , Jasmine Y. Y. Sze
- & Joshua B. Edel
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Article
| Open AccessSelf-organization of swimmers drives long-range fluid transport in bacterial colonies
Motile and non-motile subpopulations often coexist in bacterial communities. Here, Xu et al. show that motile cells in colonies of common flagellated bacteria can self-organize into two adjacent motile rings, driving stable flows of fluid and materials around the colony.
- Haoran Xu
- , Justas Dauparas
- & Yilin Wu
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Article
| Open AccessMechanism of the electroneutral sodium/proton antiporter PaNhaP from transition-path shooting
Cation-proton antiporters mediate selective ion exchange across cellular membranes to control pH, salt concentration and cell volume. Here the authors present a transition-path sampling method that overcomes the timescale gap between simulations (µs) and transport processes (s), which allows them to resolve the Na+ and H+ transport cycle of the Na+/H+ antiporter NhaP from Pyrococcus abyssi.
- Kei-ichi Okazaki
- , David Wöhlert
- & Gerhard Hummer
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Article
| Open AccessCentromere mechanical maturation during mammalian cell mitosis
During mitosis, tension at the centromere occurs from the spindle but the role of centromere mechanics in controlling metaphase tension is poorly understood. Here, the authors report that mechanical stiffnness of the centromere matures during mitotic progression and is amplified specifically at metaphase.
- Lauren A. Harasymiw
- , Damien Tank
- & Melissa K. Gardner
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Article
| Open AccessCharacterising side chains in large proteins by protonless 13C-detected NMR spectroscopy
Analysis of side-chain motions by NMR has so far been restricted to small proteins and methyl-bearing side chains. Here, the authors present NMR methods based on 13C direct detection of highly deuterated protein samples that yield sharp and well-resolved signals and allow the characterisation of side-chain conformational dynamics of six different amino acid types in medium-to-large proteins.
- Ruth B. Pritchard
- & D. Flemming Hansen
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Article
| Open AccessVisualizing conformation transitions of the Lipid II flippase MurJ
MurJ is the flippase for the lipid-linked peptidoglycan precursor Lipid II, a key player in bacterial cell wall synthesis, but the flipping mechanism remains poorly understood. Here authors report crystal structures of MurJ in different conformations which shed light on the MurJ transitions that mediate lipid flipping.
- Alvin C. Y. Kuk
- , Aili Hao
- & Seok-Yong Lee
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Article
| Open AccessDirect observation of coordinated DNA movements on the nucleosome during chromatin remodelling
Chromatin remodelling enzymes (remodellers) regulate DNA accessibility of eukaryotic genomes, which rely in large part on an ability to reposition nucleosomes. Here the authors use three-colour single-molecule FRET to simultaneously monitor remodeller-induced DNA movements on both sides of the nucleosome in real-time.
- Anton Sabantsev
- , Robert F. Levendosky
- & Sebastian Deindl
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Article
| Open AccessMicrotubule end conversion mediated by motors and diffusing proteins with no intrinsic microtubule end-binding activity
During cell division, it is currently unclear how kinetochores transit from lateral microtubule attachment to durable association to dynamic microtubule plus ends. Here, using in vitro reconstitution and computer modeling, the authors provide biophysical mechanism for microtubule end-conversion driven by two kinetochore components, CENP-E and Ndc80 complex
- Manas Chakraborty
- , Ekaterina V. Tarasovetc
- & Ekaterina L. Grishchuk
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Article
| Open AccessMultimodal interference-based imaging of nanoscale structure and macromolecular motion uncovers UV induced cellular paroxysm
Methods to track molecular motion in eukaryotic cells mostly rely on fluorescent labels, transfection or photobleaching. Here the authors use multimodal partial wave spectroscopy to perform label-free live cell measurements of nanoscale structure and macromolecular motion with millisecond temporal resolution.
- Scott Gladstein
- , Luay M. Almassalha
- & Vadim Backman
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Article
| Open AccessQuantifying dissipation using fluctuating currents
The determination of entropy production from experimental data is a challenge but a recently introduced theoretical tool, the thermodynamic uncertainty relation, allows one to infer a lower bound on entropy production. Here the authors provide a critical assessment of the practical implementation of this tool.
- Junang Li
- , Jordan M. Horowitz
- & Nikta Fakhri
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Article
| Open AccessInfluenza A virus ribonucleoproteins form liquid organelles at endoplasmic reticulum exit sites
Influenza A virus forms cytosolic inclusions containing viral ribonucleoproteins. Here, the authors show that viral inclusions form juxtaposed the endoplasmic reticulum and have liquid properties, likely constituting sites of assembly of epidemic and pandemic influenza genomes.
- Marta Alenquer
- , Sílvia Vale-Costa
- & Maria João Amorim
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Article
| Open AccessDifferent soluble aggregates of Aβ42 can give rise to cellular toxicity through different mechanisms
Amyloid beta (Aβ42) peptides form heterogeneous mixtures of aggregates, which are closely linked to Alzheimer’s disease. This study shows how different types of Aβ42 aggregates are associated with distinct mechanisms of toxicity
- Suman De
- , David C. Wirthensohn
- & David Klenerman
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Article
| Open AccessSingle-molecule characterization of extrinsic transcription termination by Sen1 helicase
Yeast’s Sen1 helicase is involved in the suppression of antisense transcription from bidirectional eukaryotic promoters. Here authors develop and utilize a quantitative single-molecule assay reporting on the kinetics of extrinsic eukaryotic transcription termination by the Sen1 helicase and a reaction intermediate in which the Pol II transcription bubble appears half-rewound.
- S. Wang
- , Z. Han
- & T. R. Strick
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Article
| Open AccessCa2+-dependent regulation of sodium channels NaV1.4 and NaV1.5 is controlled by the post-IQ motif
Skeletal muscle voltage-gated Na+ channel (NaV1.4) activity is subject to calmodulin (CaM) mediated Ca2 +-dependent inactivation while cardiac NaV1.5 is not. Here authors use structural biology, binding and electrophysiology to parse the Ca2 +-dependent changes of CaM when bound to the NaV1.4.
- Jesse B. Yoder
- , Manu Ben-Johny
- & L. Mario Amzel
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Article
| Open AccessTunable microsecond dynamics of an allosteric switch regulate the activity of a AAA+ disaggregation machine
Large protein machines are tightly regulated through allosteric communication channels. Here authors use single-molecule FRET and demonstrate the involvement of ultrafast conformational dynamics in the allosteric regulation of ClpB, a hexameric AAA+ machine that rescues aggregated proteins.
- Hisham Mazal
- , Marija Iljina
- & Gilad Haran
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Article
| Open AccessX-ray structures of the high-affinity copper transporter Ctr1
Copper (Cu) is an essential trace element for growth and development and the Cu+ transporter Ctr1 is crucial for both dietary Cu uptake and peripheral distribution. Here authors solve Cu+ -free and Cu+ -bound Ctr1 structures which adopt a homo-trimeric Cu+ -selective ion channel-like architecture
- Feifei Ren
- , Brandon L. Logeman
- & Peng Yuan
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Article
| Open AccessSelective binding of a toxin and phosphatidylinositides to a mammalian potassium channel
G-protein-gated inward rectifying potassium channels (GIRKs) require Gβγ subunits and phosphorylated phosphatidylinositides (PIPs) for gating. Here authors use native ion mobility mass spectrometry to monitor small molecule binding events to GIRK2 and shed light on the selectivity of GIRK2 towards PIPs.
- Yang Liu
- , Catherine E. LoCaste
- & Arthur Laganowsky
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Article
| Open AccessThe conserved NxNNWHW motif in Aha-type co-chaperones modulates the kinetics of Hsp90 ATPase stimulation
Hsp90 is a molecular chaperone that acts together with co-chaperones to ensure folding and activation of many client proteins. Here authors show that a N-terminal motif in Aha-type co-chaperones modulates the apparent affinity of Hsp90 for nucleotide substrates.
- Rebecca Mercier
- , Annemarie Wolmarans
- & Paul LaPointe
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Article
| Open AccessGrowth strategy of microbes on mixed carbon sources
Bacteria grown on two carbon sources either consume both sources simultaneously or consume them sequentially. Here the authors use a metabolic network model of E. coli to show that optimal protein resource allocation and topological features of the network can explain the choice of carbon acquisition.
- Xin Wang
- , Kang Xia
- & Chao Tang
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Article
| Open AccessDistinct G protein-coupled receptor phosphorylation motifs modulate arrestin affinity and activation and global conformation
The cellular functions of arrestins are determined in part by the pattern of phosphorylation on the G protein-coupled receptors (GPCRs) to which arrestins bind. Here, authors use a library of synthetic phosphopeptide analogues of the GPCR rhodopsin C-terminus and determine the ability of these peptides to bind and activate arrestins using a variety of biochemical and biophysical methods.
- Daniel Mayer
- , Fred F. Damberger
- & Dmitry B. Veprintsev
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Article
| Open AccessSimulations suggest a constrictive force is required for Gram-negative bacterial cell division
It is unclear whether a constrictive force is exerted on the membrane from inside during bacterial cell division, or cell wall remodeling alone drives membrane constriction from outside. Here, the authors use simulations to explore different mechanisms for cell wall division, supporting that a constrictive force is required.
- Lam T. Nguyen
- , Catherine M. Oikonomou
- & Grant J. Jensen
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Article
| Open AccessMembrane-cytoskeletal crosstalk mediated by myosin-I regulates adhesion turnover during phagocytosis
Phagocytosis of pathogens is thought to proceed through the sequential engagement of Fc-receptors on the phagocyte with antibodies on the target surface. Here authors show that myosin 1e and myosin 1f link the actin cytoskeleton to the membrane and are required for efficient phagocytosis of antibody-opsonized targets.
- Sarah R. Barger
- , Nicholas S. Reilly
- & Nils C. Gauthier