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| Open AccessLabel-free identification of protein aggregates using deep learning
The authors use deep learning to detect and segment unlabeled and unaltered protein aggregates in living cells from transmitted-light images. The method provides a way to quantitatively study protein aggregation dynamics in a simple, fast and accurate way.
- Khalid A. Ibrahim
- , Kristin S. Grußmayer
- & Aleksandra Radenovic
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Article
| Open AccessLipIDens: simulation assisted interpretation of lipid densities in cryo-EM structures of membrane proteins
Interpretation of lipid-like densities in cryo-EM structures of membrane proteins is challenging. Here authors present LipIDens, enabling molecular dynamics analysis of protein-lipid interactions.
- T. Bertie Ansell
- , Wanling Song
- & Mark S. P. Sansom
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Article
| Open AccessSynaptotagmin-7 outperforms synaptotagmin-1 to promote the formation of large, stable fusion pores via robust membrane penetration
Synaptotagmin-1 and -7 are calcium sensors that distinctly drive vesicular exocytosis. Here, using wild-type proteins but manipulating the composition of the target membranes, the authors show that synaptotagmin-7 is unusually robust at penetrating membranes.
- Kevin C. Courtney
- , Taraknath Mandal
- & Edwin R. Chapman
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Article
| Open AccessStochastic chain termination in bacterial pilus assembly
Adhesive type-1 pili from Escherichia coli are filamentous protein complexes consisting of a short tip and a long rod formed by up to several thousand copies of a major subunit. Here, Giese et al. reconstitute the entire type-1 pilus rod assembly reaction in vitro, using all constituent protein subunits, and identify a subunit that acts as an irreversible assembly terminator.
- Christoph Giese
- , Chasper Puorger
- & Rudi Glockshuber
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Article
| Open AccessDynamical control enables the formation of demixed biomolecular condensates
In this work, the authors report that protein-RNA condensates with shared proteins and distinct RNAs can form and persist in vitro and in cells as distinct entities if the nonshared RNA molecules are dynamically arrested, but the shared protein components are dynamically exchangeable.
- Andrew Z. Lin
- , Kiersten M. Ruff
- & Rohit V. Pappu
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| Open AccessThe heat shock protein LarA activates the Lon protease in response to proteotoxic stress
The Lon protease is an important protein degradation machine and is conserved across the three domains of life. Here, the authors describe a small proteotoxic stress-induced protein that functions as an allosteric activator of Lon.
- Deike J. Omnus
- , Matthias J. Fink
- & Kristina Jonas
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Article
| Open AccessAcoustofluidic Interfaces for the Mechanobiological Secretome of MSCs
Efficient production of MSC secretome for therapeutic applications remains a challenging task. Here, the authors present an approach whereby an acoustofluidic mechanobiological environment can form reproducible 3D MSC aggregates, allowing for secretome production with high efficiency.
- Ye He
- , Shujie Yang
- & Tony Jun Huang
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Article
| Open AccessQuantification of ligand and mutation-induced bias in EGFR phosphorylation in direct response to ligand binding
The authors show that the oncogenic L834R EGFR mutation induces bias in EGFR signal transduction across the plasma membrane. While EGFR signalling is biased toward Y1068 phosphorylation, the mutation switches the preference to Y1173 phosphorylation.
- Daniel Wirth
- , Ece Özdemir
- & Kalina Hristova
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Article
| Open AccessMyr-Arf1 conformational flexibility at the membrane surface sheds light on the interactions with ArfGAP ASAP1
An integrated approach combing solution and solid-state NMR, molecular dynamics simulations and neutron reflectometry is applied to characterize dynamic membrane bound forms of ADP-ribosylation factor 1 (Arf1).
- Yue Zhang
- , Olivier Soubias
- & R. Andrew Byrd
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Article
| Open AccessHIV-1 Gag targeting to the plasma membrane reorganizes sphingomyelin-rich and cholesterol-rich lipid domains
Quantitative microscopies and specific lipid probes revealed that multimerizing HIV-1 Gag in the plasma membrane inner leaflet brings the outer leaflet sphingomyelin-rich and cholesterol-rich lipid domains closer in a curvature-dependent manner.
- Nario Tomishige
- , Maaz Bin Nasim
- & Toshihide Kobayashi
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Article
| Open AccessVesicles driven by dynein and kinesin exhibit directional reversals without regulators
Intracellular transport along microtubules involves runs, pauses and directional reversals. Here, D’Souza et al. mimic these dynamics in vitro using a minimal system of Dynein-Dynactin-BICD2 and Kinesin-3 on vesicles without the need for regulators.
- Ashwin I. D’Souza
- , Rahul Grover
- & Stefan Diez
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Article
| Open AccessActivation and substrate specificity of the human P4-ATPase ATP8B1
Asymmetric phospholipid distribution in cell membranes is vital for cellular function. Here, authors reveal how ATP8B1, a P4-ATPase, can transport different lipids, including phosphatidylinositol.
- Thibaud Dieudonné
- , Felix Kümmerer
- & Poul Nissen
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Article
| Open AccessMembrane potential accelerates sugar uptake by stabilizing the outward facing conformation of the Na/glucose symporter vSGLT
Sodium glucose transporters are critical for maintaining glucose homeostasis. Here, authors provide a detailed framework for how SGLTs utilize cellular membrane potentials to stabilize their substrate accepting conformation leading to accelerated transport.
- Farha Khan
- , Matthias Elgeti
- & Jeff Abramson
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Article
| Open AccessMechanically-primed voltage-gated proton channels from angiosperm plants
The authors describe a proton channel protein in the vasculature of Arabidopsis thaliana that requires both mechanical and electrical stimuli to turn on. A mechanistic analysis identifies the molecular determinants for the hybrid activation process.
- Chang Zhao
- , Parker D. Webster
- & Francesco Tombola
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Article
| Open AccessPatterning and dynamics of membrane adhesion under hydraulic stress
Hydraulic fracturing remodels cell-cell adhesions in physiology and during development. Here, authors combine vesicle experiments and computational modeling to identify the physical principles behind biological fracking.
- Céline Dinet
- , Alejandro Torres-Sánchez
- & Margarita Staykova
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Article
| Open AccessSimulation-guided engineering of split GFPs with efficient β-strand photodissociation
Green fluorescent proteins (GFPs) are ubiquitous for protein tagging and live cell imaging. Here, authors have used computational methods to engineer a fast-dissociating split GFP, which could be used to study macromolecular interactions.
- Yasmin Shamsudin
- , Alice R. Walker
- & Steven G. Boxer
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Article
| Open AccessThe structural and functional investigation into an unusual nitrile synthase
The nitrile synthase AetD is a crucial component in the biosynthetic pathway of neurotoxin aetokthonotoxin (AETX). Here, the authors solved crystal structures of AetD in complex with different substrates, revealing that AetD represents a new type of HO-like diiron enzyme and the possibility of expanding its substrate spectrum.
- Hao Li
- , Jian-Wen Huang
- & Chun-Chi Chen
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Article
| Open AccessStructural and dynamic mechanisms for coupled folding and tRNA recognition of a translational T-box riboswitch
T-box riboswitches are RNA-based gene regulators, composed of highly structured noncoding RNAs: the T-box and a tRNA ligand. Here, the authors assess the folding of a translational T-box aptamer and dissect the role of Mg2+, intra- and intermolecular RNA-RNA interactions in modulating its folding and function.
- Xiaolin Niu
- , Zhonghe Xu
- & Xianyang Fang
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Article
| Open AccessThe GET insertase exhibits conformational plasticity and induces membrane thinning
Tail-anchored (TA) membrane protein biogenesis is mediated by the GET insertase. Here, authors present cryo-EM and X-ray structures, MD simulations and functional data for human and fungal insertases showing membrane remodeling for TA insertion.
- Melanie A. McDowell
- , Michael Heimes
- & Irmgard Sinning
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| Open AccessMultiplexed detection of viral antigen and RNA using nanopore sensing and encoded molecular probes
Fast discrimination of SARS-CoV-2 variants in clinical samples remains a challenge. Here, authors report on single molecule nanopore sensing combined with DNA molecular probes to simultaneously detect various antigens and RNA mutations of SARS-CoV-2 variants in patient samples.
- Ren Ren
- , Shenglin Cai
- & Joshua B. Edel
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Article
| Open AccessCryo-EM structures of the plant anion channel SLAC1 from Arabidopsis thaliana suggest a combined activation model
Phosphorylation-mediated activation of SLAC1 anion channel is crucial in plant responses for abiotic stresses including drought. Here, authors determine the open and closed structures of SLAC1, revealing how phosphorylation can activate SLAC1.
- Yeongmok Lee
- , Hyeon Seong Jeong
- & Sangho Lee
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Article
| Open AccessLong-term cargo tracking reveals intricate trafficking through active cytoskeletal networks in the crowded cellular environment
Leveraging a label-free interferometric scattering microscope, scientists tracked numerous cargos within a crowded cellular environment. Intriguingly, cells employ effective strategies echoing human transportation systems to manage such transportation hurdles.
- Jin-Sung Park
- , Il-Buem Lee
- & Minhaeng Cho
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| Open AccessSingle-molecule FRET unmasks structural subpopulations and crucial molecular events during FUS low-complexity domain phase separation
Using single-molecule FRET, the authors discover hidden structural subpopulations of the intrinsically disordered prion-like low-complexity domain of FUS and dissect key molecular events that drive dynamic network formation during phase separation.
- Ashish Joshi
- , Anuja Walimbe
- & Samrat Mukhopadhyay
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Article
| Open AccessLocal membrane source gathering by p62 body drives autophagosome formation
Phase separated p62 body plays pivotal roles in autophagy. Here, the authors describe a spatial membrane gathering mode by which p62 body functions in autophagosome formation.
- Xuezhao Feng
- , Daxiao Sun
- & Na Mi
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Article
| Open AccessIntra- and inter-molecular regulation by intrinsically-disordered regions governs PUF protein RNA binding
FBF-2 and LST-1 repress gld-1 mRNA expression to maintain C. elegans germline stem cells. The authors show that an intrinsically-disordered region of FBF-2 autoinhibits its RNA binding. LST-1 antagonizes this interaction to promote RNA binding.
- Chen Qiu
- , Zihan Zhang
- & Traci M. Tanaka Hall
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Article
| Open AccessEnvironmental memory boosts group formation of clueless individuals
Indirect coordination among individuals through the environment typically requires some basic levels of communication and information processing. Dias et al. introduce a coordination mechanism that emerges in a population of clueless individuals, facilitated by environmental memory, culminating in group formation.
- Cristóvão S. Dias
- , Manish Trivedi
- & Giorgio Volpe
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Article
| Open AccessCryo-EM structure of TMEM63C suggests it functions as a monomer
TMEM63s are mechanosensitive ion channels activated by hypo-osmolality. Here, the authors determine the cryo-EM structure of mouse TMEM63C confirming its predominant monomeric state and the significance of TM0-TM6 coupling in channel activity.
- Yuqi Qin
- , Daqi Yu
- & Shangyu Dang
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Article
| Open AccessNde1 promotes Lis1-mediated activation of dynein
Lis1 and Nde1/Ndel1 mediate the initiation of dynein-driven transport, but the mechanism remains unclear. Here, the authors reveal that Nde1 recruits Lis1 to autoinhibited dynein and promotes Lis1-mediated assembly of active dynein transport machinery.
- Yuanchang Zhao
- , Sena Oten
- & Ahmet Yildiz
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Article
| Open AccessProgesterone activation of β1-containing BK channels involves two binding sites
Progesterone is used in recovery of cerebral ischemia however the mechanism of action is unknown. Authors report here that micromolar progesterone activates mouse cerebrovascular myocyte BK channels, involving two steroid binding sites.
- Kelsey C. North
- , Andrew A. Shaw
- & Alex M. Dopico
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Article
| Open AccessAsymmetric conformations and lipid interactions shape the ATP-coupled cycle of a heterodimeric ABC transporter
Multidrug resistance through active extrusion of molecules by transporters is a pressing clinical problem. Here, authors dissect the mechanism by which an ABC transporter from B. Subtilis binds and removes drugs by consuming the energy of ATP hydrolysis.
- Qingyu Tang
- , Matt Sinclair
- & Hassane S. Mchaourab
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Article
| Open AccessCryo-EM structures of human magnesium channel MRS2 reveal gating and regulatory mechanisms
Magnesium homeostasis is key for cellular functions. Here, authors report structures of human mitochondrial Mg2+ channel MRS2 and identified key residues in gating. This work provides insights into the gating and regulatory mechanisms of MRS2.
- Louis Tung Faat Lai
- , Jayashree Balaraman
- & Doreen Matthies
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Article
| Open AccessTargeting nucleic acid phase transitions as a mechanism of action for antimicrobial peptides
In this work the authors describe antimicrobial peptides (AMPs)-driven phase transitions of intracellular nucleic acids, whereby AMPs induce compaction and phase separation of nucleic acids, resulting in their sequestration and eventual cell death.
- Tomas Sneideris
- , Nadia A. Erkamp
- & Tuomas P. J. Knowles
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Article
| Open AccessStructural basis of peptide secretion for Quorum sensing by ComA
Quorum sensing is a regulatory mechanism controlling bacterial signaling and ComA, a conserved efflux pump, is responsible for the maturation and secretion of peptide signals. Here, authors determine the 3D structure and demonstrate its function as an ABC transporter.
- Lin Yu
- , Xin Xu
- & Min Luo
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Article
| Open AccessStructural insights into the modulation of coronavirus spike tilting and infectivity by hinge glycans
In this work, the authors combine cryo-electron tomography of vitrified virions, mass spectrometry, modeling, molecular dynamics and infectivity assay and report that a hinge glycan on viral spike protein influences virus infection and immune evasion.
- David Chmielewski
- , Eric A. Wilson
- & Wah Chiu
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Article
| Open AccessElevator-like movements of prestin mediate outer hair cell electromotility
Probing the molecular dynamics of the membrane motor, prestin, with biophysical measures and MD simulations, Kuwabara et al. find that an elevator-like domain movement across the membrane produces the unique piezoelectric behavior.
- Makoto F. Kuwabara
- , Bassam G. Haddad
- & Dominik Oliver
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Article
| Open AccessDual function of OmpM as outer membrane tether and nutrient uptake channel in diderm Firmicutes
Outer membrane tethering is important for cell envelope integrity in diderm bacteria. Here, the authors present structures and functional analyses of the stalked porin OmpM, which is the main outer membrane tethering system within the Terrabacteria.
- Augustinas Silale
- , Yiling Zhu
- & Bert van den Berg
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Article
| Open AccessStructure and function of the EA1 surface layer of Bacillus anthracis
S-layers form continuous protein lattices on the surface of bacteria. Here, authors use S-layer depolymerizing nanobodies to solve the structure of the EA1 S-layer in the pathogen Bacillus anthracis and show its role as cell wall supportive structure”
- Adrià Sogues
- , Antonella Fioravanti
- & Han Remaut
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Article
| Open AccessDNA strand breaks and gaps target retroviral intasome binding and integration
Here the authors use biochemical assays and single molecule imaging to show that DNA breaks and single-stranded gaps modulate dynamic PFV retroviral intasome interactions with target DNA and encourage site-specific integration.
- Gayan Senavirathne
- , James London
- & Kristine E. Yoder
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Article
| Open AccessEfficient optical plasmonic tweezer-controlled single-molecule SERS characterization of pH-dependent amylin species in aqueous milieus
Studying rare species in mixtures is challenging. Here, authors utilize on-and-off optical plasmonic trapping to control SERS-active nanocavity to analyse pH-dependent amylin species at single-molecule level, unveiling amyloid aggregation mechanisms.
- Wenhao Fu
- , Huanyu Chi
- & Jinqing Huang
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Article
| Open AccessIn situ quantification of osmotic pressure within living embryonic tissues
Osmotic pressure is thought to play a key role in many cellular and developmental processes, but remains challenging to measure it in cells and tissues. Here, the authors present a sensor based on double emulsion droplets that allows quantification of osmotic pressure in situ and in vivo.
- Antoine Vian
- , Marie Pochitaloff
- & Otger Campàs
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Article
| Open AccessCancer-associated fibroblasts actively compress cancer cells and modulate mechanotransduction
Cancer-associated fibroblasts (CAFs) can produce ECM and form a physical barrier around the tumour. Here, the authors show in transgenic mouse models and in vitro systems that CAFs are able to actively compress cancer cells using actomyosin contractility and this leads to a modulation of cancer cell mechanosensing and tumour reorganisation.
- Jorge Barbazan
- , Carlos Pérez-González
- & Danijela Matic Vignjevic
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Article
| Open AccessAn apical Phe-His pair defines the Orai1-coupling site and its occlusion within STIM1
The intermembrane complexes mediating calcium signals are crucial but poorly understood. Here the authors identify a Phe-His pair in the calcium-sensing STIM1 protein that controls both activation and pairing of STIM1 with Orai channels to generate calcium signals
- Yandong Zhou
- , Michelle R. Jennette
- & Donald L. Gill
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Article
| Open AccessStructural titration reveals Ca2+-dependent conformational landscape of the IP3 receptor
Inositol 1,4,5-trisphosphate receptors (IP3Rs) are intracellular Ca2+ channels that produce Ca2+ oscillations in response to GPCR and RTK activation. Here, Paknejad et al. resolve the conformational landscape of IP3Rs that gives rise to the biphasic dependence on Ca2+ for channel activity.
- Navid Paknejad
- , Vinay Sapuru
- & Richard K. Hite
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Article
| Open AccessFolding correctors can restore CFTR posttranslational folding landscape by allosteric domain–domain coupling
The conformational biogenesis of multi-domain ABC-transporters is poorly understood. Here the authors show the critical role of dynamic allosteric coupling networks, its perturbation and restoration in CFTR folding, misfolding, and pharmacological rescue, respectively.
- Naoto Soya
- , Haijin Xu
- & Gergely L. Lukacs
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Article
| Open AccessChromatinization modulates topoisomerase II processivity
Here the authors discover that chromatin stimulates topoisomerase II function by enabling the enzyme to achieve exceptionally high processivity and efficient supercoiling relaxation, even under low torsional stress.
- Jaeyoon Lee
- , Meiling Wu
- & Michelle D. Wang
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Article
| Open AccessSmall leucine-rich proteoglycans inhibit CNS regeneration by modifying the structural and mechanical properties of the lesion environment
The mechanical properties of central nervous system (CNS) scar tissue are considered to contribute to axon regeneration failure. Here, the authors identify members of the small leucine-rich proteoglycan family as modulators of the inhibitory viscoelastic response of CNS lesions.
- Julia Kolb
- , Vasiliki Tsata
- & Daniel Wehner
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Article
| Open AccessPhosphorylation-dependent pseudokinase domain dimerization drives full-length MLKL oligomerization
How the necroptosis executioner, MLKL, converts to a killer form has been mysterious. Here, authors show RIPK3-mediated phosphorylation of human MLKL is the cue for pseudokinase domain dimerization before assembly of pro-necroptotic MLKL tetramers.
- Yanxiang Meng
- , Sarah E. Garnish
- & James M. Murphy
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Article
| Open AccessGSG1L-containing AMPA receptor complexes are defined by their spatiotemporal expression, native interactome and allosteric sites
TARPs and GSG1L are evolutionarily- and structurally-related AMPA receptor auxiliary subunits that differ in function through unresolved mechanisms. Here, the authors provide insight into the spatiotemporal expression, composition, and functionality of GSG1L-containing protein complexes.
- Amanda M. Perozzo
- , Jochen Schwenk
- & Derek Bowie
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Article
| Open AccessRecognition and coacervation of G-quadruplexes by a multifunctional disordered region in RECQ4 helicase
In this work, the authors report a three-step charge-driven coacervation model involving dynamic complexes between a positively charged IDR of human RECQ4 and G-quadruplexes. The IDR also interacts with Replication Protein A, implying RECQ4’s regulatory role.
- Anna C. Papageorgiou
- , Michaela Pospisilova
- & Konstantinos Tripsianes