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Activation of G-protein-coupled receptors correlates with the formation of a continuous internal water pathway
The crystal structure of the A2A GPCR suggested that water molecules might form a continuous pathway that becomes disrupted during receptor activation. Here Yuan et al.instead show that a conserved layer of hydrophobic residues forms a gate that opens to form a continuous water channel upon receptor activation.
- Shuguang Yuan
- , Slawomir Filipek
- & Horst Vogel
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| Open AccessProtein co-translocational unfolding depends on the direction of pulling
Protein unfolding and translocation through membrane pores occurs in several biological processes and has implications in nanopore technologies. Here, the authors show that the kinetics of unfolding differ depending on which end of the chain enters the pore first.
- David Rodriguez-Larrea
- & Hagan Bayley
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Dynactin functions as both a dynamic tether and brake during dynein-driven motility
It remains unclear how the dynactin complex activates cytoplasmic dynein motor proteins. Ayloo et al.use single molecule imaging to observe dynein–dynactin behaviour on microtubules, and show that dynactin recruits dynein to microtubules and acts as a brake to slow the motor.
- Swathi Ayloo
- , Jacob E. Lazarus
- & Erika L. F. Holzbaur
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| Open AccessAn atomic model of brome mosaic virus using direct electron detection and real-space optimization
Recent developments in cryo-electron microscopy have enabled structure determination of large protein complexes at almost atomic resolution. Wang et al.combine some of these technologies into an effective workflow, and demonstrate the protocol by solving the atomic structure of an icosahedral RNA virus.
- Zhao Wang
- , Corey F. Hryc
- & Wah Chiu
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Solution-state conformation and stoichiometry of yeast Sir3 heterochromatin fibres
Heterochromatin is a ‘repressed’ chromatin state involved in the generation of centromeres, the protection of telomeres and the maintenance of genome integrity. Here Swygert et al.show that Sir3 - a key factor in the formation of heterochromatin - promotes a chromatin structure distinct from the canonical 30 nm fibre.
- Sarah G. Swygert
- , Benjamin J. Manning
- & Craig L. Peterson
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| Open AccessActin–microtubule coordination at growing microtubule ends
The structural cross-talk between components of the eukaryotic cytoskeleton remains poorly understood. Here the authors engineer an actin-binding microtubule tip-tracking protein that guides microtubule growth along actin bundles, and allows microtubule growing ends to pull and bundle actin filaments.
- Magdalena Preciado López
- , Florian Huber
- & Marileen Dogterom
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Molecular determinants of magnesium-dependent synaptic plasticity at electrical synapses formed by connexin36
Electrical synaptic transmission is known to be modulated by intracellular magnesium. Here, Palacios-Prado et al.show that electrical synapses formed by connexin36 in the thalamic reticular nucleus are bidirectionally modulated by changes in magnesium concentration via pore-lining sensitive domains.
- Nicolás Palacios-Prado
- , Sandrine Chapuis
- & Feliksas F. Bukauskas
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| Open AccessQuantitative super-resolution imaging of Bruchpilot distinguishes active zone states
Complex molecular interactions occur in the active zone cytomatrix (CAZ) within the presynaptic terminal to regulate synaptic plasticity. Here, the authors use imaging techniques to show that the CAZ is composed of units containing on average 137 Bruchpilot proteins, many of which are arranged into clusters.
- Nadine Ehmann
- , Sebastian van de Linde
- & Robert J. Kittel
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Documentation and localization of force-mediated filamin A domain perturbations in moving cells
Biosensors designed to respond to mechanical force in cells have provided insights into the force landscape within a cell. Here, Nakamura et al. design a FRET probe in the actin crosslinking protein filamin A and show that it unfolds under force only in newly protruding regions of the cell.
- Fumihiko Nakamura
- , Mia Song
- & Thomas P. Stossel
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Tension on the linker gates the ATP-dependent release of dynein from microtubules
Unlike most processive motor proteins, the stepping motion of cytoplasmic dynein’s two linked motor domains is not precisely coordinated. Cleary et al.show that the ATPase activity of just one head is required for processive movement, and that tension on the linker gates the release of the motor from microtubules.
- Frank B. Cleary
- , Mark A. Dewitt
- & Ahmet Yildiz
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ATP-induced electron transfer by redox-selective partner recognition
Some biological reactions can require thermodynamically unfavourable electron transfer processes, the occurrence of which are not yet fully understood. Here, the authors provide the structural basis of energy transduction during the reductive activation of B12-dependent methyltransferases.
- Sandra E. Hennig
- , Sebastian Goetzl
- & Holger Dobbek
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General rules for the arrangements and gating motions of pore-lining helices in homomeric ion channels
Rearrangements of the pore-lining helix (PLH) bundles of ion channels are central to their gating mechanisms. Here, Dai et al. use a modelling approach to define the general rules that govern the arrangements and gating motions of the PLHs in homomeric ion channels.
- Jian Dai
- & Huan-Xiang Zhou
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| Open AccessSingle-molecule force spectroscopy reveals force-enhanced binding of calcium ions by gelsolin
The application of force can influence biological processes such as ligand and protein–protein binding, with mechanical stress typically hindering such interactions. Here, the authors use atomic force microscopy to show that the binding of calcium to gelsolin can be improved under stress.
- Chunmei Lv
- , Xiang Gao
- & Wei Wang
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Force-dependent conformational switch of α-catenin controls vinculin binding
At cell–cell adhesions, α-catenin contains a cryptic vinculin-binding site. Here, Yao et al. demonstrate, using magnetic tweezers, that physiologically relevant forces unfurl α-catenin to reveal the vinculin-binding site, and allow the reversible binding of vinculin to mechanically reinforce the adhesion.
- Mingxi Yao
- , Wu Qiu
- & Jie Yan
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Cementing proteins provide extra mechanical stabilization to viral cages
Some viruses possess ‘decoration’ proteins, such as gpD in lambda phage, that stabilize the viral particles in poorly understood ways. Here the authors show that gpD incorporation into lambda particles provides mechanical reinforcement and increased resistance to punctual deformations and collisions.
- M. Hernando-Pérez
- , S. Lambert
- & P. J. de Pablo
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| Open AccessMulti-protein assemblies underlie the mesoscale organization of the plasma membrane
Although many proteins adopt uneven distributions in the plasma membrane, it is not clear how these nanoscale heterogeneities relate to the general protein patterning of the membrane. Saka et al. use click chemistry to reveal the mesoscale organization of membrane proteins into multi-protein assemblies.
- Sinem K. Saka
- , Alf Honigmann
- & Silvio O. Rizzoli
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| Open AccessArrayed lipid bilayer chambers allow single-molecule analysis of membrane transporter activity
The development of small volume chamber arrays has greatly facilitated high throughput biological assays of soluble proteins. Here, Watanabe et al.adapt this approach to develop an arrayed lipid bilayer chamber system for single molecule level measurements of membrane transporter activity.
- Rikiya Watanabe
- , Naoki Soga
- & Hiroyuki Noji
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| Open AccessRetrieving the intracellular topology from multi-scale protein mobility mapping in living cells
Numerous obstacles posed by cellular subcompartments and structures constrain protein transport in the cell. Here, Baum et al.map the intracellular topology from a diffusing protein’s point of view by measuring the diffusive movements of fluorescently labelled reporter proteins in living cells on multiple time and length scales.
- Michael Baum
- , Fabian Erdel
- & Karsten Rippe
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Substrate-bound outward-open state of the betaine transporter BetP provides insights into Na+ coupling
The Na+-coupled betaine transporter BetP is representative of a structural superfamily of symporters, for which different conformational states of the transport cycle are described. Perez et al.provide a structure for the elusive substrate-bound outward-open state, and propose a mechanism for sodium-coupled transport.
- Camilo Perez
- , Belinda Faust
- & Christine Ziegler
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A distinct sodium channel voltage-sensor locus determines insect selectivity of the spider toxin Dc1a
β-Diguetoxin-Dc1a, a component of desert bush spider venom, targets insect voltage-gated sodium channels, but not those of humans. Bende et al. find that American, but not German cockroaches are sensitive to the toxin, and identify two residues in the voltage-sensor domain that underlie this difference.
- Niraj S. Bende
- , Sławomir Dziemborowicz
- & Frank Bosmans
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Economic photoprotection in photosystem II that retains a complete light-harvesting system with slow energy traps
Photosystem II possesses a protection mechanism to prevent damage when exposed to high-intensity light. Here, the authors analyze the functional consequences of structural changes associated with this process, and show that protection does not undermine energy capture by open reaction centres.
- Erica Belgio
- , Ekaterina Kapitonova
- & Alexander V. Ruban
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IgGs are made for walking on bacterial and viral surfaces
Antibody–antigen recognition is one of the important aspects of immunity, but the nanomechanical process of this recognition is not fully understood. Here, using high-speed atomic force microscopy, the authors observe that on membranes containing a high density of immobile antigens antibodies move in a ‘random walking’ motion.
- Johannes Preiner
- , Noriyuki Kodera
- & Peter Hinterdorfer
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Taking snapshots of photosynthetic water oxidation using femtosecond X-ray diffraction and spectroscopy
Photosystem II is the biosynthetic machinery that allows the conversion of water to oxygen using light. Here, the authors combine X-ray emission and diffraction data to probe the structural changes that take place during photosystem II catalysis.
- Jan Kern
- , Rosalie Tran
- & Vittal K. Yachandra
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| Open AccessA hydrophobic barrier deep within the inner pore of the TWIK-1 K2P potassium channel
K2P potassium channels have a structure dissimilar to other potassium channels. Here, the authors study the K2P channel TWIK-1 and show that the protein contains a deep pore hydrophobic barrier that blocks ion channel conductance.
- Prafulla Aryal
- , Firdaus Abd-Wahab
- & Stephen J. Tucker
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| Open AccessSubstrate–water exchange in photosystem II is arrested before dioxygen formation
The oxygen-evolving complex of photosystem II converts water into oxygen during photosynthesis, but how this process occurs is not yet fully understood. Here, the authors use modified complexes with reduced reaction rates to study the process of oxygen evolution in more detail.
- Håkan Nilsson
- , Fabrice Rappaport
- & Johannes Messinger
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| Open AccessProtruding knob-like proteins violate local symmetries in an icosahedral marine virus
Some viruses are spherical particles in which protein components are organized with well-defined icosahedral and local symmetries. Here, Gipson et al. describe a unique arrangement of proteins, breaking all expected local symmetries, in particles of a marine bacterial virus.
- Preeti Gipson
- , Matthew L. Baker
- & Wah Chiu
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Molecular origins of internal friction effects on protein-folding rates
The interaction of water molecules with a protein results in a frictional force that influences protein conformational dynamics and folding, though the nature of the protein also influences the friction. Here, the authors use molecular simulations to examine the origin of this protein contribution.
- David de Sancho
- , Anshul Sirur
- & Robert B. Best
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| Open AccessDynamic protein conformations preferentially drive energy transfer along the active chain of the photosystem II reaction centre
Cofactor-mediated energy and electron transfer in photosystem II occurs preferentially through one branch of the reaction centre, despite there being a symmetric path available. Here, the authors use computational methods to determine the influence of protein conformation on this selectivity.
- Lu Zhang
- , Daniel-Adriano Silva
- & Xuhui Huang
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| Open AccessA cochlear-bone wave can yield a hearing sensation as well as otoacoustic emission
Novel headphone technology employs bone conduction to enable hearing, but the mechanism behind this remains unclear. Tchumatchenko and Reichenbach now show that bone conduction and subsequent hearing and otoacoustic emissions are in part due to deformation of the cochlear bone.
- Tatjana Tchumatchenko
- & Tobias Reichenbach
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Relative motions between left flipper and dorsal fin domains favour P2X4 receptor activation
P2X receptors are ion channels that are controlled by the level of extracellular ATP. Here, Zhao et al.describe the coordinated allosteric changes in two protein domains that couple extracellular ATP-binding to channel gating and show that these changes are essential for the function of the proteins.
- Wen-Shan Zhao
- , Jin Wang
- & Ye Yu
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Interplay between trigger factor and other protein biogenesis factors on the ribosome
Ribosome-associated protein biogenesis factors act during protein synthesis to facilitate modification, targeting and folding of the nascent polypeptide. Here, Bornemann et al.establish the dynamic interplay between these factors, thus providing new insight into the early steps of protein biogenesis.
- Thomas Bornemann
- , Wolf Holtkamp
- & Wolfgang Wintermeyer
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Evidence for an electrostatic mechanism of force generation by the bacteriophage T4 DNA packaging motor
Viral DNA packaging motors must generate large forces to package the viral capsid. Here, Migliori et al.provide functional and computational evidence that electrostatic interactions between subdomains of the T4 packaging motor provide the driving force for DNA packaging.
- Amy D. Migliori
- , Nicholas Keller
- & Douglas E. Smith
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Diminished hERG K+ channel activity facilitates strong human labour contractions but is dysregulated in obese women
Uterine muscle contracts rhythmically during labour but the underlying electrophysiological mechanisms are not fully understood. The authors of this study show that hERG1 potassium channels reduce human uterine contractions in pregnancy and are suppressed during labour in lean but not in obese women.
- Helena C. Parkington
- , Janet Stevenson
- & Roger Smith
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Stiff filamentous virus translocations through solid-state nanopores
Nanopores are promising tools for the detection and characterization of biomolecules. Here, the authors combine experiments and simulations to study how the passage of rigid viruses through solid-state nanopores differs from more flexible biomolecules.
- Angus McMullen
- , Hendrick W. de Haan
- & Derek Stein
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Coordinated DNA dynamics during the human telomerase catalytic cycle
Telomerase reverse transcriptase extends the ends of linear chromosomes with the aid of an integral RNA subunit. Here, Parks and Stone characterize the translocation kinetics of telomerase identifying distinct steps important for the processivity of the enzyme.
- Joseph W. Parks
- & Michael D. Stone
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Membrane deformation and scission by the HSV-1 nuclear egress complex
Two viral proteins form the nuclear egress complex of herpesviruses, which is essential for the exit of nascent viral capsids from the cell nucleus. Here, the authors use synthetic lipid vesicles to show that the complex can mediate membrane budding in the absence of other cellular factors.
- Janna M. Bigalke
- , Thomas Heuser
- & Ekaterina E. Heldwein
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Correlated motions are a fundamental property of β-sheets
Functional changes in protein structures are involved in a large number of biochemical processes. Here, the authors perform a simulation study of known protein structures to show how β-sheets possess the ability to facilitate concerted backbone motions.
- R. Bryn Fenwick
- , Laura Orellana
- & Xavier Salvatella
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Targeting Mycobacterium tuberculosis nucleoid-associated protein HU with structure-based inhibitors
Histone-like HU proteins play roles in chromatin architecture and DNA-dependent processes in bacteria. Here, the authors describe the crystal structure of the DNA-binding domain of HU from Mycobacterium tuberculosis, and show that the pathogen’s growth can be inhibited using HU-targeting small molecules.
- Tuhin Bhowmick
- , Soumitra Ghosh
- & Valakunja Nagaraja
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Two-way traffic of glycoside hydrolase family 18 processive chitinases on crystalline chitin
The degradation of chitin and cellulose is dependent on the processivity of degrading enzymes. Here, Igarashi et al. use high-speed atomic force microscopy to visualize the movement of two chitinases (ChiA and ChiB) and show them to move in opposite directions, allowing a molecular mechanism to be proposed.
- Kiyohiko Igarashi
- , Takayuki Uchihashi
- & Masahiro Samejima
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Physiological sodium concentrations enhance the iodide affinity of the Na+/I− symporter
Thyroid hormone synthesis requires import of iodide ions through the Na+/I− symporter, however its affinity for iodide is surprisingly low. Using a statistical thermodynamics approach, Nicola et al. show that sodium ion binding enhances iodide affinity, revealing a mechanism for iodide transport.
- Juan P. Nicola
- , Nancy Carrasco
- & L. Mario Amzel
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Centrin3 in trypanosomes maintains the stability of a flagellar inner-arm dynein for cell motility
Beating flagella are essential for the locomotion of Trypanosoma brucei, the causative agent of human sleeping sickness. Here, Wei et al. identify a role for one of five centrin proteins, TbCentrin3, in stabilizing the assembly of a dynein motor essential for flagellar motility.
- Ying Wei
- , Huiqing Hu
- & Ziyin Li
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Terahertz underdamped vibrational motion governs protein-ligand binding in solution
Terahertz-frequency underdamped vibrational modes in proteins are thought to be involved in biochemical processes, but their observation in solution is difficult. Here, the authors use femtosecond optical Kerr-effect spectroscopy to experimentally identify these modes during enzyme–ligand binding.
- David A. Turton
- , Hans Martin Senn
- & Klaas Wynne
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Resolving the molecular mechanism of cadherin catch bond formation
Cadherins are calcium-dependent adhesion molecules that can form catch bonds, characterized by longer lifetimes at higher force. Here, Manibog et al. determine the mechanism of catch bond formation, whereby tension induces hydrogen bond formation between opposing extracellular domains in a calcium-dependent manner.
- Kristine Manibog
- , Hui Li
- & Sanjeevi Sivasankar
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Cell reorientation under cyclic stretching
Cells sense their physical environment and reorient in response to cyclic mechanical deformation. Here the authors show that existing models do not adequately explain this phenomenon, and develop a new theory based on the active relaxation of passively stored elastic energy.
- Ariel Livne
- , Eran Bouchbinder
- & Benjamin Geiger
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Persistent super-diffusive motion of Escherichia coli chromosomal loci
In bacteria, chromosomal architecture exhibits spatial and temporal fluctuations, which affect cellular functions. Here, Javer et al. use high-resolution tracking of chromosomal loci in E. colito uncover rare events of unusually large and fast movements, providing new insight into bacterial chromosome dynamics.
- Avelino Javer
- , Nathan J. Kuwada
- & Marco Cosentino Lagomarsino
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Direct observation of the three regions in α-synuclein that determine its membrane-bound behaviour
α-synuclein is a protein whose aberrant aggregation is associated with Parkinson’s disease. Here, Fusco et al.characterize α-synuclein bound to lipid membranes using a combination of solution and solid-state NMR spectroscopy and provide insights into the molecular processes associated with the aggregation of this protein.
- Giuliana Fusco
- , Alfonso De Simone
- & Gianluigi Veglia
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| Open AccessSeparating NADH and NADPH fluorescence in live cells and tissues using FLIM
NAD and NADP play fundamentally different roles in cellular metabolism, and yet these pyridine nucleotides cannot be distinguished spectroscopically in living cells. Blacker et al.demonstrate that fluorescence lifetime imaging can be used to quantify NADPH/NADH balance in cultured cells and in the mammalian cochlea.
- Thomas S. Blacker
- , Zoe F. Mann
- & Michael R. Duchen
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| Open AccessThe full-length cell–cell fusogen EFF-1 is monomeric and upright on the membrane
Cell–cell fusion in Caenorhabditis elegans is mediated by EFF-1 and AFF-1 proteins. Here, the authors present an electron cryomicroscopy 3D reconstruction of EFF-1 in the membrane, and combine snapshots of membrane fusion in vitrowith a recently reported crystal structure to propose a mechanism for the fusion process.
- Tzviya Zeev-Ben-Mordehai
- , Daven Vasishtan
- & Kay Grünewald
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Mid-range Ca2+ signalling mediated by functional coupling between store-operated Ca2+ entry and IP3-dependent Ca2+ release
It remains unclear how localized calcium influx activates distant effectors in the absence of a global Ca2+ rise. Courjaret and Machaca find that mid-range Ca2+ signalling is mediated by coupling between localized store-operated calcium entry and distal IP3-dependent Ca2+ release to activate Cl−channels.
- Raphaël Courjaret
- & Khaled Machaca