Featured
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| Open AccessReciprocating RNA Polymerase batters through roadblocks
During transcription, RNA polymerases may encounter protein roadblocks along template DNA. Here, Qian et al. use magnetic tweezers to show that RNA polymerases can backtrack and ram into longer lived roadblocks to transit through them.
- Jin Qian
- , Allison Cartee
- & Laura Finzi
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Article
| Open AccessKinetic trapping organizes actin filaments within liquid-like protein droplets
Here the authors perform modelling to reveal that the timescale of actin-VASP interactions plays a critical role in actin ring formation and filament length determines droplet deformation in VASP droplets: predictions from the model were tested against VASP GAB mutant.
- Aravind Chandrasekaran
- , Kristin Graham
- & Padmini Rangamani
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Article
| Open AccessHydrophobic mismatch drives self-organization of designer proteins into synthetic membranes
The organization of membrane proteins is critical to cellular function. Here the authors explore how computational protein design, MD simulation, and cell-free systems can be combined to elucidate how membrane-protein hydrophobic mismatch affects protein folding and organization in synthetic lipid membranes.
- Justin A. Peruzzi
- , Jan Steinkühler
- & Neha P. Kamat
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Article
| Open AccessTension activation of mechanosensitive two-pore domain K+ channels TRAAK, TREK-1, and TREK-2
TRAAK, TREK-1 and TREK-2 are mechanosensitive potassium channels involved in action potential propagation among other roles. Here, authors quantify their tension response and show ultrasound can generate tension to activate ion channels.
- Ben Sorum
- , Trevor Docter
- & Stephen G. Brohawn
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Article
| Open AccessAn adaptive biomolecular condensation response is conserved across environmentally divergent species
Cells must respond to environmental changes. In three fungal species adapted to different temperatures, cellular responses are conserved yet tuned to each organism’s thermal niche, including the formation of adaptive biomolecular condensates.
- Samantha Keyport Kik
- , Dana Christopher
- & D. Allan Drummond
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Article
| Open AccessPathogenic mutations of human phosphorylation sites affect protein–protein interactions
Here the authors characterise the impact of phosphorylation site mutations in intrinsically disordered regions (IDRs) on protein-protein interactions, highlighting the critical role of phosphorylation of IDRs in health and disease.
- Trendelina Rrustemi
- , Katrina Meyer
- & Matthias Selbach
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Article
| Open AccessFuzzy recognition by the prokaryotic transcription factor HigA2 from Vibrio cholerae
Here, the authors dissect the fuzzy interaction between the prokaryote transcription factor HigA2 and its DNA target and show that specific, transient interactions drive specificity despite HigA2 remaining mostly disordered.
- San Hadži
- , Zala Živič
- & Remy Loris
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Article
| Open AccessA subgroup of light-driven sodium pumps with an additional Schiff base counterion
Light-driven sodium-pumping rhodopsins are unique ion transporters. Here, authors present a characterization of such rhodopsins with a modified active center allowing for efficient sodium transport under various environmental conditions.
- E. Podoliak
- , G. H. U. Lamm
- & K. Kovalev
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Article
| Open AccessThe assembly platform FimD is required to obtain the most stable quaternary structure of type 1 pili
Type 1 pili are crucial cell surface bacterial virulence factors. Here, the authors show that FimD is required to assemble the most stable quaternary pilus structure by ensuring that the resulting protein polymer is free of structural defects.
- Dawid S. Zyla
- , Thomas Wiegand
- & Rudi Glockshuber
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Article
| Open AccessCryo-EM structure of the human Asc-1 transporter complex
The human Asc-1-4F2hc complex plays an important role in the neural development and stability. Here, authors determine the cryo-EM structures of Asc-1-4F2hc complex in three states, revealing its substrate recognition and transport mechanism.
- Yaning Li
- , Yingying Guo
- & Renhong Yan
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Article
| Open AccessEngineering an artificial catch bond using mechanical anisotropy
Catch bonds are unique protein-protein interactions where the bond lifetime increases under external pulling forces. Here, the authors engineer an artificial catch bond based on a non-catch bonding human gut bacterial adhesion protein complex.
- Zhaowei Liu
- , Haipei Liu
- & Michael A. Nash
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Article
| Open AccessHalogen doped graphene quantum dots modulate TDP-43 phase separation and aggregation in the nucleus
Modulating amyloid protein phase separation and fibrilization may help in addressing neurodegenerative diseases. This study demonstrates that halogen-doped graphene quantum dots can modulate these processes in TDP-43 in both nucleus and cytoplasm.
- Hong Zhang
- , Huazhang Guo
- & Bin Dai
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Article
| Open AccessBioelectric stimulation controls tissue shape and size
Electrical stimulation of hollow, 3D kidney tissues causes these tissues to inflate and change shape. The authors call this process electro-inflation and connect it to electricity driving ions into the center of the tissues, causing water to follow by osmosis.
- Gawoon Shim
- , Isaac B. Breinyn
- & Daniel J. Cohen
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Article
| Open AccessStructural bases of inhibitory mechanism of CaV1.2 channel inhibitors
CaV1.2 is crucial in cardiac, vascular and neuronal function, serving as a target for many drugs. Here, authors identify the binding site of herb-derived drug tetrandrine, and explore inhibitory mechanism of L/T-type selective DHP drug benidipine.
- Yiqing Wei
- , Zhuoya Yu
- & Yan Zhao
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Article
| Open AccessHairpin trimer transition state of amyloid fibril
Amyloid fibrils are ordered protein assemblies implicated in neurodegenerative disease. Here the authors show that hairpin trimers can be transition states of fibril nucleation, explaining how different fibril isoforms may arise from alternative nucleation sites.
- Levent Sari
- , Sofia Bali
- & Milo M. Lin
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Article
| Open AccessAdhesion energy controls lipid binding-mediated endocytosis
Many bacterial toxins and viruses deform membranes prior to entering cells via clathrin independent endocytosis. Here the authors show that multivalent lipid binding by globular particles can exceed a threshold adhesion energy required for membrane deformation and that this is sufficient for internalization.
- Raluca Groza
- , Kita Valerie Schmidt
- & Helge Ewers
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Article
| Open AccessCorrelating fluorescence microscopy, optical and magnetic tweezers to study single chiral biopolymers such as DNA
It is hard to correlate force, torque and localization information. The authors report Combined Optical and Magnetic BIomolecule TWEEZers, COMBI-Tweez, that integrates optical trapping, time-resolved electromagnetic tweezers, and fluorescence microscopy: they demonstrate visualisation of higher order structural motifs in DNA.
- Jack W. Shepherd
- , Sebastien Guilbaud
- & Mark C. Leake
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Article
| Open AccessA rapid inducible RNA decay system reveals fast mRNA decay in P-bodies
Studying RNA decay remains a challenging task. Here, the authors present a technology that enables inducible rapid degradation of targeted mRNAs. Visualizing mRNA decay dynamics unveils insights into P-body function in RNA metabolism.
- Lauren A. Blake
- , Leslie Watkins
- & Bin Wu
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Article
| Open AccessArchitecture and activation of human muscle phosphorylase kinase
High-resolution cryo-EM study of human muscle phosphorylase kinase reveals its complex structure and how calcium ions activate it, offering insights into glycogen metabolism and kinase regulation.
- Xiaoke Yang
- , Mingqi Zhu
- & Junyu Xiao
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Article
| Open AccessThe SARS-CoV-2 neutralizing antibody response to SD1 and its evasion by BA.2.86
Due to the focus of vaccination on the SARS CoV-2 spike protein, spike has been associated with high levels of viral mutation and subsequent immune escape. Here the authors study a conserved epitope in SARS CoV-2 sub-domain-1 and characterise the neutralising antibody response and evasion in contemporary SARS COV-2 viral strains.
- Daming Zhou
- , Piyada Supasa
- & Gavin R. Screaton
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Article
| Open AccessDirect observation of a crescent-shape chromosome in expanded Bacillus subtilis cells
The spatial structure of the bacterial chromosome is resolved in the absence of confinement by the cell boundary. Size-expanded cells reveal a crescent-shaped Bacillus subtilis chromosome and the effects of ParB and SMC proteins on chromosome shape.
- Miloš Tišma
- , Florian Patrick Bock
- & Cees Dekker
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Article
| Open AccessPhotocobilins integrate B12 and bilin photochemistry for enzyme control
Photoreceptor proteins utilise biological chromophores to regulate a large range of cellular processes in response to light. Here the authors identify and characterise a sub-family of multi-centre photoreceptors, termed photocobilins, that not only utilise B12 but also contain biliverdin (BV) as an additional chromophore.
- Shaowei Zhang
- , Laura N. Jeffreys
- & Nigel S. Scrutton
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Article
| Open AccessHigh-throughput prediction of protein conformational distributions with subsampled AlphaFold2
Protein dynamics, crucial for life, are difficult and expensive to predict. This study shows that AI-based structure prediction methods can be modified for rapidly predicting the conformational landscapes of proteins, with strong correlations with experimentally-measured relative state populations.
- Gabriel Monteiro da Silva
- , Jennifer Y. Cui
- & Brenda M. Rubenstein
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Article
| Open AccessDiverse roles of the metal binding domains and transport mechanism of copper transporting P-type ATPases
Controlling copper levels is essential for life, causing disease when impaired. Here, structures of a copper transporter sheds light on the function of its metal binding domains and unifies previous theories on the details of copper transport.
- Zongxin Guo
- , Fredrik Orädd
- & Pontus Gourdon
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Article
| Open AccessTomosyns attenuate SNARE assembly and synaptic depression by binding to VAMP2-containing template complexes
SNARE-dependent membrane fusion underlies neurotransmission in the nervous system. Here, the authors demonstrate how, in mammalian neurons, the synaptic protein tomosyn controls secretion by increasing the energy barrier for fusion.
- Marieke Meijer
- , Miriam Öttl
- & Matthijs Verhage
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Article
| Open AccessStructure of the intact tail machine of Anabaena myophage A-1(L)
The Myoviridae cyanophage A-1(L) specifically infects the model cyanobacteria Anabaena sp. PCC 7120. Here, authors present the high-resolution cryo-EM structure of its intact tail machine, and identify multiple hydrolytic and binding modules.
- Rong-Cheng Yu
- , Feng Yang
- & Cong-Zhao Zhou
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Article
| Open AccessBidirectional ATP-driven transport of cobalamin by the mycobacterial ABC transporter BacA
ABC transporters are generally considered to be unidirectional. Here, the authors develop a fluorescence-based transport assay and show that the mycobacterial ABC transporter BacA instead acts as a bidirectional transporter for cobalamin.
- Mark Nijland
- , Solène N. Lefebvre
- & Dirk J. Slotboom
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Article
| Open AccessAn optofluidic antenna for enhancing the sensitivity of single-emitter measurements
Single molecule investigations are often performed in fluidic environments, but molecular diffusion and limited photon counts can compromise studies of processes with fast or slow dynamics. The authors introduce a planar optofluidic antenna which enhances the fluorescence signal from molecules, applicable to a diverse range of studies.
- Luis Morales-Inostroza
- , Julian Folz
- & Vahid Sandoghdar
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Article
| Open AccessThe binding and mechanism of a positive allosteric modulator of Kv3 channels
To promote the development of effective small molecule modulators that may help treat diverse neuropsychiatric disorders, this study elucidates the mechanism of a specific positive modulator of neuronal potassium channels at near-atomic resolution.
- Qiansheng Liang
- , Gamma Chi
- & Manuel Covarrubias
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Article
| Open AccessStructure of an open KATP channel reveals tandem PIP2 binding sites mediating the Kir6.2 and SUR1 regulatory interface
KATP channels regulate insulin secretion and are activated by PIP2. Here, the authors show PIP2 binds between SUR1 and Kir6.2 to open the channel, and a neonatal diabetes mutation stabilizes KATP channels in a PIP2-bound open conformation.
- Camden M. Driggers
- , Yi-Ying Kuo
- & Show-Ling Shyng
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Article
| Open AccessDissecting the mechanism of atlastin-mediated homotypic membrane fusion at the single-molecule level
The detailed process of membrane fusion mediated by dynamin-like GTPase atlastin (ATL) remains unclear. Here, authors reveal the conformational dynamics of ATL coupled with GTP hydrolysis cycle at the single molecule level.
- Lijun Shi
- , Chenguang Yang
- & Xin Bian
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Article
| Open AccessDrug-resistant EGFR mutations promote lung cancer by stabilizing interfaces in ligand-free kinase-active EGFR oligomers
The Epidermal Growth Factor Receptor (EGFR) is frequently found to be mutated in non-small cell lung cancer. Here, the authors show that EGFR lung cancer mutations promote the assembly of kinase-active dimers within ligand-free EGFR oligomers. These dimers bind ligand with high affinity and promote tumor growth.
- R. Sumanth Iyer
- , Sarah R. Needham
- & Marisa L. Martin-Fernandez
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Article
| Open AccessStructural basis for autoinhibition by the dephosphorylated regulatory domain of Ycf1
Yeast cadmium factor 1 (Ycf1), a heavy metal and glutathione transporter, is regulated by an intrinsically disordered region called the regulatory domain. In this work, the authors show that this domain controls activity through autoinhibition of the glutathione cavity when it is dephosphorylated.
- Nitesh Kumar Khandelwal
- & Thomas M. Tomasiak
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Article
| Open AccessArchitecture of symbiotic dinoflagellate photosystem I–light-harvesting supercomplex in Symbiodinium
Here the authors determine the cryoEM structure of Symbiodinium photosystem I, revealing a distinct architecture and pigment network of this light-harvesting supercomplex.
- Long-Sheng Zhao
- , Ning Wang
- & Yu-Zhong Zhang
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Article
| Open AccessStructure of full-length ERGIC-53 in complex with MCFD2 for cargo transport
ERGIC-53 engages in the ER-to-Golgi transport of secretory and membrane proteins by unknown mechanisms. Here authors report a long flexible tetrameric structure of full-length ERGIC-53 complexed with its functional partner MCFD2 by cryo-EM.
- Satoshi Watanabe
- , Yoshiaki Kise
- & Kenji Inaba
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Article
| Open AccessComplexes of tubulin oligomers and tau form a viscoelastic intervening network cross-bridging microtubules into bundles
X-ray scattering and electron microscopy are used in concert to show that complexes of tubulin oligomers and tau are building blocks of an intervening network that cross-bridge microtubules into bundles with the same linear geometry observed in neurons.
- Phillip A. Kohl
- , Chaeyeon Song
- & Cyrus R. Safinya
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Article
| Open AccessDual receptor-sites reveal the structural basis for hyperactivation of sodium channels by poison-dart toxin batrachotoxin
The poison dart toxin batrachotoxin is the most lethal voltage-gated sodium channel toxin. Here authors identify the toxin bound specifically at two homologous receptor sites, which cause channel hyperactivation by positively modulating channel gating and altering ion conductance.
- Lige Tonggu
- , Goragot Wisedchaisri
- & William A. Catterall
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Article
| Open AccessTriggered contraction of self-assembled micron-scale DNA nanotube rings
Contractile rings are formed from cytoskeletal filaments, specific crosslinkers and motor proteins during cell division. Here, authors form micron-scale contractile DNA rings from DNA nanotubes and synthetic crosslinkers, with both simulations and experiments showing ring contraction without motor proteins, offering a potential first step towards synthetic cell division machinery.
- Maja Illig
- , Kevin Jahnke
- & Kerstin Göpfrich
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Article
| Open AccessTERRA-LSD1 phase separation promotes R-loop formation for telomere maintenance in ALT cancer cells
Here the authors show that the telomere repeat-containing RNA (TERRA) undergoes phase separation with the lysine-specific demethylase 1A (LSD1) to promote R-loop formation for homology-directed telomere DNA synthesis in the alternative lengthening of telomere (ALT) pathway.
- Meng Xu
- , Dulmi Senanayaka
- & Huaiying Zhang
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Article
| Open AccessMachine learning predictor PSPire screens for phase-separating proteins lacking intrinsically disordered regions
Here the authors report a machine learning model, PSPire, which integrates both residue-level and structure-level features and outperforms tools in identifying phase-separating proteins lacking intrinsically disordered regions.
- Shuang Hou
- , Jiaojiao Hu
- & Yong Zhang
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Article
| Open AccessA three-level regulatory mechanism of the aldo-keto reductase subfamily AKR12D
Here, the authors characterise an aldo-keto reductase AKRtyl, which belongs to a previously unidentified subfamily AKR12D. They uncover a complex mechanism of allosteric regulation that is mediated by 3 distinct states.
- Zhihong Xiao
- , Jinyin Zha
- & Shaobo Dai
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Article
| Open AccessChloride intracellular channel (CLIC) proteins function as fusogens
The Chloride Intracellular Channel (CLIC) protein family is highly conserved, yet their function remains a matter of ongoing research. Here, authors reveal their ability to facilitate membrane fusion, shedding light on their physiological role.
- Bar Manori
- , Alisa Vaknin
- & Yoni Haitin
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Article
| Open AccessRNA compaction and iterative scanning for small RNA targets by the Hfq chaperone
Small RNAs (sRNAs) turn bacterial genes on or off by base pairing with mRNAs. Here the authors employ single molecule fluorescence to show how sRNAs and their chaperone Hfq quickly locate the proper target by repeatedly scanning an mRNA until a stable match is found.
- Ewelina M. Małecka
- & Sarah A. Woodson
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Article
| Open AccessCryo-EM structures reveal how phosphate release from Arp3 weakens actin filament branches formed by Arp2/3 complex
Arp2/3 complex forms branched actin filaments for cell movements. Here, the authors report cryo-EM structures of branch junctions with ADP or ADPBeFx (to mimic γ-phosphate) bound to Arp3 to explain why γ-phosphate dissociation destabilizes branches.
- Sai Shashank Chavali
- , Steven Z. Chou
- & Charles V. Sindelar
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Article
| Open AccessIn-cell NMR suggests that DNA i-motif levels are strongly depleted in living human cells
I-Motifs (iM) are non-canonical DNA structures potentially forming in the accessible, single stranded, cytosine-rich genomic region, but the specific contributions of several factors involved in their formation are unknown. Using in-cell NMR, the authors examined DNA i-motif formation in human cells at body temperature, suggesting i-M occur in a small portion (<1%) of genomic sites predisposed to its formation.
- Pavlína Víšková
- , Eva Ištvánková
- & Lukáš Trantírek
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Article
| Open AccessStructural basis for the modulation of MRP2 activity by phosphorylation and drugs
The ABC transporter MRP2/ABCC2 is a polyspecific efflux transporter of organic anions expressed in hepatocyte canalicular membranes. Dysfunction leads to Dubin-Johnson syndrome. Here the authors provide structural and biochemical evidence on the modulation of MRP2 by intracellular kinases and inhibition by therapeutic drugs.
- Tiziano Mazza
- , Theodoros I. Roumeliotis
- & Konstantinos Beis
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Article
| Open AccessAlternative low-populated conformations prompt phase transitions in polyalanine repeat expansions
Here, the authors show that pathogenic mutations in the polyalanine expansions of PHOX2B promote nascent structural conformations that trigger irreversible phase transitions that arrest wild-type PHOX2B, disrupting function.
- Rosa Antón
- , Miguel Á. Treviño
- & Javier Oroz
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Article
| Open AccessHigh-density volumetric super-resolution microscopy
Current approaches for volumetric super-resolution microscopy can yield large and complex PSF spatial footprints. Here, the authors show a super-resolution microscopy approach using a hexagonal microlens array, which offers speed improvements in volumetric imaging compared to other single-molecule methods.
- Sam Daly
- , João Ferreira Fernandes
- & Steven F. Lee
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Article
| Open AccessStructure-guided engineering of biased-agonism in the human niacin receptor via single amino acid substitution
GPR109A is a prototypical GPCR and a key drug target for dyslipidemia. Here, the authors present cryo-EM structures of this receptor to elucidate agonist-binding and activation, and design receptor mutants with transducer-coupling-bias.
- Manish K. Yadav
- , Parishmita Sarma
- & Arun K. Shukla