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| Open AccessTransport mechanism of human bilirubin transporter ABCC2 tuned by the inter-module regulatory domain
Human ABC transporter ABCC2 transports conjugated bilirubin from hepatocyte to bile duct, dysfunction of which causes Dubin-Johnson syndrome. Here, the authors provide structural insights into the substrate specificity of ABCC2 and the transport mechanism regulated by the R domain.
- Yao-Xu Mao
- , Zhi-Peng Chen
- & Yuxing Chen
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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 AccessAsymmetric nucleosome PARylation at DNA breaks mediates directional nucleosome sliding by ALC1
Bacic et al. demonstrate that PARP1/HPF1 preferentially modify histone tails closest to the DNA break, directing ALC1-catalyzed nucleosome sliding. These findings suggest a mechanism for rendering DNA breaks more accessible to repair factors.
- Luka Bacic
- , Guillaume Gaullier
- & Sebastian Deindl
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Matters Arising
| Open AccessAssessing the precision of morphogen gradients in neural tube development
- Marcin Zagorski
- , Nathalie Brandenberg
- & Anna Kicheva
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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 AccessA genetic circuit on a single DNA molecule as an autonomous dissipative nanodevice
Achieving genetic circuits on single DNA molecules could have varied applications. Here, authors observed proteins emerging from single DNA molecules through coupled transcription-translation complexes, and show that nascent proteins lingered on DNA, regulating cascaded reactions on the same DNA and allowing the design of a pulsatile genetic circuit.
- Ferdinand Greiss
- , Nicolas Lardon
- & Roy Bar-Ziv
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Article
| Open AccessStructural and functional insights into the lipid regulation of human anion exchanger 2
Anion exchanger 2 (AE2), a widely expressed Cl- /HCO3 - exchanger, participates in the regulation of intracellular pH. Here, the authors present the structures of AE2 and uncover the regulatory mechanism of PIP2.
- Weiqi Zhang
- , Dian Ding
- & Yuxin Yin
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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 AccessFolding pathway of a discontinuous two-domain protein
Here, using single molecule FRET, the unfolding and folding of a discontinuous two-domain protein was studied. The authors find that a dynamic, intermediate population entropically limits the rate of folding while the order of domain folding is kept in a slow-folding mutant.
- Ganesh Agam
- , Anders Barth
- & Don C. Lamb
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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 AccessEndothelial leakiness elicited by amyloid protein aggregation
This study reports endothelial leakiness in vitro, in silico and in vivo, where adherens junctions are disrupted by their exposure to the anionic oligomers and seeds of Alzheimer’s amyloid beta, preceding proinflammatory and pro-oxidative events.
- Yuhuan Li
- , Nengyi Ni
- & Pu Chun Ke
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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 AccessCochaperones convey the energy of ATP hydrolysis for directional action of Hsp90
The precise role of cochaperones and ATP hydrolysis in driving Hsp90’s chaperone cycle is largely unclear. Here, the authors use single-molecule FRET to show that several cochaperones are necessary to establish directionality in Hsp90’s conformational cycle.
- Leonie Vollmar
- , Julia Schimpf
- & Thorsten Hugel
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Article
| Open AccessMesoscale simulation of biomembranes with FreeDTS
In this work, the authors report the FreeDTS software to simulate biomembranes at the mesoscale. The software provides various membrane simulations, focusing on protein organization and shape remodeling. A versatile tool propelling realistic membrane studies and diverse applications.
- Weria Pezeshkian
- & John H. Ipsen
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Article
| Open AccessDisordered-to-ordered transitions in assembly factors allow the complex II catalytic subunit to switch binding partners
Here, the authors investigate the maturation of human respiratory Complex II, uncovering two metastable intermediates of maturation which suggest changes in intrinsic disorder ensure that the assembly steps occur in the correct sequence.
- Pankaj Sharma
- , Elena Maklashina
- & T. M. Iverson
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Article
| Open AccessLigand coupling mechanism of the human serotonin transporter differentiates substrates from inhibitors
The serotonin transporter, targeted by several medications, terminates neurotransmission by clearing serotonin from the synaptic cleft. Combining biochemical results with in silico data, the authors show the key interactions that initiate substrate transport.
- Ralph Gradisch
- , Katharina Schlögl
- & Thomas Stockner
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Article
| Open AccessCryo-EM structure and B-factor refinement with ensemble representation
Cryo-EM is the go-to method for visualizing large, flexible biomolecules. Here, authors introduce a new Gaussian mixture modelling method for cryo-EM modelling tasks, including refinement, composite map generation and ensemble representation.
- Joseph G. Beton
- , Thomas Mulvaney
- & Maya Topf
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Article
| Open AccessConformational coupling of the sialic acid TRAP transporter HiSiaQM with its substrate binding protein HiSiaP
Tripartite ATP-independent periplasmic (TRAP) transporters use an extra substrate binding protein to transport a variety of substrates in bacteria and archaea. Here the authors use a disulfide engineering approach to lock the TRAP transporter HiSiaPQM from H. influenzae in different conformational states for characterisation.
- Martin F. Peter
- , Jan A. Ruland
- & Gregor Hagelueken
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Article
| Open AccessMechanism of anion exchange and small-molecule inhibition of pendrin
Here the authors report structures of pendrin, an anion exchanger, in complex with its substrate Cl−, I−, or HCO3−, which reveal two anion binding sites in each protomer. The authors also identify binding sites of a pendrin inhibitor, niflumic acid.
- Lie Wang
- , Anthony Hoang
- & Ming Zhou
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Article
| Open AccessPIEZO1 loss-of-function compound heterozygous mutations in the rare congenital human disorder Prune Belly Syndrome
PIEZO1 is a mechanosensitive ion channel. Here, authors identify PIEZO1 human mutations in Prune Belly Syndrome. At a single molecule level these mutations exhibit loss-of-function characteristics.
- Nathalia G. Amado
- , Elena D. Nosyreva
- & Ruhma Syeda
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Article
| Open AccessTon motor conformational switch and peptidoglycan role in bacterial nutrient uptake
Gram-negative bacteria rely on the Ton system for nutrient uptake. Here, authors uncover how the ExbD protein acts as a conformational switch and the function of peptidoglycan in order to energize this transport process across the outer membrane.
- Maximilian Zinke
- , Maylis Lejeune
- & Nadia Izadi-Pruneyre
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Article
| Open AccessDCAF1-based PROTACs with activity against clinically validated targets overcoming intrinsic- and acquired-degrader resistance
Targeted protein degradation (TPD) is a key modality for drug discovery. Here the authors present the discovery and analysis of reversible DCAF1-PROTACs, which show efficacy in cellular environments resistant to VHL-PROTACs or with acquired resistance to CRBN-PROTACs.
- Martin Schröder
- , Martin Renatus
- & Claudio R. Thoma
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Article
| Open AccessThe juxtamembrane linker of synaptotagmin 1 regulates Ca2+ binding via liquid-liquid phase separation
Synaptotagmin (syt) 1 is a calcium sensor for neuronal exocytosis. Here, the authors show that the juxtamembrane linker of this integral membrane protein negatively regulates its calcium sensing activity by mediating self-association via liquid-liquid phase separation.
- Nikunj Mehta
- , Sayantan Mondal
- & Edwin R. Chapman
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Article
| Open AccessExperimental determination and mathematical modeling of standard shapes of forming autophagosomes
Autophagosome formation involves membrane morphological changes. Here, authors statistically determined average shapes of forming autophagosomes from 3D electron micrographs and established a theoretical model that quantitatively reproduces them.
- Yuji Sakai
- , Satoru Takahashi
- & Noboru Mizushima
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Article
| Open AccessLipid nanodisc scaffold and size alter the structure of a pentameric ligand-gated ion channel
The authors show that lipid nanodiscs of different scaffold type and size alter the structure of the pentameric ligand-gated ion channel, ELIC. The results suggest that nanodisc selection is an important consideration for structural studies of membrane proteins.
- Vikram Dalal
- , Mark J. Arcario
- & Wayland W. L. Cheng
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Article
| Open AccessAllosteric control of dynamin-related protein 1 through a disordered C-terminal Short Linear Motif
Drp1 is the master regulator of mitochondrial and peroxisomal fission. Here, the authors show that a C-terminal intrinsically disordered motif, named the CT-SLiM, constitutes an allosteric switch that controls Drp1 structure, assembly, and function.
- Isabel Pérez-Jover
- , Kristy Rochon
- & Rajesh Ramachandran
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Article
| Open AccessDynamic stability of Sgt2 enables selective and privileged client handover in a chaperone triad
Newly synthesized tail-anchored membrane proteins (TAs) are relayed in a chaperone triad, Hsp70, Sgt2, and Get3, for delivery to the endoplasmic reticulum. Here, the authors show how the conformational dynamics of the cochaperone Sgt2 generates a decision point to enable efficient and selective TA targeting.
- Hyunju Cho
- , Yumeng Liu
- & Shu-ou Shan
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Article
| Open AccessMolecular basis of the inositol deacylase PGAP1 involved in quality control of GPI-AP biogenesis
The inositol deacylase PGAP1 initiates glycolipid remodeling required for GPI-AP sorting and secretion. Here, authors capture three PGAP1 states in a lipid environment and with products, revealing mechanisms for substrate selectivity and catalysis.
- Jingjing Hong
- , Tingting Li
- & Dianfan Li
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Article
| Open AccessStructural heterogeneity of the ion and lipid channel TMEM16F
TMEM16F is a transmembrane protein that facilitates passive phospholipid transbilayer movement and ion conduction across membranes. Here, authors reveal a structural heterogeneity which is possibly linked to TMEM16F unique dual function.
- Zhongjie Ye
- , Nicola Galvanetto
- & Arin Marchesi
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Article
| Open AccessSelective blockade of Cav1.2 (α1C) versus Cav1.3 (α1D) L-type calcium channels by the black mamba toxin calciseptine
L-type voltage-gated calcium channels are involved in multiple physiological functions. Here the authors identify calciseptine, a toxin purified from black mamba venom, as a selective inhibitor of Cav1.2 L-type Ca2+ channels.
- Pietro Mesirca
- , Jean Chemin
- & Joël Nargeot
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Article
| Open AccessMolecular basis of human trace amine-associated receptor 1 activation
hTA1 is a drug target for several neuropsychiatric disorders. Using cryo-EM and pharmacological assays, the authors illuminate hTA1’s similarity to neurotransmitter receptors and discover that the antipsychotic asenapine potently activates the receptor.
- Gregory Zilberg
- , Alexandra K. Parpounas
- & Daniel Wacker
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Article
| Open AccessForce transmission by retrograde actin flow-induced dynamic molecular stretching of Talin
Focal adhesion proteins transmit intracellular forces to the extracellular matrix (ECM). Here, the authors show a force transmission by elastic transient clutch of Talin between ECM and constantly flowing F-actin at focal adhesions.
- Sawako Yamashiro
- , David M. Rutkowski
- & Naoki Watanabe
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Article
| Open AccessVoltage sensors of a Na+ channel dissociate from the pore domain and form inter-channel dimers in the resting state
It is believed that voltage sensor domains (VSD) of voltage-gated Na+ channels are always attached to the channel. Here, authors find that VSDs detach from the channel to form inter-channel dimers.
- Ayumi Sumino
- , Takashi Sumikama
- & Katsumasa Irie
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Article
| Open AccessBlue-shift photoconversion of near-infrared fluorescent proteins for labeling and tracking in living cells and organisms
Photolabeling of intracellular molecules is an invaluable approach to study multiple cellular processes. Here, the authors report on the near-infrared to far-red photoconversion in the miRFP family of fluorescent proteins, which enables photolabeling entirely performed in the near-infrared range.
- Francesca Pennacchietti
- , Jonatan Alvelid
- & Ilaria Testa
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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 AccessMolecular basis and cellular functions of vinculin-actin directional catch bonding
This study provides insights into the directional catch bonding of the linker protein vinculin by elucidating the molecular basis of mechanical reinforcement as well as unveiling its key role in subcellular organization and cellular processes.
- Venkat R. Chirasani
- , Mohammad Ashhar I. Khan
- & Sharon L. Campbell
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Article
| Open AccessHydrogels with tunable mechanical plasticity regulate endothelial cell outgrowth in vasculogenesis and angiogenesis
It is vital to unveil the effects of extracellular matrix cues on endothelial cell (EC) outgrowth for desirably governing vasculature formation, but the role of matrix plasticity on EC outgrowth is elusive. Here, the authors develop hydrogels with tunable mechanical plasticity independent of stiffness, and elucidate the plasticity-mediated responses of ECs during vasculogenesis and angiogenesis.
- Zhao Wei
- , Meng Lei
- & Feng Xu
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Article
| Open AccessHomo- and hetero-dimeric subunit interactions set affinity and efficacy in metabotropic glutamate receptors
The molecular basis of functional diversity between obligatorily dimeric mGluRs is not understood. The authors show that functional differences typically attributed to differences in the agonist binding pocket emerge from differences between homomeric and heteromeric Group II and III Gi-coupled mGluRs in dimerization interface interactions.
- Chris Habrian
- , Naomi Latorraca
- & Ehud Y. Isacoff
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Article
| Open AccessCENP-A and CENP-B collaborate to create an open centromeric chromatin state
Centromeres are defined by the histone variant CENP-A. Using single-molecule fluorescence and cryoEM, this study shows that CENP-A and the centromeric protein CENP-B collaborate to create dynamic and open chromatin, aiding centromeric factor binding.
- Harsh Nagpal
- , Ahmad Ali-Ahmad
- & Beat Fierz
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Article
| Open AccessSingle-photon microscopy to study biomolecular condensates
The wide variety of cellular processes involving biomolecular condensation makes their quantification a challenging task. Here, the authors present an integrated platform based on single-photon microscopy to study complex biomolecular processes.
- Eleonora Perego
- , Sabrina Zappone
- & Giuseppe Vicidomini
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Article
| Open AccessNonuniversal impact of cholesterol on membranes mobility, curvature sensing and elasticity
Cholesterol both thickens and condenses membranes, yet it also softens them under certain conditions. Here, authors uncover cholesterol’s dual role in the delicate balance of rigidity and flexibility in membranes, crucial for diverse biological functions.
- Matthias Pöhnl
- , Marius F. W. Trollmann
- & Rainer A. Böckmann
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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 AccessA minority of final stacks yields superior amplitude in single-particle cryo-EM
Here the authors develop an iterative particle sieving method called CryoSieve, demonstrating this method outperforms other cryo-EM particle sorting algorithms to reveal that most particles are unnecessary in final stacks.
- Jianying Zhu
- , Qi Zhang
- & Chenglong Bao
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Article
| Open AccessGeometric constraint-triggered collagen expression mediates bacterial-host adhesion
Cells in the body live in geometrically constrained microenvironments. Here, Feng at al report that these constraints induce collagen IV expression which is responsible for location dependent bacterial adhesion.
- Yuting Feng
- , Shuyi Wang
- & Jianyong Huang
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Article
| Open AccessThe separation pin distinguishes the pro– and anti–recombinogenic functions of Saccharomyces cerevisiae Srs2
Here the authors report that the main role of the protein Srs2 in homologous recombination is to remove Rad51 from single stranded DNA, rather than to drive synthesis-dependent strand annealing.
- Aviv Meir
- , Vivek B. Raina
- & Eric C. Greene
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Article
| Open AccessStructural and thermodynamic insights into antibody light chain tetramer formation through 3D domain swapping
Atomic-level structural examinations of antibody light chain aggregates are sparse. Here, the authors find an antibody light chain that maintains an equilibrium between monomeric and tetrameric states and show with its 3D structure that it engages in 3D domain swapping within its variable region.
- Takahiro Sakai
- , Tsuyoshi Mashima
- & Shun Hirota
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Article
| Open AccessPhospholipids are imported into mitochondria by VDAC, a dimeric beta barrel scramblase
Mitochondria depend on phospholipids supplied by the endoplasmic reticulum. Here, using biochemical assays and molecular dynamics simulations, authors identify VDAC as a scramblase-type lipid transporter that catalyze lipid entry.
- Helene Jahn
- , Ladislav Bartoš
- & Anant K. Menon
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Article
| Open AccessEnvironmental modulation of global epistasis in a drug resistance fitness landscape
Global epistasis can be used to reconstruct fitness landscapes and infer adaptive trajectories. Here, the authors investigate how environmental variation impacts patterns of global epistasis, finding that global epistasis in the malaria parasite P. falciparum can be modulated by drug concentration in the environment.
- Juan Diaz-Colunga
- , Alvaro Sanchez
- & C. Brandon Ogbunugafor
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Article
| Open AccessMachine learning-based motion tracking reveals an inverse correlation between adhesivity and surface motility of the leptospirosis spirochete
A common approach to study bacterial motility is fluorescent labelling, but this can be hampered by protein expression instability and/or interference with bacterial physiology. Here, Abe et al. describe a machine learning-based method for motion tracking of spirochetes on cultured animal cells, which does not require labelling and might be applied to study motility of other bacterial species.
- Keigo Abe
- , Nobuo Koizumi
- & Shuichi Nakamura