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Article
| Open AccessMicroparticle traction force microscopy reveals subcellular force exertion patterns in immune cell–target interactions
Traction force microscopy is an effective method for measuring cellular forces but it is limited by planar geometry. Here the authors develop a facile method to produce deformable hydrogel particles and a reference-free computational method to resolve surface traction forces from particle shape deformation.
- Daan Vorselen
- , Yifan Wang
- & Julie A. Theriot
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Article
| Open AccessActive topological glass
Glass transition in soft materials can be affected by the topology of constituent particles, but the detail remains elusive. Here, Smrek et al. show that the interplay between circular topology of ring polymers and their active segments generates a new state of matter, namely active topological glass.
- Jan Smrek
- , Iurii Chubak
- & Kurt Kremer
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Article
| Open AccessForces during cellular uptake of viruses and nanoparticles at the ventral side
Many intracellular pathogens mimic extracellular matrix motifs to specifically interact with the host membrane which may influences virus particle uptake. Here authors use single molecule tension sensors to reveal the minimal forces exerted on single virus particles and demonstrate that the uptake forces scale with the adhesion energy.
- Tina Wiegand
- , Marta Fratini
- & Joachim P. Spatz
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Article
| Open AccessDefinition of functionally and structurally distinct repressive states in the nuclear receptor PPARγ
The repressive states of peroxisome proliferator-activated receptor γ (PPARγ) are ill-defined, despite nuclear receptors being a major drug target. Here authors demonstrate multiple structurally distinct repressive states, providing a structural rationale for ligand bias in a nuclear receptor.
- Zahra Heidari
- , Ian M. Chrisman
- & Travis S. Hughes
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Article
| Open AccessA mitochondrial megachannel resides in monomeric F1FO ATP synthase
The ATP synthase has been suggested to contain the mitochondrial permeability transition pore (mPTP), which has a crucial role in cell death. Here the authors show that reconstituted ATP synthase monomers form voltage-gated and Ca2+ -activated channels with the key features of mPTP.
- Nelli Mnatsakanyan
- , Marc C. Llaguno
- & Elizabeth A. Jonas
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Article
| Open AccessUltrastructure of the axonal periodic scaffold reveals a braid-like organization of actin rings
The ultrastructural details of the periodic scaffold of actin rings under the plasma membrane of axons remain unknown. Here, the authors combine platinum-replica electron and optical super-resolution microscopy and resolve actin rings as braids made of two long, intertwined actin filaments connected by a dense mesh of aligned spectrins.
- Stéphane Vassilopoulos
- , Solène Gibaud
- & Christophe Leterrier
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Article
| Open AccessHelix 8 is the essential structural motif of mechanosensitive GPCRs
GPCRs are versatile cellular sensors for chemical stimuli but the molecular mechanisms underlying mechanically induced GPCR activation have remained elusive. Here authors identify the C-terminal helix 8 (H8) as the essential structural motif endowing H1R and other GPCRs with mechanosensitivity.
- Serap Erdogmus
- , Ursula Storch
- & Michael Mederos y Schnitzler
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Article
| Open AccessA short translational ramp determines the efficiency of protein synthesis
Several factors contribute to the efficiency of protein expression. Here the authors show that the identity of amino acids encoded by codons at position 3–5 significantly impact translation efficiency and protein expression levels.
- Manasvi Verma
- , Junhong Choi
- & Sergej Djuranovic
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Article
| Open AccessCooperative ordering of treadmilling filaments in cytoskeletal networks of FtsZ and its crosslinker ZapA
The Z-ring, constituted of the tubulin homolog FtsZ protein, plays an essential role for bacterial cell division. Here the authors use an in vitro reconstitution approach to determine how the regulatory protein ZapA affects FtsZ treadmilling and filament organization into large-scale patterns.
- Paulo Caldas
- , Mar López-Pelegrín
- & Martin Loose
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Article
| Open AccessPARP1 exhibits enhanced association and catalytic efficiency with γH2A.X-nucleosome
The poly(ADP-ribose) polymerases play a key role in maintaining genomic integrity by detecting DNA damage and mediating repair. Here the authors characterize the kinetics of PARP1 binding to a variety of nucleosomes harbouring DNA double-strand breaks.
- Deepti Sharma
- , Louis De Falco
- & Curt A. Davey
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Article
| Open AccessComputational modeling demonstrates that glioblastoma cells can survive spatial environmental challenges through exploratory adaptation
Glioblastoma cells are known to be able to adapt easily to different environments. The authors study the dynamic adaptation of glioblastoma cells to the heterogenous brain tumor microenvironment, showing that tumor cells demonstrate varying plasticity of their transcriptomic profiles and an ability to survive new stimuli, in part, by propagating stochastic perturbations over their gene-regulatory network.
- Orieta Celiku
- , Mark R. Gilbert
- & Orit Lavi
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Article
| Open AccessEngineering protein assemblies with allosteric control via monomer fold-switching
The design of protein assemblies is a major thrust for biomolecular engineering and nanobiotechnology. Here the authors demonstrate a general mechanism for designing allosteric macromolecular assemblies and showcase a proof of concept for engineered allosteric protein assembly.
- Luis A. Campos
- , Rajendra Sharma
- & Victor Muñoz
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Article
| Open AccessSingle-molecule detection on a portable 3D-printed microscope
Single-molecule in vitro assays require dedicated confocal microscopes equipped with fluorescence correlation spectroscopy (FCS) modules. Here the authors present a compact, cheap and open-source 3D-printed confocal microscope for single photon counting and FCS measurements, and use it to detect α-synuclein aggregation.
- James W. P. Brown
- , Arnaud Bauer
- & Yann Gambin
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Article
| Open AccessGiant single molecule chemistry events observed from a tetrachloroaurate(III) embedded Mycobacterium smegmatis porin A nanopore
Engineered biological nanopores enable observation of single molecule chemistry events; however a cylindrical pore geometry can have undesired effects. The authors report a conical biological pore which was embedded with tetrachloroaurate(III) to allow for discrimination between different biothiols.
- Jiao Cao
- , Wendong Jia
- & Shuo Huang
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Article
| Open AccessA large size-selective DNA nanopore with sensing applications
Artificial nanopores can perform selective gating of molecules analogous to transmembrane proteins. Here, the authors design a DNA origami pore with a controllable lid for size-selective gating and translocation of macromolecules and evaluate its biosensing properties by single particle assay.
- Rasmus P. Thomsen
- , Mette Galsgaard Malle
- & Jørgen Kjems
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Article
| Open AccessSelective small molecule PARG inhibitor causes replication fork stalling and cancer cell death
PARG catalyzes the removal of poly(ADP-ribose) (PAR) from target proteins and executes critical functions in the DNA damage response. Here the authors provide structural and biological insight with small molecule PARG inhibitors and show that PARG inhibition sensitizes cells to ionizing radiation and kills cancer cells through replication fork defects.
- Jerry H. Houl
- , Zu Ye
- & John A. Tainer
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Article
| Open AccessDeciphering protein evolution and fitness landscapes with latent space models
Multiple sequence alignments of proteins carry information about evolution, the protein’s fitness landscape and its stability in the face of mutations. Here, the authors demonstrate the utility of latent space models learned using variational autoencoders to infer these properties from sequences.
- Xinqiang Ding
- , Zhengting Zou
- & Charles L. Brooks III
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Article
| Open AccessPermeability of membranes in the liquid ordered and liquid disordered phases
Increasing evidence supports the existence of ordered nanodomains (or rafts) in cholesterol rich cell membranes. Here authors present molecular dynamics simulations and EPR experiments to monitor permeation of oxygen and water through membranes in the liquid ordered and liquid disordered phases.
- An Ghysels
- , Andreas Krämer
- & Richard W. Pastor
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Article
| Open AccessHigh-resolution label-free 3D mapping of extracellular pH of single living cells
Current methods to measure extracellular pH are often limited in resolution and response times. Here the authors present a label-free nanoprobe, consisting of a zwitterionic nanomembrane at the tip of a nanopipette, which enables high spatiotemporal resolution pH measurements and topography-pH 3D mapping in live cancer cells.
- Yanjun Zhang
- , Yasufumi Takahashi
- & Yuri Korchev
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Article
| Open AccessConformational pathway provides unique sensitivity to a synaptic mGluR
Metabotropic glutamate receptors (mGluRs) are dimeric G-protein–coupled receptors that operate at neural synapses. Here authors use FRET assays in live cells to monitor mGluR2/7’s activation and reveal how heterodimerization can alter the glutamate response of an mGluR.
- Chris H. Habrian
- , Joshua Levitz
- & Ehud Y. Isacoff
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Article
| Open AccessChemical unfolding of protein domains induces shape change in programmed protein hydrogels
Tailoring and programing the behavior of protein biomaterials is complex. Here, the authors report on the use of polyelectrolytes for controlling the stiffness to allow programing of protein hydrogels and generate reversible shape changes via folding and unfolding reactions.
- Luai R. Khoury
- & Ionel Popa
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Article
| Open AccessAutomated sequence design of 2D wireframe DNA origami with honeycomb edges
Wireframe DNA origami is a powerful approach to creating 2D and 3D geometries. Here the authors introduce an automated computational design approach that programs structures with high structural fidelity.
- Hyungmin Jun
- , Xiao Wang
- & Mark Bathe
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Article
| Open AccessThe ABCG2 multidrug transporter is a pump gated by a valve and an extracellular lid
The human ATP-binding cassette transporter ABCG2 plays critical roles in anticancer resistance but the molecular mechanism of ABCG2-mediated substrate transport remains enigmatic. Here authors use extensive mutagenesis and molecular dynamics simulations to reveal a mechanistic basis for the function of the di-leucine valve and the roof organization in the transport cycle.
- Narakorn Khunweeraphong
- , Daniel Szöllősi
- & Karl Kuchler
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Article
| Open AccessLipid order and charge protect killer T cells from accidental death
Cytotoxic T lymphocytes (CTLs) eliminate virus-infected and cancerous cells by secreting the pore-forming protein (perforin) and pro-apoptotic serine proteases (granzymes). Here authors show that two mechanisms protect the membranes of CTLs from disruption by perforin and granzymes.
- Jesse A. Rudd-Schmidt
- , Adrian W. Hodel
- & Ilia Voskoboinik
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Article
| Open AccessMolecular mechanism of a potassium channel gating through activation gate-selectivity filter coupling
Potassium channels such as MthK are presumed to have two allosterically coupled gates, the activation gate and the selectivity filter gate, that control gating transitions. Here authors use X-ray crystallography and molecular dynamics simulations on MthK and observe crosstalk between the gates.
- Wojciech Kopec
- , Brad S. Rothberg
- & Bert L. de Groot
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Article
| Open AccessChemotactic behaviour of Escherichia coli at high cell density
Swimming bacteria perform collective motion at high cell density, yet it is unclear how this behaviour affects their ability to follow substance gradients in the environment. Here, Colin et al. address this question by studying motion of Escherichia coli in controlled chemical gradients.
- Remy Colin
- , Knut Drescher
- & Victor Sourjik
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Article
| Open AccessStructure of the native supercoiled flagellar hook as a universal joint
The bacterial flagellar hook is a molecular universal joint that connects the rotary motor and long helical propeller of the bacterial flagellum. Here the authors present the 3.6 Å resolution cryo-EM structure of the native supercoiled Salmonella hook that provides insights into the dynamic changes of subunit conformations and intermolecular interactions of the hook protein FlgE.
- Takayuki Kato
- , Fumiaki Makino
- & Keiichi Namba
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Article
| Open AccessDynamic constriction and fission of endoplasmic reticulum membranes by reticulon
The endoplasmic reticulum (ER) is an intracellular network characterized by highly dynamic behavior whose control mechanisms are unclear. Here, the authors show that the ER-membrane protein Reticulon (Rtnl1) can constrict ER bilayers and lead to ER fission.
- Javier Espadas
- , Diana Pendin
- & Andrea Daga
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Article
| Open AccessMutL sliding clamps coordinate exonuclease-independent Escherichia coli mismatch repair
The mechanics of MMR strand specific excision that begins at a distant ssDNA break are not yet clear. Here the authors have used multiple single molecule imaging techniques to visualize the behavior of MMR components on mismatched DNA substrates and reveal an exonuclease-independent mechanism for E.coli MMR.
- Jiaquan Liu
- , Ryanggeun Lee
- & Richard Fishel
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Article
| Open AccessAMPA receptors in the synapse turnover by monomer diffusion
The mechanisms regulating the turnover of the AMPARs in the synapse, which is critically important to sustain basic synaptic activity, remains unclear. In this study, authors used single-molecule imaging techniques to demonstrate that AMPAR tetramers are not stable entities and readily fall apart to dimers and monomers that could reform to tetramers at the synapse, and that rapidly diffusing monomers in the plasma membrane are primarily responsible for the AMPAR turnover in the synapse.
- Jyoji Morise
- , Kenichi G. N. Suzuki
- & Shogo Oka
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Article
| Open AccessMyosin 1b is an actin depolymerase
Former evidence suggests a correlation between the function of non-conventional myosin motors and actin dynamics. Here authors use in vitro assays in which they observe that actin sliding on myosin 1b immobilized or bound to a fluid bilayer enhances actin depolymerization at the barbed end.
- Julien Pernier
- , Remy Kusters
- & Evelyne Coudrier
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Article
| Open AccessActive DNA unwinding and transport by a membrane-adapted helicase nanopore
Active translocation of DNA through nanopores usually needs enzyme assistance. Here authors present a nanopore derived from helicase E1 of bovine papillomavirus (BPV) which acts as a conductive pore embedded in lipid membrane to allow the translocation of ssDNA and unwinding of dsDNA.
- Ke Sun
- , Changjian Zhao
- & Jia Geng
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Article
| Open AccessA tool for functional brain imaging with lifespan compliance
Magnetoencephalography (MEG) recordings are sensitive to movement and therefore are especially challenging with young participants. Here the authors develop a wearable MEG system based on a modified bicycle helmet, which enables reliable recordings in toddlers, children, teenagers and adults.
- Ryan M. Hill
- , Elena Boto
- & Matthew J. Brookes
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Article
| Open AccessDynamic modulation of the lipid translocation groove generates a conductive ion channel in Ca2+-bound nhTMEM16
A membrane-exposed groove in Ca2+-gated TMEM16 scramblases forms the translocation pathway for ions and lipids. Here authors combine molecular dynamics with cryo-EM and functional assays to uncover the conformational transitions of the groove leading to a non-selective ion channel pore.
- George Khelashvili
- , Maria E. Falzone
- & Harel Weinstein
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Article
| Open AccessUnique structure and function of viral rhodopsins
Rhodopsin genes have been identified in some large double-stranded DNA viruses, but the structure and functions of viral rhodopsins remain unknown. Here authors present crystal structure and characterization of an Organic Lake Phycodnavirus rhodopsin II (OLPVRII) which forms a pentamer and is a weak proton pump.
- Dmitry Bratanov
- , Kirill Kovalev
- & Valentin Gordeliy
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Article
| Open AccessAutomatic structure-based NMR methyl resonance assignment in large proteins
The structures and dynamics of large proteins can be studied with methyl-based NMR but peak assignment is still challenging. Here the authors present MethylFLYA that allows automated assignment of methyl groups and apply it to five proteins with molecular weights in the range from 28 to 358 kDa.
- Iva Pritišanac
- , Julia M. Würz
- & Peter Güntert
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Article
| Open AccessReverberant 3D optical coherence elastography maps the elasticity of individual corneal layers
Elastic mapping of individual layers of the cornea with elastography uses Lamb waves, which are dependent on the thickness of each layer and the direction of propagation. Here the authors present Reverberant 3D Optical Coherence Elastography to measure elasticity of single layers using waves propagating in all directions.
- Fernando Zvietcovich
- , Pornthep Pongchalee
- & Kevin J. Parker
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Article
| Open AccessModeling and simulation of complex dynamic musculoskeletal architectures
Natural creatures, from fish to snake and birds, combine neural control, sensory feedback and compliant mechanics to operate across uncertain environments. Here the authors present a versatile modeling approach to the dynamic simulation of their architectures based on the assembly of Cosserat rods.
- Xiaotian Zhang
- , Fan Kiat Chan
- & Mattia Gazzola
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Article
| Open AccessProtein folding while chaperone bound is dependent on weak interactions
Spy is an ATP independent chaperone that allows folding of its client protein Im7 while continuously bound to Spy. Here the authors employ kinetics measurements to study the folding of another Spy client protein SH3 and find that Spy’s ability to allow a client to fold while bound is inversely related to how strongly it interacts with that client.
- Kevin Wu
- , Frederick Stull
- & James C. A. Bardwell
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Article
| Open AccessMolecular features of the UNC-45 chaperone critical for binding and folding muscle myosin
Myosin, a motor protein essential for intracellular transport to muscle contraction, requires a chaperone UNC-45 for folding and assembly. Here authors use in vitro reconstitution and structural biology to characterize the interplay between UNC-45 and muscle myosin MHC-B.
- Doris Hellerschmied
- , Anita Lehner
- & Tim Clausen
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Article
| Open AccessDNA mechanotechnology reveals that integrin receptors apply pN forces in podosomes on fluid substrates
Podosomes are protrusive structures that coordinate diverse functions related to cell invasion, migration, bone resorption and immune surveillance. Here the authors integrate DNA nanotechnology with FLIM-FRET to demonstrate that podosomes apply pN integrin tensile forces to sense and respond to substrate mechanics.
- Roxanne Glazier
- , Joshua M. Brockman
- & Khalid Salaita
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Article
| Open AccessPhagocytosis is mediated by two-dimensional assemblies of the F-BAR protein GAS7
The Bin/Amphiphysin/Rvs167 (BAR) domain superfamily, which includes FCH-BAR (F-BAR) domain proteins are membrane-sculpting proteins. Here the authors combine a range of techniques and show that the F-BAR domain of growth-arrest specific protein 7 (GAS7) forms two-dimensional sheets on flat membranes and that these oligomeric assemblies of GAS7 are required for the formation of phagocytic cups in macrophages.
- Kyoko Hanawa-Suetsugu
- , Yuzuru Itoh
- & Shiro Suetsugu
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Article
| Open AccessThe free energy landscape of retroviral integration
Retroviral integration of DNA into the host genome is a point of no return in the replication cycle but how efficient integration can take place remains unclear. Here the authors demonstrate that consecutive nucleoprotein intermediates are increasingly stable, resulting in a net forward rate.
- Willem Vanderlinden
- , Tine Brouns
- & Jan Lipfert
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Article
| Open AccessNEXAFS imaging to characterize the physio-chemical composition of cuticle from African Flower Scarab Eudicella gralli
Biology serves as inspiration in materials development; this requires improved understanding of the surface chemistry responsible for processes which are being mimicked. Here, the authors report on the use of near edge X-ray absorption fine structure (NEXAFS) imaging to analyze the surface chemistry of insect cuticle.
- Joe E. Baio
- , Cherno Jaye
- & Tobias Weidner
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Article
| Open AccessPathogenesis of hypertension in a mouse model for human CLCN2 related hyperaldosteronism
Mutations in the chloride channel ClC-2 have been found in primary aldosteronism (PA). Here, Göppner et al. generate transgenic mice expressing a mutant form of ClC-2 that displays increased chloride currents like patient mutations, and find it recapitulates the key pathological features of PA.
- Corinna Göppner
- , Ian J. Orozco
- & Thomas J. Jentsch
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Article
| Open AccessTopology, landscapes, and biomolecular energy transport
Understanding vibrational energy transfer in macromolecules has been challenging to both theory and experiment. Here the authors use non-equilibrium molecular dynamics to reveal the relationship between heat transport in a model peptide, emergent nonlinearity, and the underlying free energy landscape.
- Justin E. Elenewski
- , Kirill A. Velizhanin
- & Michael Zwolak
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Article
| Open AccessSpontaneous ssDNA stretching on graphene and hexagonal boron nitride in plane heterostructures
Single stranded DNA analysis is of interest for a range of applications; however, natural folding of DNA can cause problems with this. Here, the authors report on the in silico analysis of graphene and hexagonal-boron-nitride structures for the stretching and unfolding of DNA to allow for analysis.
- Binquan Luan
- & Ruhong Zhou
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Article
| Open AccessAllosteric activation of an ion channel triggered by modification of mechanosensitive nano-pockets
How mechanosensitive ion channels, such as MscL, are activated by lipids and physical properties of the membrane remains unclear. Here authors use PELDOR/DEER spectroscopy and identify a single site which generated an allosteric structural response in the absence of membrane tension.
- Charalampos Kapsalis
- , Bolin Wang
- & Christos Pliotas
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Article
| Open AccessThermodynamic control of −1 programmed ribosomal frameshifting
Programmed ribosomal frameshifting (PRF) is an alternative translation strategy that causes controlled slippage of the ribosome along the mRNA, changing the sequence of the synthesized protein. Here the authors provide a thermodynamic framework that explains how mRNA sequence determines the efficiency of frameshifting.
- Lars V. Bock
- , Neva Caliskan
- & Helmut Grubmüller