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| Open AccessCholesterol-mediated allosteric regulation of the mitochondrial translocator protein structure
The outer mitochondrial membrane translocator protein (TSPO) mediates several mitochondrial functions and binds cholesterol with a high affinity. Here the authors use solid-state NMR to show that cholesterol binding to TSPO results in allosteric changes that modulate TSPO oligomerization.
- Garima Jaipuria
- , Andrei Leonov
- & Markus Zweckstetter
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Article
| Open AccessDomain-dependent effects of insulin and IGF-1 receptors on signalling and gene expression
Despite being structurally similar, the insulin receptor (IR) and insulin growth factor I receptor (IGF1R) elicit distinct signalling pathways. Here the authors use receptor chimeras to unveil that IR and IGF1R signalling is related primarily to differences in their intracellular juxtamembrane region.
- Weikang Cai
- , Masaji Sakaguchi
- & C. Ronald Kahn
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Article
| Open AccessCationic amino acid transporters play key roles in the survival and transmission of apicomplexan parasites
Apicomplexans are parasites that use membrane transporters to scavenge essential nutrients from the host. Here the authors identify and characterize two apicomplexans transporters showing that these are crucial for cationic amino acid uptake, parasite survival and virulence.
- Esther Rajendran
- , Sanduni V. Hapuarachchi
- & Giel G. van Dooren
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Article
| Open AccessDirect PIP2 binding mediates stable oligomer formation of the serotonin transporter
The human serotonin transporter (SERT) mediates the uptake of neurotransmitters to terminate neuronal signalling. Here the authors use single-molecule imaging to get insight into the molecular origin of SERT oligomerization and their pre-set stoichiometry at the plasma membrane.
- Andreas Anderluh
- , Tina Hofmaier
- & Gerhard J. Schütz
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Article
| Open AccessCoupled ATPase-adenylate kinase activity in ABC transporters
ATP-binding cassette (ABC) transporters hydrolyse ATP to transport molecules across the cell membrane. Here Vogelet al. show that the ABC exporter MsBA can couple ATP hydrolyse to an adenylate kinase activity that seems to be predominant at low ATP levels and a general feature of ABC exporters.
- Hundeep Kaur
- , Andrea Lakatos-Karoly
- & Clemens Glaubitz
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Article
| Open AccessTransport of lipophilic carboxylates is mediated by transmembrane helix 2 in multidrug transporter AcrB
The AcrB module of the AcrAB-TolC multidrug efflux pump sequesters drugs from the periplasm and outer leaflet of the inner membrane. Here, Oswaldet al. provide evidence that lipophilic carboxylated substrates bind to a groove between transmembrane helices TM1 and TM2, for further transport by an upward movement of TM2.
- Christine Oswald
- , Heng-Keat Tam
- & Klaas M. Pos
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Article
| Open AccessThe STIM1-binding site nexus remotely controls Orai1 channel gating
How plasma membrane Orai Ca2+ channels are activated by STIM proteins to activate Ca2+signals is still not fully known. Here the authors show that a nexus region located at the Orai1 C-terminus allows channel gating without a direct interaction of STIM1 with the channel pore.
- Yandong Zhou
- , Xiangyu Cai
- & Donald L. Gill
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Article
| Open AccessCoupled binding mechanism of three sodium ions and aspartate in the glutamate transporter homologue GltTk
In neurons and glia, glutamate transporters catalyse the reuptake of this neurotransmitter by coupling it with cation transport. Here the authors combine X-ray crystallography and molecular dynamics simulations of the archeal glutamate transporter GltTkto get insight into the coupled transport mechanism.
- Albert Guskov
- , Sonja Jensen
- & Dirk Jan Slotboom
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Article
| Open AccessCrystal structure of bacterial haem importer complex in the inward-facing conformation
Pathogenic bacteria acquire iron from heme cofactors imported by ABC heme transporters. Here the authors present crystal structures of Burkholderia cenocepaciaheme importer BhuUV with and without the heme-binding protein BhuT, gathering mechanistic insight into the catalytic cycle of heme import.
- Youichi Naoe
- , Nozomi Nakamura
- & Hiroshi Sugimoto
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Article
| Open AccessFunctional competence of a partially engaged GPCR–β-arrestin complex
β-arrestins initially contact with the phosphorylated carboxyl-terminus of GPCRs before engaging with the GPCR core. Here, the authors use a chimeric GPCR partially and fully engaged with β-arrestin1 and show that the core interaction is dispensable for receptor endocytosis and signalling.
- Punita Kumari
- , Ashish Srivastava
- & Arun K. Shukla
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Article
| Open AccessEGFR oligomerization organizes kinase-active dimers into competent signalling platforms
Epidermal growth factor receptors have been shown to oligomerise upon binding to their cognate ligands. Here, the authors use biochemical, biophysical and cell biology techniques to analyse the structures of these oligomers, and argue that these formations are required for signalling.
- Sarah R. Needham
- , Selene K. Roberts
- & Marisa L. Martin-Fernandez
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Article
| Open AccessA modular platform for one-step assembly of multi-component membrane systems by fusion of charged proteoliposomes
Assembling multiple biological components into synthetic lipid vesicles is a limiting step in the manufacture of biomimetic cell-like structures. Here the authors use fusogenic proteoliposomes of opposite charge for fast assembly of a minimal electron transport chain consisting of F1F0 ATP-synthase and the proton pump bo3-oxidase.
- Robert R. Ishmukhametov
- , Aidan N. Russell
- & Richard M. Berry
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Article
| Open AccessMechanism of pH-dependent activation of the sodium-proton antiporter NhaA
The pH dependence of the activity of Escherichia colimain sodium-proton antiporter NhaA is still not fully understood. Here, the authors use continuous constant pH molecular dynamics simulations to identify NhaA proton carrier residues and elucidate its gating and ion transport processes.
- Yandong Huang
- , Wei Chen
- & Jana Shen
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Article
| Open AccessSingle-molecule visualization of dynamic transitions of pore-forming peptides among multiple transmembrane positions
Assessing protein localization within lipid membranes is problematic. Here, the authors describe a single molecule visualization method based on surface-induced fluorescence attenuation (SIFA) to determine the insertion depth and lateral diffusion of a peptide in a lipid bilayer.
- Ying Li
- , Zhenyu Qian
- & Ming Li
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Article
| Open AccessTransition metal ion FRET uncovers K+ regulation of a neurotransmitter/sodium symporter
The neurotransmitter transporter SERT counter transport K+ to transport serotonin. Here the authors show that the activity of the prokaryotic orthologue LeuT is also modulated by this cation, suggesting a general regulatory role for K+on neutrotrasmitter:sodium symporters function.
- Christian B. Billesbølle
- , Jonas S. Mortensen
- & Claus J. Loland
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Article
| Open AccessCold sensitivity of TRPA1 is unveiled by the prolyl hydroxylation blockade-induced sensitization to ROS
The transient receptor potential ankyrin 1 (TRPA1) is a cation channel that is involved in nociceptive pain sensing. Here, the authors show that hydroxylation of a proline in the N terminus of TRPA1 renders it sensitive to reactive oxygen species resulting from noxious cold.
- Takahito Miyake
- , Saki Nakamura
- & Shuji Kaneko
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Article
| Open AccessRetinal orientation and interactions in rhodopsin reveal a two-stage trigger mechanism for activation
Rhodopsin signalling is triggered by the light-induced isomerization of its 11-cisretinal chromophore. Here, the authors use NMR spectroscopy to define retinal orientation and interactions in the active metarhodopsin II intermediate, proposing a two-stage mechanism for rhodopsin activation.
- Naoki Kimata
- , Andreyah Pope
- & Steven O. Smith
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Article
| Open AccessCrystal structure and functional characterization of a light-driven chloride pump having an NTQ motif
The atypical rhodopsin ClR from flavobacterium Nonlabens marinusis a light-driven chloride-pumping protein. Here, the authors show that ClR crystal structure presents two chloride ion-binding sites, proposing a molecular pathway for ion transport by this light-driven pump.
- Kuglae Kim
- , Soon-Kyeong Kwon
- & Hyun-Soo Cho
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Article
| Open AccessATP-dependent substrate transport by the ABC transporter MsbA is proton-coupled
ABC exporters mediate the translocation of cytotoxic compounds to the cell exterior via ATP hydrolysis. Here, the authors show that the bacterial transporter MsbA requires additional energy from the transmembrane electrochemical proton gradient to facilitate drug transport.
- Himansha Singh
- , Saroj Velamakanni
- & Hendrik W. van Veen
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Article
| Open AccessStructural and functional insights into IZUMO1 recognition by JUNO in mammalian fertilization
Sperm-egg fusion requires the interaction between IZUMO1 on the sperm and JUNO on the egg. Here, the authors report the crystal structure of mouse JUNO, and use it to explain its lack of binding to folate, along with in vivofunctional analyses.
- Kazuki Kato
- , Yuhkoh Satouh
- & Osamu Nureki
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Article
| Open AccessStructural basis of transcobalamin recognition by human CD320 receptor
Cellular uptake of vitamin B12 (cobalamin) requires the binding of holo-transcobalamin (TC) from plasma by CD320. Here, the authors report the structure of a complex between CD320 and TC loaded with cyanocobalamin, alongside additional functional analysis.
- Amer Alam
- , Jae-Sung Woo
- & Kaspar P. Locher
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Article
| Open AccessActivation of D2 dopamine receptor-expressing neurons in the nucleus accumbens increases motivation
Striatal D1 and D2-receptor expressing neurons have been shown to have opposing effects on reward-related behaviours. Here the authors reveal that specific activation of both D1 and D2 neurons in the nucleus accumbens leads to increase in motivational drive in rodents.
- Carina Soares-Cunha
- , Barbara Coimbra
- & Ana J. Rodrigues
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Article
| Open AccessA CD36 ectodomain mediates insect pheromone detection via a putative tunnelling mechanism
The CD36-related Sensory Neuron Membrane Protein 1 (SNMP1) facilitates pheromone detection by insect odorant receptors. Here Gomez-Diaz et al.show that the SNMP1 ectodomain is essential for function and propose that it forms a tunnel that transports pheromones from the extracellular fluid to their cognate receptors.
- Carolina Gomez-Diaz
- , Benoîte Bargeton
- & Richard Benton
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Article
| Open AccessThe Parkinson’s disease-associated genes ATP13A2 and SYT11 regulate autophagy via a common pathway
Mutations in ATP13A2 are associated with lysosomal dysfunction and early onset Parkinson’s disease. Here Bento et al. show that ATP13A2 depletion negatively regulates SYT11, at both transcriptional and post-translational levels, which in turn impairs function of the autophagy-lysosome pathway.
- Carla F. Bento
- , Avraham Ashkenazi
- & David C. Rubinsztein
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Article
| Open AccessSyndecan-4 negatively regulates antiviral signalling by mediating RIG-I deubiquitination via CYLD
Syndecans are transmembrane proteoglycans implicated in diverse cellular activities. Here the authors show that Syndecan-4 via its cytosolic domain negatively regulates antiviral immunity by enhancing RIG-I interaction with a deubiquitinating enzyme CYLD, thus inhibiting the activating K63-linked RIG-I ubiquitination.
- Wei Lin
- , Jing Zhang
- & Qinmiao Sun
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Article
| Open AccessMitochondrial uncouplers inhibit clathrin-mediated endocytosis largely through cytoplasmic acidification
Plant cells maintain strict proton gradients over different membranes. Here, Dejonghe et al. show that several protonophores, including the known tyrosine kinase inhibitor TyrphostinA23, inhibit clathrin-mediated endocytosis by disturbing these gradients and causing cytoplasmic acidification.
- Wim Dejonghe
- , Sabine Kuenen
- & Eugenia Russinova
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Article
| Open AccessThe T300A Crohn’s disease risk polymorphism impairs function of the WD40 domain of ATG16L1
The T300A substitution in ATG16L is associated with Crohn’s disease risk and disrupts clearance of intracellular pathogens by autophagy. Here the authors show that the mutation impairs interaction of ATG16L with TMEM59 and disrupts unconventional TMEM-induced autophagy, an aspect of innate immunity.
- Emilio Boada-Romero
- , Inmaculada Serramito-Gómez
- & Felipe X. Pimentel-Muiños
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Article
| Open AccessLRP6 acts as a scaffold protein in cardiac gap junction assembly
LRP6 is known for its role as a Wnt co-receptor essential for the canonical Wnt/β-catenin signaling. Here, Li et al. show that LRP6 exerts a Wnt-independent scaffold function and regulates connexin 43 gap junction formation and coupling of cardiomyocytes in mouse hearts.
- Jun Li
- , Changming Li
- & Yi-Han Chen
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Article
| Open AccessA conserved leucine occupies the empty substrate site of LeuT in the Na+-free return state
Neurotransmitter:sodium symporters (NSS) perform Na+-dependent amino-acid uptake, but a full structural description of their function is lacking. Here the authors present a structure of the bacterial NSS LeuT in the outward-oriented empty state and show that a Leu residue occupies the empty substrate site and is essential for function.
- Lina Malinauskaite
- , Saida Said
- & Poul Nissen
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Article
| Open AccessISPD produces CDP-ribitol used by FKTN and FKRP to transfer ribitol phosphate onto α-dystroglycan
Mutations in genes required for the glycosylation of α-dystroglycan lead to dystroglycanopathies. Here, the authors show that three of these enzymes (ISPD, FKTN and FKRP) work together to attach ribitol phosphate to α-dystroglycan.
- Isabelle Gerin
- , Benoît Ury
- & Guido T. Bommer
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Article
| Open AccessThe fast-recycling receptor Megalin defines the apical recycling pathway of epithelial cells
Basolateral recycling and transcytotic pathways in epithelial cells are defined by specific markers, however the apical recycling pathway is poorly understood. Perez Bay et al. show that Megalin is a marker for this pathway, which intersects with the other routes in shared perinuclear recycling endosomes.
- Andres E. Perez Bay
- , Ryan Schreiner
- & Enrique J. Rodriguez-Boulan
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| Open AccessA combined computational and structural model of the full-length human prolactin receptor
The prolactin receptor consists of a folded extracellular domain, a transmembrane domain and an intracellular intrinsically disordered domain. Here the authors use a combined experimental and computational approach to obtain a structure of a class I cytokine receptor, the human prolactin receptor.
- Katrine Bugge
- , Elena Papaleo
- & Birthe B. Kragelund
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Article
| Open AccessPhosphatidylserine exposure is required for ADAM17 sheddase function
ADAM17 is a member of the ‘Disintegrin and Metalloproteinase’ family of proteases, that cleaves transmembrane substrates from the surfaces of cells. Here the authors show that surface exposure of phosphatidylserine is required for ADAM17 sheddase activity, possibly by directing the protease to its substrates.
- Anselm Sommer
- , Felix Kordowski
- & Karina Reiss
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Article
| Open AccessLaminin regulates PDGFRβ+ cell stemness and muscle development
Muscle PDGFRβ+ cells are interstitial stem/progenitor cells with myogenic potential. Here, Yao et al. show that PDGFRβ+cell-derived laminin actively regulates their proliferation, differentiation and fate determination.
- Yao Yao
- , Erin H. Norris
- & Sidney Strickland
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Article
| Open AccessClec4A4 is a regulatory receptor for dendritic cells that impairs inflammation and T-cell immunity
Clec4A4 is a C-type lectin receptor highly expressed by CD8α− dendritic cells. Here the authors show that its loss of function results in enhanced T cell responses and exacerbated autoimmunity, implicating Clec4A4 in limiting activation of the CD8α−dendritic cells.
- Tomofumi Uto
- , Tomohiro Fukaya
- & Katsuaki Sato
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Article
| Open AccessUnconventional endosome-like compartment and retromer complex in Toxoplasma gondii govern parasite integrity and host infection
The retromer complex is a multi-protein component of the endosomal protein sorting machinery. Here, Sangaré et al. identify unique features in the retromer complex of the parasite Toxoplasma gondii, and show that it is crucial for the biogenesis of secretory organelles in this pathogen.
- Lamba Omar Sangaré
- , Tchilabalo Dilezitoko Alayi
- & Stanislas Tomavo
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Article
| Open AccessKappa opioid receptor activation alleviates experimental autoimmune encephalomyelitis and promotes oligodendrocyte-mediated remyelination
Current treatments of multiple sclerosis are aimed at immunosuppression. Here the authors show that kappa opioid receptor is important for oligodendrocyte differentiation and myelination and the receptor agonists are protective in a mouse model of multiple sclerosis.
- Changsheng Du
- , Yanhui Duan
- & Xin Xie
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Article
| Open AccessNeogenin recruitment of the WAVE regulatory complex maintains adherens junction stability and tension
The stability of epithelial adherens junctions depends on tension generated by actomyosin contractility. Here Lee et al. describe a novel role for the axon guidance receptor Neogenin in maintaining junctional stability by recruiting actin nucleation machinery to adherens junctions.
- Natalie K. Lee
- , Ka Wai Fok
- & Helen M. Cooper
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Article
| Open AccessStructural insight in the toppling mechanism of an energy-coupling factor transporter
Prokaryotes use energy-coupling factor transporters to uptake required micronutrients and an unusual toppling mechanism has been proposed for their function. Here, the authors provide structural support for this mechanism, allowing direct visualization of the toppled state.
- Lotteke J. Y. M. Swier
- , Albert Guskov
- & Dirk J. Slotboom
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Article
| Open AccessEphrin-B3 coordinates timed axon targeting and amygdala spinogenesis for innate fear behaviour
The molecular mechanism underlying initial circuit wiring in amygdala is poorly understood. Here the authors show that ephrin-B3 is required for axon targeting and amygdala spinogenesis during a critical period in development, and plays an important role in amygdala mediated fear responses.
- Xiao-Na Zhu
- , Xian-Dong Liu
- & Nan-Jie Xu
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Article
| Open AccessHaem-dependent dimerization of PGRMC1/Sigma-2 receptor facilitates cancer proliferation and chemoresistance
PGRMC1 binds to EGFR and cytochromes P450, and is known to be involved in cancer proliferation and in drug resistance. Here, the authors determine the structure of the cytosolic domain of PGRMC1, which forms a dimer via haem–haem stacking, and propose how this interaction could be involved in its function.
- Yasuaki Kabe
- , Takanori Nakane
- & Makoto Suematsu
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Article
| Open AccessMapping the dynamics and nanoscale organization of synaptic adhesion proteins using monomeric streptavidin
The advent of fluorescence-based super-resolution microscopy has created a need for labeling strategies relying on small probes that minimally perturb protein function. Here the authors describe a labeling method that reduces protein tag and label sizes, allowing for accurate protein targeting and measurements of protein dynamics in tight cellular spaces.
- Ingrid Chamma
- , Mathieu Letellier
- & Olivier Thoumine
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Article
| Open AccessTargeting neurotransmitter receptors with nanoparticles in vivo allows single-molecule tracking in acute brain slices
Single quantum dot tracking is an established technique used in cultured neurons and organotypic brain slices. Here, the authors demonstrate in vivotargeting of dopamine receptors via ventricular injection of functionalized quantum dots and track single nanoparticle-receptors in acute rat brain slices.
- Juan A. Varela
- , Julien P. Dupuis
- & Laurent Groc
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Article
| Open AccessShisa6 traps AMPA receptors at postsynaptic sites and prevents their desensitization during synaptic activity
Auxiliary AMPA receptor subunits can affect gating and surface mobility. Here the authors show that Shisa6 traps AMPA receptors at postsynaptic sites via PSD-95, and keeps them in an activated state in the presence of glutamate, preventing full desensitization and consequently synaptic depression.
- Remco V. Klaassen
- , Jasper Stroeder
- & August B. Smit
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Article
| Open AccessGSG1L suppresses AMPA receptor-mediated synaptic transmission and uniquely modulates AMPA receptor kinetics in hippocampal neurons
The molecular mechanism controlling the trafficking and function of AMPARs at synapses are not fully understood. Here the authors show that GSG1L, a membrane protein, negatively regulates AMPAR-mediated synaptic transmission and represents a new class of AMPAR auxiliary subunit.
- Xinglong Gu
- , Xia Mao
- & Wei Lu
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Article
| Open AccessIntracellular mGluR5 plays a critical role in neuropathic pain
mGluR5 has been shown to play a role in chronic pain regulation. Here, the authors use membrane permeable and non-transported, impermeable mGluR5 antagonists to show that spinal analgesic effects in vivoare mediated by intracellular rather than cell surface mGluR5.
- Kathleen Vincent
- , Virginia M. Cornea
- & Terence J. Coderre
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Article
| Open AccessMembrane potential shapes regulation of dopamine transporter trafficking at the plasma membrane
The dopaminergic system has important roles in a number of cognitive process. Here, the authors use detailed analysis of dopamine transporter trafficking to show its levels at the cell surface are sensitive to changes in membrane potential.
- Ben D. Richardson
- , Kaustuv Saha
- & Habibeh Khoshbouei
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Article
| Open AccessIntracellular repair of oxidation-damaged α-synuclein fails to target C-terminal modification sites
α-synuclein is a protein linked to the occurrence of Parkinson's disease. Here, the authors use time-resolved in-cell NMR spectroscopy to study the repair of methionine-oxidized α-synuclein by endogenous cellular enzymes.
- Andres Binolfi
- , Antonio Limatola
- & Philipp Selenko
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Article
| Open AccessStructures of the E. coli translating ribosome with SRP and its receptor and with the translocon
The co-translational insertion of proteins into membranes requires interaction between a ribosome-bound signal recognition particle (SRP) and a membrane-bound translocon. Here the authors use cryo-EM and single particle reconstructions to obtain a comprehensive view of the co-translational protein targeting process.
- Ahmad Jomaa
- , Daniel Boehringer
- & Nenad Ban