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| Open AccessRemote loop evolution reveals a complex biological function for chitinase enzymes beyond the active site
Loop regions play a key role in protein evolution. Herein the authors demonstrate how GH19 chitinase acquired additional antifungal activity by introducing remote loops, without compromising its original function. This work offers an innovative approach to expand enzyme function.
- Dan Kozome
- , Adnan Sljoka
- & Paola Laurino
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Article
| Open AccessFunctional protein dynamics in a crystal
Work by Klyshko and Kim et al. lays the foundation for simulating pump-probe experiments and demonstrates how the dynamic behaviour of proteins extends to the crystal environment, emphasizing the need for an ensemble view in understanding functional motions.
- Eugene Klyshko
- , Justin Sung-Ho Kim
- & Sarah Rauscher
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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 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 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 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 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 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 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 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 AccessDynamic control of DNA condensation
Artificial biomolecular condensates are valuable tools to study the design principles of phase separation. Here, the authors demonstrate and characterize a model system of artificial DNA condensates whose kinetic formation and dissolution depends on DNA inputs that activate or deactivate the phase separating DNA subunits.
- Siddharth Agarwal
- , Dino Osmanovic
- & Elisa Franco
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Article
| Open AccessSpecificity, synergy, and mechanisms of splice-modifying drugs
Two small-molecule drugs, risdiplam and branaplam, have been developed for treating spinal muscular atrophy. Here the authors develop quantitative modeling methods for the sequence-specific and concentration-dependent effects of these and other splice-modifying drugs.
- Yuma Ishigami
- , Mandy S. Wong
- & Justin B. Kinney
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Article
| Open AccessToxoplasma gondii actin filaments are tuned for rapid disassembly and turnover
Actin is critical to the survival of the parasite Toxoplasma gondii. In this study, Hvorecny and Sladewski et al. show that T. gondii actin forms intrinsically dynamic filaments in vitro due to differences in assembly contacts in the D-loop.
- Kelli L. Hvorecny
- , Thomas E. Sladewski
- & Aoife T. Heaslip
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Article
| Open AccessA release of local subunit conformational heterogeneity underlies gating in a muscle nicotinic acetylcholine receptor
Authors show that agonist binding to the muscle acetylcholine receptor releases local conformational heterogeneity transitioning all subunits into a symmetric open state. A release of conformational heterogeneity underlies allosteric communication.
- Mackenzie J. Thompson
- , Farid Mansoub Bekarkhanechi
- & John E. Baenziger
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Article
| Open AccessEmergence of slip-ideal-slip behavior in tip-links serve as force filters of sound in hearing
In this work, the authors report that tetrameric tip-link complex, pivotal for force transmission, forms slip-ideal-slip bonds under tension, serving as efficient force-filters in the auditory process.
- Nisha Arora
- , Jagadish P. Hazra
- & Sabyasachi Rakshit
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Article
| Open AccessAn alpha-helical lid guides the target DNA toward catalysis in CRISPR-Cas12a
CRISPR-Cas12a is a powerful RNA-guided genome-editing system. Saha et al. show that an alpha-helical lid plays the central role in guiding the target DNA toward the single RuvC nuclease domain, resulting in a double-stranded DNA break.
- Aakash Saha
- , Mohd Ahsan
- & Giulia Palermo
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Article
| Open AccessDynamics of activation in the voltage-sensing domain of Ciona intestinalis phosphatase Ci-VSP
Understanding the molecular basis of voltage-sensing is of great importance in biology. Here, the authors use computational analysis and simulations to reveal atomic level insights into the mechanism of an isolated voltage-sensing domain.
- Spencer C. Guo
- , Rong Shen
- & Aaron R. Dinner
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Article
| Open AccessBinding kinetics drive G protein subtype selectivity at the β1-adrenergic receptor
The authors show G protein subtype selectivity at the β1-adrenergic receptor is driven by the binding kinetics of ternary complex formation. Bound to G protein, the receptor adopts conformations that differ from its agonist-bound solution states.
- Andrew J. Y. Jones
- , Thomas H. Harman
- & Daniel Nietlispach
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Article
| Open AccessPredicting DNA structure using a deep learning method
In this work, the authors report a deep learning method, Deep DNAshape, to predict the influence of flanking regions on three-dimensional DNA structure and in structural readout mechanisms of protein-DNA binding.
- Jinsen Li
- , Tsu-Pei Chiu
- & Remo Rohs
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Article
| Open AccessHeterotypic interactions can drive selective co-condensation of prion-like low-complexity domains of FET proteins and mammalian SWI/SNF complex
Prion-like domains are intrinsically disordered regions found in many RNA- and DNA-binding proteins. Here, the authors show that these domains can drive sequence-specific co-phase separation of chromatin remodeling complex with FET oncofusion proteins.
- Richoo B. Davis
- , Anushka Supakar
- & Priya R. Banerjee
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Article
| Open AccessLocal structural preferences in shaping tau amyloid polymorphism
In this work, using a combination of Cryo-EM, in-cell experiments and biophysical analysis, the authors decoded the aggregation propensity of tau, revealing 5 central hot spots in its primary sequence and identify PAM4 as short segment that determines both the structure, as well as the cellular propagation of tau aggregates extracted from Alzheimer’s disease, corticobasal degeneration, and progressive supranuclear palsy patients.
- Nikolaos Louros
- , Martin Wilkinson
- & Joost Schymkowitz
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Article
| Open AccessA high affinity switch for cAMP in the HCN pacemaker channels
Cyclic AMP modulation of HCN channels underlies beta adrenergic stimulation of heart rate. Here, authors describe an intramolecular mechanism that controls cAMP affinity of the cyclic nucleotide binding domain of these channels.
- Alessandro Porro
- , Andrea Saponaro
- & Anna Moroni
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Article
| Open AccessAn extensive disulfide bond network prevents tail contraction in Agrobacterium tumefaciens phage Milano
Sonani et al. report the cryo-EM structures of the Milano phage tail, unraveling the mechanism of its flexible-to-rigid transformation, the inter-chain disulfide network hindering tail contraction and the structural organization of receptor binding proteins.
- Ravi R. Sonani
- , Lee K. Palmer
- & Edward H. Egelman
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Article
| Open AccessOrigin of the multi-phasic quenching dynamics in the BLUF domains across the species
Here the authors combine 19 F NMR and femtosecond transient absorption to characterise the structural origin of the multiphasic quenching dynamics in various species of BLUF domains, highlighting the importance of the heterogeneous active-site H-bond network.
- Yalin Zhou
- , Siwei Tang
- & Dongping Zhong
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Article
| Open AccessMolecular switching in transcription through splicing and proline-isomerization regulates stress responses in plants
Transcription factor DREB2A interacts with Med25 to regulate stress responses. Here, the authors show that DREB2A uses splicing and proline-isomerization for this regulation and that proline cis-trans switching introduces structural frustration facilitating regulator exchange.
- Frederik Friis Theisen
- , Andreas Prestel
- & Karen Skriver
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Article
| Open AccessLocal energetic frustration conservation in protein families and superfamilies
Energetic local frustration in proteins may have been positively selected by evolution when related to function such as ligand binding, allostery and other. Here the authors present a methodology to analyze local frustration patterns within protein families and superfamilies.
- Maria I. Freiberger
- , Victoria Ruiz-Serra
- & Alfonso Valencia
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Article
| Open AccessConformational plasticity of RAS Q61 family of neoepitopes results in distinct features for targeted recognition
The authors use an integrative structural biology approach to elucidate molecular features of the RAS Q61 family of public tumor antigens. This information can be used to develop targeted therapeutics to combat a range of cancers.
- Andrew C. McShan
- , David Flores-Solis
- & Nikolaos G. Sgourakis
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Article
| Open AccessStructural basis of antibody inhibition and chemokine activation of the human CC chemokine receptor 8
CCR8 is a promising target in cancer immunotherapy. Here, authors generated mAb1, an antagonist antibody against CCR8 and determined structures of CCR8 in complex with mAb1 or the agonist CCL1, providing insights into CCR8 inhibition and activation.
- Dawei Sun
- , Yonglian Sun
- & Matthieu Masureel
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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 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 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 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 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 AccessLiquid spherical shells are a non-equilibrium steady state of active droplets
Dissipative structures are governed by non-equilibrium thermodynamics. Here, the authors describe a size-dependent transition from active droplets to active spherical shells—a dissipative structure that arises from reaction diffusion gradients.
- Alexander M. Bergmann
- , Jonathan Bauermann
- & Job Boekhoven
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Article
| Open AccessA concerted ATPase cycle of the protein transporter AAA-ATPase Bcs1
Bcs1, a transmembrane AAA-ATPase, facilitates the translocation of folded ISP across the inner mitochondrial membrane. This study shows that the Bcs1 ATPase cycle conformational changes are highly concerted, unlike the canonical hand-over-hand mechanism.
- Yangang Pan
- , Jingyu Zhan
- & Simon Scheuring
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Article
| Open AccessDetermining subunit-subunit interaction from statistics of cryo-EM images: observation of nearest-neighbor coupling in a circadian clock protein complex
Deciphering interactions between subunits in protein complexes is an important problem. By combining cryo-EM imaging and statistical modeling, Han and colleagues reveal a significant cooperativity between subunits in the clock protein hexamer KaiC.
- Xu Han
- , Dongliang Zhang
- & Qi Ouyang
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Article
| Open AccessChronic cough relief by allosteric modulation of P2X3 without taste disturbance
P2X3 activation requires tightening the inner pocket of the head domain (IP-HD) following ATP binding. Here the authors demonstrate that targeting the IP-HD with allosteric small molecules presents a potential strategy for the development of therapeutics for refractory chronic cough without taste abnormalities.
- Chang-Run Guo
- , Zhong-Zhe Zhang
- & Ye Yu
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Article
| Open AccessElevated concentrations cause upright alpha-synuclein conformation at lipid interfaces
The misfolding of alpha-synuclein is associated with neurodegenerative disorders such as Parkinson’s disease. The authors report a mechanism explaining why lipid membranes catalyze the formation of harmful aggregates at elevated concentrations.
- Steven J. Roeters
- , Kris Strunge
- & Tobias Weidner
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Article
| Open AccessExtracellular calcium functions as a molecular glue for transmembrane helices to activate the scramblase Xkr4
Dying cells display an “eat me” signal through phospholipid scrambling. Here, the authors show that activation of the plasma membrane-bound Xkr4 scramblase requires extracellular calcium as a “molecular glue” for connecting transmembrane regions.
- Panpan Zhang
- , Masahiro Maruoka
- & Jun Suzuki
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Article
| Open AccessHeterogeneity in M. tuberculosis β-lactamase inhibition by Sulbactam
Here, the reaction of the suicide inhibitor sulbactam with the M. tuberculosis β-lactamase (BlaC) is investigated with time-resolved crystallography. Singular Value Decomposition is implemented to extract kinetic information despite changes in unit cell parameters during the time-course of the reaction.
- Tek Narsingh Malla
- , Kara Zielinski
- & Marius Schmidt
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Article
| Open AccessDirect observation of tRNA-chaperoned folding of a dynamic mRNA ensemble
T-box riboswitch RNAs directly bind to specific tRNA and regulate the transcription or translation of downstream genes in bacteria. Using single-molecule FRET and ensemble biophysical analyses, here the authors uncover a Venus flytrap-like mechanism where tRNA binding to a T-box riboswitch mRNA triggers its rapid domain closure.
- Krishna C. Suddala
- , Janghyun Yoo
- & Jinwei Zhang
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Article
| Open AccessControl of intracellular pH and bicarbonate by CO2 diffusion into human sperm
Bicarbonate (HCO3−) is critical in sperm for stimulation of cAMP synthesis during fertilization, though there is dispute over how HCO3− is transported into sperm. Here the authors use limit-of-detection LC/MS to characterize sperm protein expression and show that HCO3− is produced from CO2 diffusion into sperm rather than active transport.
- Elena Grahn
- , Svenja V. Kaufmann
- & U.Benjamin Kaupp
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Article
| Open AccessThermodynamic principle to enhance enzymatic activity using the substrate affinity
Currently, there is no well-defined strategy to increase the activity of enzymes. Here, the authors provide mathematical evidence that adjusting the Michaelis-Menten constant to the substrate concentration maximizes enzymatic activity.
- Hideshi Ooka
- , Yoko Chiba
- & Ryuhei Nakamura
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Article
| Open AccessRedox driven B12-ligand switch drives CarH photoresponse
CarH is a bacterial B12-binding photoreceptor involved in transcriptional regulation. Here, the authors provide insights into B12 dynamics and associated cobalt redox changes following light activation. These demonstrate the CarH response integrates light and oxygen sensing.
- Harshwardhan Poddar
- , Ronald Rios-Santacruz
- & David Leys
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Article
| Open AccessNetwork-wide thermodynamic constraints shape NAD(P)H cofactor specificity of biochemical reactions
NADH and NADPH are redox cofactors coexisting in all living cells. Here, the authors present a computational study suggesting that evolved NAD(P)H reaction specificities in E. coli are largely shaped by metabolic network structure enabling maximal thermodynamic driving forces close to the theoretical optimum.
- Pavlos Stephanos Bekiaris
- & Steffen Klamt
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Article
| Open AccessMolecular basis of the pleiotropic effects by the antibiotic amikacin on the ribosome
Here the authors use fast kinetics, X-ray crystallography, and cryo-EM to uncover the mechanism of ribosome inhibition by amikacin and kanamycin. They find that amikacin binds near the P-site tRNA, offering new strategies to fight antibiotic resistance.
- Savannah M. Seely
- , Narayan P. Parajuli
- & Matthieu G. Gagnon
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Article
| Open AccessStructural basis for receptor binding and broader interspecies receptor recognition of currently circulating Omicron sub-variants
SARS-CoV-2 Omicron variant evolves into multiple sub-variants. Here, authors evaluate the binding capacity of these sub-variants to human and animal ACE2s and reveal molecular bases for their receptor binding and broader interspecies recognition.
- Zhennan Zhao
- , Yufeng Xie
- & Jianxun Qi
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Article
| Open AccessSpatial and functional arrangement of Ebola virus polymerase inside phase-separated viral factories
Here, the authors characterized the phase separation properties and internal structures of intracellular viral factories induced by Ebola virus and correlated these properties to important steps of viral biogenesis.
- Jingru Fang
- , Guillaume Castillon
- & Erica Ollmann Saphire