Featured
-
-
Article
| Open AccessNon-cooperative 4E-BP2 folding with exchange between eIF4E-binding and binding-incompatible states tunes cap-dependent translation inhibition
Phosphorylation of eIF4E binding proteins (4E-BPs) controls their folding and regulates cap-dependent translation. Here, the authors show that phosphorylation of the C-terminal disordered region stabilizes the non-cooperatively folded 4E-BP domain to an eIF4E binding-incompatible state to control translation.
- Jennifer E. Dawson
- , Alaji Bah
- & Julie D. Forman-Kay
-
Article
| Open AccessA dietary fatty acid counteracts neuronal mechanical sensitization
PIEZO2 is a critical component of the mechanism by which innocuous touch causes pain (tactile allodynia). Here, authors find that the dietary fatty acid margaric acid decreases PIEZO2 function in a dose-dependent manner and counteracts neuronal mechanical sensitization by a proalgesic agent.
- Luis O. Romero
- , Rebeca Caires
- & Valeria Vásquez
-
Article
| Open AccessA constricted opening in Kir channels does not impede potassium conduction
The transition between conducting and non-conducting states of K+ channels has been explained by conformational changes at the intracellular entrance to the conduction pathway. Here authors demonstrate that control over K+ currents in Kir channels is not explained by the canonical pore-gating model, as conduction is not impaired by a constricted inner helix bundle.
- Katrina A. Black
- , Sitong He
- & Jacqueline M. Gulbis
-
Article
| Open AccessTug-of-war between actomyosin-driven antagonistic forces determines the positioning symmetry in cell-sized confinement
Symmetric or asymmetric positioning of intracellular structures such as the nucleus and mitotic spindle steers various biological processes. Here authors use an in vitro model and show that a tug-of-war between centripetal actomyosin waves and percolation of bulk actomyosin network direct the positioning.
- Ryota Sakamoto
- , Masatoshi Tanabe
- & Makito Miyazaki
-
Article
| Open AccessAβ(1-42) tetramer and octamer structures reveal edge conductivity pores as a mechanism for membrane damage
Formation of amyloid-beta (Aβ) oligomer pores in the membrane of neurons has been proposed to explain neurotoxicity in Alzheimer´s disease. Here authors present the 3D- structure of an Aβ oligomer formed in a membrane mimicking environment and observe that Aβ tetramers and octamers inserted into lipid bilayers as well-defined pores.
- Sonia Ciudad
- , Eduard Puig
- & Natàlia Carulla
-
Article
| Open AccessCell size sets the diameter of the budding yeast contractile ring
Budding yeast cell polarization is known to self-assemble, but it is still not clear what controls the size of the resulting septin ring. Here the authors show that the septin ring diameter is set by cell volume, ensuring that larger cells have larger rings.
- I. V. Kukhtevich
- , N. Lohrberg
- & K. M. Schmoller
-
Article
| Open AccessLarge-scale simulation of biomembranes incorporating realistic kinetics into coarse-grained models
Explicit molecular modelling of biological membrane systems is computationally expensive due to the large number of solvent particles and slow membrane kinetics. Here authors present a framework for integrating coarse-grained membrane models with continuum-based hydrodynamics which facilitates efficient simulation of large biomembrane systems.
- Mohsen Sadeghi
- & Frank Noé
-
Article
| Open AccessSingle molecule secondary structure determination of proteins through infrared absorption nanospectroscopy
While infrared nanospectroscopy methods based on thermomechanical detection (AFM-IR) enables the acquisition of absorption spectra at the nanoscale, single molecule detection has not been possible so far. Here, the authors present off-resonance, low power and short pulse infrared nanospectroscopy (ORS-nanoIR), which allows measuring infrared absorption spectra at the single molecule level in a time scale of seconds with high throughput and demonstrate that the secondary structure of single protein molecules can be determined with this method.
- Francesco Simone Ruggeri
- , Benedetta Mannini
- & Tuomas P. J. Knowles
-
Article
| Open AccessStructure and dynamics of the ASB9 CUL-RING E3 Ligase
Multi-subunit Cullin (CUL)-RING ligases (CRL) form the largest family of E3 ligases and are composed of a substrate receptor, a CUL, and a RING-box (RBX) protein. Here, the authors use cryo-EM and HDX-MS to characterise the ASB9 CUL-RING E3 ligase and present the structure of ASB9-ELOB/C bound to the substrate creatine kinase and the full-length CUL5 structure in complex with RBX2, and they propose a revised allosteric mechanism for CUL-E3 ligase function.
- Ryan J. Lumpkin
- , Richard W. Baker
- & Elizabeth A. Komives
-
Article
| Open AccessDNA origami-based single-molecule force spectroscopy elucidates RNA Polymerase III pre-initiation complex stability
TATA-binding protein (TBP) and a transcription factor (TF) IIB-like factor are important constituents of all eukaryotic initiation complexes. Here, the authors use a DNA origami-based force clamp to investigate the assembly dynamics of human initiation complexes in the RNAP II and RNAP III systems at the single-molecule level under pico newton forces.
- Kevin Kramm
- , Tim Schröder
- & Dina Grohmann
-
Article
| Open AccessThe effect of flow on swimming bacteria controls the initial colonization of curved surfaces
Bacterial colonization of surfaces has a profound environmental, technological and medical impact. Here, Secchi et al. show how fluid flow affects the magnitude and location of bacterial colonization on curved surfaces through its coupling with cell morphology and motility.
- Eleonora Secchi
- , Alessandra Vitale
- & Roman Stocker
-
Article
| Open AccessUbiquitin transfer by a RING E3 ligase occurs from a closed E2~ubiquitin conformation
The mechanism of ubiquitin transfer from the ubiquitin-conjugated E2 enzyme (E2~Ub) to the substrate is still under debate. Here, the authors use FRET assays to show that RING E3 ligases transfer ubiquitin to the substrate from a closed E2~Ub conformation.
- Emma Branigan
- , J. Carlos Penedo
- & Ronald T. Hay
-
Article
| Open AccessEffects of nonequilibrium fluctuations on ultrafast short-range electron transfer dynamics
Ultrafast electron-transfer reactions are fundamental to protein functions. Here the authors show that these reaction dynamics are affected by the ruggedness of protein energy landscape, which even modifies the reaction free energy and reorganization energy.
- Yangyi Lu
- , Mainak Kundu
- & Dongping Zhong
-
Article
| Open AccessExtent of N-terminus exposure of monomeric alpha-synuclein determines its aggregation propensity
In Parkinson’s disease (PD) the monomeric protein alpha-synuclein (aSyn) misfolds and aggregates into insoluble fibrils. Here the authors use NMR measurements and hydrogen–deuterium exchange mass spectrometry and find that the more solvent exposed the N-terminus of aSyn is, the more aggregation prone its conformation becomes, and further show how PD mutations and post translational modifications influence the extent of the N-terminus solvent exposure.
- Amberley D. Stephens
- , Maria Zacharopoulou
- & Gabriele S. Kaminski Schierle
-
Article
| Open AccessPolyamine regulation of ion channel assembly and implications for nicotinic acetylcholine receptor pharmacology
Small molecule polyamines participate in diverse aspects of cell growth and differentiation and are known to regulate ion channel gating. Here authors reveal that cellular polyamines control nicotinic acetylcholine receptor (nAChR) biogenesis, and either catabolic degradation or inhibition of polyamine production augments nAChR assembly.
- Madhurima Dhara
- , Jose A. Matta
- & David S. Bredt
-
Article
| Open AccessTetrameric architecture of an active phenol-bound form of the AAA+ transcriptional regulator DmpR
DmpR is a bacterial enhancer binding protein from the AAA+ family of ATPases that binds aromatic compounds and controls the transcription of genes involved in the degradation of toxic pollutants. Here, the authors present the crystal structure of phenol-bound DmpR, which forms a tetramer and discuss its signal transduction mechanism.
- Kwang-Hyun Park
- , Sungchul Kim
- & Eui-Jeon Woo
-
Article
| Open AccessHuman ESCRT-III polymers assemble on positively curved membranes and induce helical membrane tube formation
ESCRT-III complexes assemble in vivo inside membrane structures with a negative Gaussian curvature, but how membrane shape influences ESCRT-III polymerization remains unclear. Here authors use structural and biophysical methods to show how human ESCRT-III polymers assemble on positively curved membranes and induce helical membrane tube formation.
- Aurélie Bertin
- , Nicola de Franceschi
- & Patricia Bassereau
-
Article
| Open AccessCryo-EM structures provide insight into how E. coli F1Fo ATP synthase accommodates symmetry mismatch
F1Fo ATP synthase consists of two coupled rotary molecular motors: the soluble ATPase F1 and the transmembrane Fo. Here, the authors present cryo-EM structures of E. coli ATP synthase in four discrete rotational sub-states at 3.1-3.4 Å resolution and observe a rotary sub-step of the Fo motor cring that reveals the mechanism of elastic coupling between the two rotary motors, which is essential for effective ATP synthesis.
- Meghna Sobti
- , James L. Walshe
- & Alastair G. Stewart
-
Article
| Open AccessParkinson’s disease associated mutation E46K of α-synuclein triggers the formation of a distinct fibril structure
The E46K α-synuclein mutation causes familial Parkinson’s disease. Here, the authors present the cryo-EM structure of N-terminally acetylated E46K α-synuclein fibrils and find that it is distinct from other known α-synuclein fibril structures.
- Kun Zhao
- , Yaowang Li
- & Cong Liu
-
Article
| Open AccessKinesin-14 motors drive a right-handed helical motion of antiparallel microtubules around each other
Some kinesins exhibit off-axis power strokes but their impact on motility and force generation in microtubule overlaps has not been investigated so far. Here authors use a 3D in vitro motility assay and find that Ndc’s off-axis motor forces generate torque in antiparallel microtubules which causes microtubule twisting and coiling.
- Aniruddha Mitra
- , Laura Meißner
- & Stefan Diez
-
Article
| Open AccessCryo-EM structures from sub-nl volumes using pin-printing and jet vitrification
There is a need to further improve the automation of cryo-EM sample preparation to make it more easily accessible for non-specialists, reduce sample waste and increase reproducibility. Here, the authors present VitroJet, a single device, where sub-nl volumes of samples are deposited by pin printing thus eliminating the need for sample blotting, which is followed by jet vitrification, and they show that high-resolution structures can be obtained using four standard proteins.
- Raimond B. G. Ravelli
- , Frank J. T. Nijpels
- & Peter J. Peters
-
Article
| Open AccessA role for actin flexibility in thin filament-mediated contractile regulation and myopathy
The α-cardiac actin M305L hypertrophic cardiomyopathy-causing mutation is located near residues that help confine tropomyosin to an inhibitory position along thin filaments. Here the authors assessed M305L actin in vivo, in vitro, and in silico to characterize emergent pathological properties and define the mechanistic basis of disease.
- Meera C. Viswanathan
- , William Schmidt
- & Anthony Cammarato
-
Article
| Open AccessCooperative transport mechanism of human monocarboxylate transporter 2
Proton-linked monocarboxylate transporters (MCTs) facilitate monocarboxylate efflux in glycolytically active cells and regulate transport down in glycolytically inactive cells. Here authors show a steep dependence of human MCT2 activity on substrate concentration and show the structural basis of cooperative transport.
- Bo Zhang
- , Qiuheng Jin
- & Sheng Ye
-
Article
| Open AccessPlasma membrane H+-ATPases sustain pollen tube growth and fertilization
Cytosolic ion gradients in growing pollen tubes are thought to be required for polar growth. Here the authors show that the Arabidopsis plasma membrane H+ ATPases, AHA6, AHA8, and AHA9, maintain tip-to-shank proton gradients, oscillations in cytosolic pH and actin organization to enable pollen tube elongation.
- Robert D. Hoffmann
- , Maria Teresa Portes
- & Michael Palmgren
-
Article
| Open AccessChemotaxing neutrophils enter alternate branches at capillary bifurcations
Neutrophils mobilize rapidly and travel through the vasculature and microcirculation en masse in response to inflammatory stimuli. Here the authors use a microfluidic device and intravital microscopy to show neutrophils move through tissues in a highly ordered pattern, taking turns to file into alternate branches at bifurcations.
- Xiao Wang
- , Mokarram Hossain
- & Daniel Irimia
-
Article
| Open AccessBackmapping triangulated surfaces to coarse-grained membrane models
Computer simulations of large-scale changes in membrane shape are challenging since they occur across a wide range of spatiotemporal scales. Here, authors present a multiscale algorithm that backmaps a continuum membrane model represented as a dynamically triangulated surface to its corresponding molecular model based on the coarse-grained Martini force field.
- Weria Pezeshkian
- , Melanie König
- & Siewert J. Marrink
-
Article
| Open AccessFlexibility of intrinsically disordered degrons in AUX/IAA proteins reinforces auxin co-receptor assemblies
Auxin-mediated recruitment of AUX/IAAs by the F-box protein TIR1 prompts rapid AUX/IAA ubiquitylation and degradation. By resolving auxin receptor topology, the authors show that intrinsically disordered regions near the degrons of two Aux/IAA proteins reinforce complex assembly and position Aux/IAAs for ubiquitylation.
- Michael Niemeyer
- , Elena Moreno Castillo
- & Luz Irina A. Calderón Villalobos
-
Article
| Open AccessPar complex cluster formation mediated by phase separation
The evolutionarily conserved complex, the Par proteins, regulates cell polarity. Here, the authors show that in Drosophila neuroblasts, the Par complex exhibits liquid–liquid phase separation dependent on the cell cycle.
- Ziheng Liu
- , Ying Yang
- & Wenyu Wen
-
Article
| Open AccessMechanoradicals in tensed tendon collagen as a source of oxidative stress
The existence, nature and biological relevance of mechanoradicals in proteins are unknown. Here authors show that mechanical stress on collagen produces radicals and subsequently reactive oxygen species and suggest that collagen I evolved as a radical sponge against mechano-oxidative damage.
- Christopher Zapp
- , Agnieszka Obarska-Kosinska
- & Frauke Gräter
-
Article
| Open AccessNucleoplasmic signals promote directed transmembrane protein import simultaneously via multiple channels of nuclear pores
The contribution of central and peripheral channels of nuclear pores to transport of transmembrane proteins is unclear. Here the authors show that most inner nuclear membrane proteins use only peripheral channels, but some extend nuclear localization signals into the central channel for directed nuclear transport.
- Krishna C. Mudumbi
- , Rafal Czapiewski
- & Weidong Yang
-
Article
| Open AccessLipid-protein interactions modulate the conformational equilibrium of a potassium channel
Potassium (K+) channels, such as MthK, are essentional for many biological processes, but how lipid-protein interactions regulate ion permeation of K+ channels remained unclear. Here authors conducted molecular dynamics simulations of MthK and observed different ion permeation rates of MthK in membranes with different properties.
- Ruo-Xu Gu
- & Bert L. de Groot
-
Article
| Open AccessDIP/Dpr interactions and the evolutionary design of specificity in protein families
Dpr (Defective proboscis extension response) and DIP (Dpr Interacting Proteins) are immunoglobulin-like cell-cell adhesion proteins that form highly specific pairwise interactions, which control synaptic connectivity during Drosophila development. Here, the authors combine a computational approach with binding affinity measurements and find that DIP/Dpr binding specificity is controlled by negative constraints that interfere with non-cognate binding.
- Alina P. Sergeeva
- , Phinikoula S. Katsamba
- & Barry Honig
-
Article
| Open AccessMolecular mechanism of light-driven sodium pumping
The Na+-pumping KR2 rhodopsin from Krokinobacter eikastus is a light-driven non-proton cation pump whose mechanism of pumping remains to be understood. Here authors solved crystal structures of the O-intermediate state of the pentameric form of KR2 and its D116N and H30A mutants, which sheds light on the mechanism of non-proton cation light-driven pumping.
- Kirill Kovalev
- , Roman Astashkin
- & Valentin Gordeliy
-
Article
| Open AccessReal-time monitoring of PARP1-dependent PARylation by ATR-FTIR spectroscopy
The mechanism of PARP1-dependent poly-ADP-ribosylation in response to DNA damage is still under debate. Here, the authors use ATR-FTIR spectroscopy to provide time-resolved insights into the molecular details of this process under near physiological conditions.
- Annika Krüger
- , Alexander Bürkle
- & Aswin Mangerich
-
Article
| Open AccessControlled packing and single-droplet resolution of 3D-printed functional synthetic tissues
Precise patterning of lipid-stabilised aqueous droplets is a key challenge in building synthetic tissue designs. Here, the authors show how the interactions between pairs of droplets direct the packing of droplets within 3D-printed networks, enabling the formation of synthetic tissues with high-resolution features.
- Alessandro Alcinesio
- , Oliver J. Meacock
- & Hagan Bayley
-
Article
| Open AccessA HaloTag-TEV genetic cassette for mechanical phenotyping of proteins from tissues
Testing mechanical forces on native molecules in natural environments remains a challenge. Here the authors engineer titin to carry a HaloTag-TEV insertion to allow analysis of dynamics under force in muscle fibers.
- Jaime Andrés Rivas-Pardo
- , Yong Li
- & Jorge Alegre-Cebollada
-
Article
| Open AccessDeep learning enables structured illumination microscopy with low light levels and enhanced speed
Super-resolution microscopy typically requires high laser powers which can induce photobleaching and degrade image quality. Here the authors augment structured illumination microscopy (SIM) with deep learning to reduce the number of raw images required and boost its performance under low light conditions.
- Luhong Jin
- , Bei Liu
- & Klaus M. Hahn
-
Article
| Open AccessSuper-resolution imaging reveals the evolution of higher-order chromatin folding in early carcinogenesis
Aberrant chromatin structure is often found in cancer. Here, the authors optimise super-resolution microscopy for pathological tissue and discovered a significant decompaction of chromatin folding in early carcinogenesis prior to tumour formation.
- Jianquan Xu
- , Hongqiang Ma
- & Yang Liu
-
Article
| Open AccessQuantifying the heterogeneity of macromolecular machines by mass photometry
Mass photometry is a label-free optical approach capable of detecting, imaging and accurately measuring the mass of single biomolecules in solution. Here, the authors demonstrate the potential of mass photometry for quantitatively characterizing sample heterogeneity of purified protein complexes with implications for structural studies specifically and in vitro studies more generally.
- Adar Sonn-Segev
- , Katarina Belacic
- & Philipp Kukura
-
Article
| Open AccessLipoprotein Lpp regulates the mechanical properties of the E. coli cell envelope
Lipoprotein Lpp provides a covalent crosslink between the outer membrane and the peptidoglycan in E. coli. Here, the authors use atomic force microscopy to show that Lpp contributes to cell envelope stiffness by covalently connecting the two layers and by controlling the width of the periplasmic space.
- Marion Mathelié-Guinlet
- , Abir T. Asmar
- & Yves F. Dufrêne
-
Article
| Open AccessMembrane mediated toppling mechanism of the folate energy coupling factor transporter
Energy coupling factor (ECF) transporters are responsible for the uptake of micronutrients and consist of an integral membrane unit, the S-component, which confers substrate specificity. Here, authors present multi-scale molecular dynamics simulations and in vitro experiments to study the molecular toppling mechanism of the S-component of a folate-specific ECF transporter.
- Ignacio Faustino
- , Haleh Abdizadeh
- & Siewert J. Marrink
-
Article
| Open AccessRigidity enhances a magic-number effect in polymer phase separation
The phase separation of two species of associating polymers is suppressed by a magic-number effect for certain combinations of the numbers of binding sites. Here the authors use lattice simulations and analytical calculations to show that this magic-number effect can be greatly enhanced if one component has a rigid shape.
- Bin Xu
- , Guanhua He
- & Ned S. Wingreen
-
Article
| Open AccessStructural insights into catalytic mechanism and product delivery of cyanobacterial acyl-acyl carrier protein reductase
Acyl-acyl carrier protein reductase (AAR) and aldehyde deformylating oxygenase (ADO) are the two enzymes in a cyanobacterial alkane biosynthesis pathway that is of interest for biofuel production. Here the authors provide insights into the catalytic mechanisms of AAR and the coupling between the two enzymes by determining the crystal structures of AAR alone and three AAR–ADO complexes with various bound ligands.
- Yu Gao
- , Hongmei Zhang
- & Mei Li
-
Article
| Open AccessExfoliated near infrared fluorescent silicate nanosheets for (bio)photonics
Near-infrared (NIR) fluorophores have attracted interest for bioimaging; yet availability, biocompatibility and application can be an issue. Here, the authors report on the development of Egyptian Blue nanosheets with high NIR fluorescence and photostability demonstrating bioimaging applications in vivo.
- Gabriele Selvaggio
- , Alexey Chizhik
- & Sebastian Kruss
-
Article
| Open AccessThe cryo-EM structure of the SNX–BAR Mvp1 tetramer
SNX-BAR proteins are a family of PX and BAR domain-containing proteins with pivotal roles in trafficking processes. Here authors present the cryo-EM structure of the full-length fungal SNX-BAR Mvp1, which is an autoinhibited tetramer and provides critical insight into SNX-BAR function and regulation.
- Dapeng Sun
- , Natalia V. Varlakhanova
- & Marijn G. J. Ford
-
Article
| Open AccessSingle-molecule live-cell imaging visualizes parallel pathways of prokaryotic nucleotide excision repair
In Escherichia coli, the UvrAB damage sensor recognizes helix-distorting lesions by itself or via Mfd bound to stalled RNA polymerase. Here authors use single-molecule fluorescence imaging to quantify the kinetic signatures of interactions of UvrA with Mfd and UvrB in live cells.
- Harshad Ghodke
- , Han Ngoc Ho
- & Antoine M. van Oijen
-
Article
| Open AccessSingle-molecule imaging reveals molecular coupling between transcription and DNA repair machinery in live cells
Mfd recognizes stalled transcriptional complexes at sites of lesions and recruits the nucleotide excision repair proteins (UvrAB) to the site. Here the authors use live cell imaging in E. coli to demonstrate that coordinated ATP hydrolysis by UvrA and loading of UvrB on DNA facilitate the dissociation of Mfd from the handoff complex.
- Han Ngoc Ho
- , Antoine M. van Oijen
- & Harshad Ghodke
-
Article
| Open AccessEndophilin-A3 and Galectin-8 control the clathrin-independent endocytosis of CD166
How and which cell surface molecules are taken up by clathrin-independent endocytosis is an ongoing area of research. Here, the authors show that the tumor marker CD166 is a clathrin-independent cargo that is taken up by endophilin-A3 and galectin-8, which regulates cancer cell migration.
- Henri-François Renard
- , François Tyckaert
- & Pierre Morsomme
-
Article
| Open AccessGating mechanism of hyperpolarization-activated HCN pacemaker channels
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are essential for rhythmic activity in the heart and brain. Here authors reverse the voltage dependence of HCN channels by mutating only two residues located at the interface between the voltage sensor and the pore domain.
- Rosamary Ramentol
- , Marta E. Perez
- & H. Peter Larsson