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| Open AccessAn electrostatic mechanism for Ca2+-mediated regulation of gap junction channels
Intercellular signalling can be mediated by gap junction channels, and calcium blocks this signally during tissue injury. Here, the authors use X-ray crystallography and molecular dynamics to show that the calcium forms an electrostatic barrier to prevent transport of cations.
- Brad C. Bennett
- , Michael D. Purdy
- & Mark Yeager
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Article
| Open AccessMechanism of FGF receptor dimerization and activation
Different fibroblast growth factor (fgf) ligands elicit specific biological responses, but the mechanism directing this specificity is unknown. Here the authors show that fgf1 and fgf2 impose specific reorganizations on the fgf receptor dimer trans-membrane helices that result in distinct level of receptor activation.
- Sarvenaz Sarabipour
- & Kalina Hristova
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Article
| Open AccessThe experimental power of FR900359 to study Gq-regulated biological processes
Pertussis toxin is used extensively for perturbing Gαi/o pathways in the study of physiology and disease, but an equivalent inhibitor of Gαq signalling is not currently available to the research community. Here the authors characterize FR900359 as a specific Gq inhibitor and demonstrate its utility to dissect GPCR signalling and its potential to inhibit melanoma cells.
- Ramona Schrage
- , Anna-Lena Schmitz
- & Evi Kostenis
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Article
| Open AccessMammalian SRP receptor switches the Sec61 translocase from Sec62 to SRP-dependent translocation
Sec62 is a membrane-bound protein that is involved in the translocation of proteins via the signal recognition particle-independent pathway. Here, the authors show that the receptor SRα displaces Sec62 from the translocon and isolate the domain on SRα that is responsible for this.
- Bhalchandra Jadhav
- , Michael McKenna
- & Martin R. Pool
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Article
| Open AccessAnkyrin-mediated self-protection during cell invasion by the bacterial predator Bdellovibrio bacteriovorus
The bacterium Bdellovibrio bacteriovorus invades and kills other bacteria, but it is unclear how it avoids degradation of its own cell wall. Here the authors identify the B. bacteriovorusprotein Bd3460 as an endopeptidase inhibitor that prevents hydrolysis of the predator’s peptidoglycan during invasion of prey.
- Carey Lambert
- , Ian T. Cadby
- & Andrew L. Lovering
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Article
| Open AccessTransmembrane protein sorting driven by membrane curvature
The accumulation of chemoreceptor proteins at bacterial poles is thought to depend on their clustering into arrays. Strahl et al. show that in Bacillus subtilis, the chemoreceptor TlpA uses high membrane curvature as a spatial cue for polar localization, through the intrinsic curvature sensitivity of the receptor complex.
- H. Strahl
- , S. Ronneau
- & L. W. Hamoen
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Article
| Open AccessIRSp53 senses negative membrane curvature and phase separates along membrane tubules
The inverted-BAR domain protein IRSp53 associates with the inner leaflet of tubular membranes such as filopodia. Here, Prévostet al. demonstrate that the I-BAR domain of IRSp53 senses negative membrane curvature, and undergoes phase separation which may aid its clustering upon filopodia generation.
- Coline Prévost
- , Hongxia Zhao
- & Patricia Bassereau
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Article
| Open AccessSubstrate specificity and transport mechanism of amino-acid transceptor Slimfast from Aedes aegypti
Anautogenous mosquitoes need to obtain essential amino acids from a blood meal for reproduction. Here, the authors examine the amino acid transporter Slimfast from the yellow-fever mosquito and describe both its specificity and mechanism of action.
- Dmitri Y. Boudko
- , Hitoshi Tsujimoto
- & Immo A. Hansen
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Article
| Open AccessMembrane stiffening by STOML3 facilitates mechanosensation in sensory neurons
To maintain viability, cells must be able to sense and respond to mechanical stimuli. Here, Qi et al. show that the STOML3 protein acts in mechanosensation by binding cholesterol and regulating membrane stiffness which can in turn regulate ion flux through mechanosensitive channels.
- Yanmei Qi
- , Laura Andolfi
- & Jing Hu
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Article
| Open AccessQuantifying the stabilizing effects of protein–ligand interactions in the gas phase
Relatively few techniques can quantitatively measure the effect of ligands on membrane protein stability. Here the authors demonstrate the use of ion-mobility mass spectrometry to accurately measure and quantify ligand-induced protein stabilization in the gas phase.
- Timothy M. Allison
- , Eamonn Reading
- & Carol V. Robinson
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Evolutionarily conserved intercalated disc protein Tmem65 regulates cardiac conduction and connexin 43 function
Mechanical and electrical activity in the heart is propagated through unique cardiomyocyte membrane structures, the intercalated discs (ID). Sharma et al.identify a novel ID protein, Tmem65, that controls Ca2+ signalling and electrical coupling by interacting with and functionally regulating the gap junction protein Cx43.
- Parveen Sharma
- , Cynthia Abbasi
- & Anthony O. Gramolini
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Article
| Open AccessWnt signalling tunes neurotransmitter release by directly targeting Synaptotagmin-1
The mechanisms by which signalling proteins dynamically modulate neurotransmitter release remain poorly understood. Here, Cianiet al. show Wnt signalling influences vesicle pool availability in an activity-dependent manner via direct interactions with Dishevelled-1 and the synaptic vesicle calcium sensor Synaptotagmin-1.
- Lorenza Ciani
- , Aude Marzo
- & Patricia C. Salinas
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Article
| Open AccessPhospho-selective mechanisms of arrestin conformations and functions revealed by unnatural amino acid incorporation and 19F-NMR
G-protein-coupled receptors (GPCRs) signal via G proteins or arrestin-mediated pathways; the plasticity of arrestin proteins is thought to underlie their function. Here, the authors use NMR to examine how β-arrestin-1 recognizes different GPCR phospho-barcodes, and how this triggers structural rearrangements to fulfill selective functions.
- Fan Yang
- , Xiao Yu
- & Jin-Peng Sun
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Article
| Open AccessAtomic basis for therapeutic activation of neuronal potassium channels
The antiepileptic drug retigabine potentiates neuronal KCNQ potassium channels. Here, the authors use a combination of unnatural amino acid mutagenesis and electrophysiology to show that retigabine acts by hydrogen bonding with a tryptophan indole nitrogen in the channel pore.
- Robin Y. Kim
- , Michael C. Yau
- & Harley T. Kurata
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Article
| Open AccessOptical control of NMDA receptors with a diffusible photoswitch
N-methyl-D-aspartate receptors (NMDARs) play a central role in synaptic plasticity, learning and memory. Here the authors describe azobenzene-triazole-glutamate (ATG), a new diffusible photoswitchable agonist that allows precise temporal control over NMDAR activity.
- Laura Laprell
- , Emilienne Repak
- & Dirk Trauner
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Article
| Open AccessDual-topology insertion of a dual-topology membrane protein
Dual-topology membrane proteins consist of subunits that have identical sequence but reside in the membrane in two inverted orientations. Here, Woodall et al.find that the dual topology of the transporter EmrE is largely achieved by initial insertion in both topologies rather than major rearrangements after insertion.
- Nicholas B. Woodall
- , Ying Yin
- & James U. Bowie
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Article
| Open AccessTranscriptional regulation of Annexin A2 promotes starvation-induced autophagy
Starvation triggers autophagy by inhibiting mTOR signalling. Here, Moreau et al.identify an alternative, transcriptional activation pathway: starvation-induced JNK signalling upregulates Annexin A2 transcription, which in turn enhances actin-dependent transport of Atg9 vesicles from endosomes to autophagosomes.
- Kevin Moreau
- , Ghita Ghislat
- & David C. Rubinsztein
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Article
| Open AccessThe molecular mechanism of Zinc acquisition by the neisserial outer-membrane transporter ZnuD
ZnuD is a conserved zinc transporter expressed in several bacterial pathogens with potential as a target against infection. Here the authors demonstrate a requirement for ZnuD in systemic infection by N. meningitidisand define the molecular mechanism of ZnuD-mediated Zinc transport across the bacterial outer membrane.
- Charles Calmettes
- , Christopher Ing
- & Trevor F. Moraes
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Article
| Open AccessStructures of FolT in substrate-bound and substrate-released conformations reveal a gating mechanism for ECF transporters
Substrate specificity of ECF transporters is determined by the transmembrane EcfS protein subunit. Here Zhao et al.present substrate-bound and substrate-released structures of a bacterial folate transporter EcfS and suggest a gating mechanism for ECF transporters.
- Qin Zhao
- , Chengcheng Wang
- & Peng Zhang
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Pirt reduces bladder overactivity by inhibiting purinergic receptor P2X3
The cause of overactive bladder is largely unknown and there is currently no effective therapy. Gaoet al. show that a membrane protein Pirt controls bladder emptying by inhibiting the neuronal purinergic receptor P2X3 and that treatment with a small Pirt fragment prevents bladder overactivity in mice.
- Xiao-Fei Gao
- , Ji-Feng Feng
- & Cheng He
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The sorting protein PACS-2 promotes ErbB signalling by regulating recycling of the metalloproteinase ADAM17
ErbB signalling is stimulated by the release of its ligands from the cell surface through metalloproteinase-dependent cleavage. Dombernowsky et al. show that this process is controlled by the sorting protein PACS-2, which enhances ErbB ligand release by regulating trafficking of the metalloprotease ADAM17.
- Sarah Louise Dombernowsky
- , Jacob Samsøe-Petersen
- & Marie Kveiborg
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Article
| Open AccessA mosquito lipoxin/lipocalin complex mediates innate immune priming in Anopheles gambiae
A soluble factor induced by Plasmodiuminfection promotes hemocyte differentiation and increases mosquitoe resistance to subsequent infections. Here the authors show that this factor consists of a Lipocalin/Lipoxin A4 complex, and that insects can metabolize arachidonic acid to produce lipoxins.
- Jose Luis Ramirez
- , Giselle de Almeida Oliveira
- & Carolina Barillas-Mury
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Aquaporin-3-mediated hydrogen peroxide transport is required for NF-κB signalling in keratinocytes and development of psoriasis
Aquaporin-3 (AQP3) mediates cellular uptake of water and hydrogen peroxide (H2O2). Here, the authors show that TNF-induced H2O2enters keratinocytes via AQP3, eliciting NF-κB activation and the development of psoriasis, and identify AQP3 as a potential therapeutic target for this inflammatory immune-mediated disease.
- Mariko Hara-Chikuma
- , Hiroki Satooka
- & A. S. Verkman
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Article
| Open AccessCD24 tracks divergent pluripotent states in mouse and human cells
Characterizing the cellular stages that lead to induced reprogramming is of much interest and cell surface markers could offer unique advantages for this. Here the authors use surface proteomics and discover CD24 as a marker that tracks reprogramming-responsive cells and enables the analysis and enrichment of transgene-dependent and -independent induced pluriopotent stem cells.
- Nika Shakiba
- , Carl A. White
- & Peter W Zandstra
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Article
| Open AccessMolecular snapshots of the Pex1/6 AAA+ complex in action
Pex1 and Pex6 form a heterohexameric AAA+ ATPase complex with triangular geometry at the peroxisome membrane. Here the authors use electron microscopy to show that the complex undergoes conformational changes upon ATP hydrolysis, and demonstrate inter-domain communication between neighbouring nucleotide-binding domains.
- Susanne Ciniawsky
- , Immanuel Grimm
- & Petra Wendler
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Article
| Open AccessSmall-molecule activation of SERCA2a SUMOylation for the treatment of heart failure
SUMOylation of the cardiac calcium pump SERCA2a affects its activity and promotes cardiomyocyte contractility. Here the authors identify a small molecule N106 that increases SERCA2 SUMOylation and improves heart function in mice, and propose a promising therapeutic strategy for treatment of heart failure.
- Changwon Kho
- , Ahyoung Lee
- & Roger J. Hajjar
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Article
| Open AccessSteady-state cross-correlations for live two-colour super-resolution localization data sets
Quantitative live cell super-resolution microscopy is currently limited by the time it takes to acquire a well sampled image. Here Stone and Veatch develop a cross-correlation analysis that does not rely on image reconstruction and apply this method to quantify the co-distribution of Lyn kinase and the B-cell receptor during antigen stimulation.
- Matthew B. Stone
- & Sarah L. Veatch
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Article
| Open AccessOptogenetic control of contractile function in skeletal muscle
Nerve damage can lead to skeletal muscle paralysis. The authors show that localized photostimulation of skeletal muscle expressing the light-sensitive channel Channelrhodopsin-2 generates contraction in the absence of neural impulses and prove that this strategy can be used for optogenetic opening of explanted murine vocal cords.
- Tobias Bruegmann
- , Tobias van Bremen
- & Philipp Sasse
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Article
| Open AccessCooperative folding of intrinsically disordered domains drives assembly of a strong elongated protein
Staphylococcal biofilm formation is promoted by the surface protein SasG. Here, the authors characterize the structure and remarkable mechanical strength of the repeat region of SasG, and show how elongation is achieved by obligate folding of the disordered regions within the repeating units.
- Dominika T. Gruszka
- , Fiona Whelan
- & Jane Clarke
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Evolutionary-guided de novo structure prediction of self-associated transmembrane helical proteins with near-atomic accuracy
While the transmembrane regions of single-pass transmembrane proteins play critical roles in receptor signalling, they remain difficult to characterize structurally. Here the authors present a computational approach for accurate structure prediction of associated single-pass transmembrane helical proteins.
- Y. Wang
- & P. Barth
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Article
| Open AccessStructural basis for binding of human IgG1 to its high-affinity human receptor FcγRI
FcγRs are cell-surface receptors for IgGs that play key roles in the humoral and cellular immune response to infection. Here, the authors present a high-resolution crystal structure of the hFcγRI-Fc complex to reveal the molecular mechanisms underlying the high specificity of this important immunological interaction.
- Masato Kiyoshi
- , Jose M.M. Caaveiro
- & Kouhei Tsumoto
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In vivo model with targeted cAMP biosensor reveals changes in receptor–microdomain communication in cardiac disease
cAMP is a second messenger that acts in distinct intracellular locations regulating diverse cellular functions. Here the authors design a FRET-based cAMP biosensor and use it to measure in vivodynamics of cAMP concentration changes in the sarcoplasmatic reticulum of mouse cardiomyocytes in health and disease.
- Julia U. Sprenger
- , Ruwan K. Perera
- & Viacheslav O. Nikolaev
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Heparanase is a host enzyme required for herpes simplex virus-1 release from cells
Herpesviruses bind to heparan sulphate (HS) on the surface of cells before infecting them. Here, the authors show that heparanase, a host enzyme that degrades HS and is upregulated on viral infection, is required for the release of newly formed viruses from infected cells.
- Satvik R. Hadigal
- , Alex M. Agelidis
- & Deepak Shukla
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Regulation of endogenous transmembrane receptors through optogenetic Cry2 clustering
Signaling through transmembrane receptors regulates diverse biological processes including cell proliferation, motility and differentiation. Here, the authors demonstrate the optogenetic control of endogenous transmembrane receptor activity through clustering using a new modular strategy.
- L. J. Bugaj
- , D. P. Spelke
- & D. V. Schaffer
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Article
| Open AccessOsmosensing and scaffolding functions of the oligomeric four-transmembrane domain osmosensor Sho1
The yeast high osmolarity glycerol pathway activates the Hog1 MAP kinase via two branches, SLN1 and SHO, but the identity of the osmosensor has only been shown for the SLN1 branch. Here the authors demonstrate that the four-TM domain protein Sho1 functions as both an osmosensor and adaptor protein necessary for Hog1 activation.
- Kazuo Tatebayashi
- , Katsuyoshi Yamamoto
- & Haruo Saito
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| Open AccessDynamic caveolae exclude bulk membrane proteins and are required for sorting of excess glycosphingolipids
Recent data question the long-assumed link between caveolae and endocytosis of membrane proteins. Shvets et al. use genome editing to tag and trace endogenous caveolar proteins, providing evidence that these structures exclude membrane proteins and are instead required for proper sorting of excess membrane lipids.
- Elena Shvets
- , Vassilis Bitsikas
- & Benjamin J. Nichols
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Article
| Open AccessRadixin regulates synaptic GABAA receptor density and is essential for reversal learning and short-term memory
Lateral diffusion of receptors between synaptic and extrasynaptic sites is known to mediate plasticity. Hausrat et al. show that diffusion of α5-containing GABAAreceptors is controlled by phosphorylation of the extrasynaptic anchoring protein Radixin, and reveal a role for Radixin in learning and memory.
- Torben J. Hausrat
- , Mary Muhia
- & Matthias Kneussel
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Article
| Open AccessAnalgesia and unwanted benzodiazepine effects in point-mutated mice expressing only one benzodiazepine-sensitive GABAA receptor subtype
Benzodiazepines (BDZs) target GABAA receptors to alleviate pain but these also cause side effects. Here the authors use mice in which only one GABAA receptor is BDZ-sensitive at a time to identify α2GABAAas the receptor that provides maximal analgesic activity but minimal side-effects in response to BDZs.
- William T. Ralvenius
- , Dietmar Benke
- & Hanns Ulrich Zeilhofer
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Article
| Open AccessMaking water-soluble integral membrane proteins in vivo using an amphipathic protein fusion strategy
The study of integral membrane proteins (IMPs) is hampered by yields and the difficulty in retaining activity once they have been solubilized. Here Mizrachi et al. develop a strategy for in vivoexpression and solubilization of IMPs in functionally relevant states by fusing them to truncated apolipoprotein A-I.
- Dario Mizrachi
- , Yujie Chen
- & Matthew P. DeLisa
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Article
| Open AccessA highly potent human antibody neutralizes dengue virus serotype 3 by binding across three surface proteins
There is no licensed vaccine or therapeutic for dengue virus (DENV) infection. Here, the authors show that a highly potent human monoclonal antibody binds to DENV particles in an unusual and very effective way by interacting with three viral envelope proteins.
- Guntur Fibriansah
- , Joanne L. Tan
- & Shee-Mei Lok
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Article
| Open AccessA balance between membrane elasticity and polymerization energy sets the shape of spherical clathrin coats
A relationship between membrane tension and clathrin polymerization during endocytosis has not been experimentally established. Here, the authors show using an in vitroreconstituted system and theoretical modelling that membrane tension regulates clathrin polymerization into spherical cages by varying the membrane budding energy.
- Mohammed Saleem
- , Sandrine Morlot
- & Aurélien Roux
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Article
| Open AccessCiliary membrane proteins traffic through the Golgi via a Rabep1/GGA1/Arl3-dependent mechanism
Polycystins (PC) 1 and 2 are large transmembrane proteins that play a vital role in the function of primary cilia. Here, Kim et al. identify the requirements for polycystin trafficking to the cilium, involving a PC1–PC2 interaction, PC1 proteolytic cleavage and a specific trafficking module at the trans-Golgi network.
- Hyunho Kim
- , Hangxue Xu
- & Feng Qian
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Versatile in vitro system to study translocation and functional integration of bacterial outer membrane proteins
The mechanisms of protein translocation across and integration into bacterial outer membranes are poorly understood. Here, Norell et al. reconstitute type-V secretion and β-barrel protein biogenesis in proteoliposomes providing a versatile cell-free system to study integration and translocation.
- Derrick Norell
- , Alexander Heuck
- & Enguo Fan
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Reconstitution of a nanomachine driving the assembly of proteins into bacterial outer membranes
The translocation and assembly module (TAM) is a nanomachine responsible for assembly of proteins into the outer membrane of pathogenic bacteria. Here, Shen et al.use magnetic contrast neutron reflectrometry to visualize movements within the TAM and insertion of a substrate protein into the lipid bilayer.
- Hsin-Hui Shen
- , Denisse L. Leyton
- & Trevor Lithgow
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Article
| Open AccessLateral opening of the bacterial translocon on ribosome binding and signal peptide insertion
Integral membrane proteins laterally partition from the SecYEG translocon into the phospholipid bilayer. Here, the authors use photo-induced electron transfer to show that ribosome binding induces the opening of the lateral gate, and demonstrate that lateral opening does not happen at low temperature.
- Yan Ge
- , Albena Draycheva
- & Wolfgang Wintermeyer
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A sub-nanometre view of how membrane curvature and composition modulate lipid packing and protein recruitment
Membrane curvature and lipid composition direct the binding of many peripheral membrane proteins. Here, Vanni et al. use a combination of in vitroand molecular dynamics approaches to quantify how lipid-packing defects in membranes of various composition and curvature dictate the membrane adsorption of a model lipid-binding protein.
- Stefano Vanni
- , Hisaaki Hirose
- & Romain Gautier
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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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Article
| 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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SNARE-fusion mediated insertion of membrane proteins into native and artificial membranes
The study of cell membrane proteins can be simplified by incorporating them into lipid bilayers, but doing this for multiple proteins can be challenging. Here, the authors present a technique to achieve this, and show reconstitution of a bacterial respiratory chain from individual components.
- Gustav Nordlund
- , Peter Brzezinski
- & Christoph von Ballmoos