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| Open AccessConformational changes in the human Cx43/GJA1 gap junction channel visualized using cryo-EM
Gap junction intercellular channels (GJIChs) facilitate direct communication between adjacent cells. Here, authors provide high-resolution information on dynamic structural changes in Cx43 GJICh that are necessary to understand the gating mechanism.
- Hyuk-Joon Lee
- , Hyung Jin Cha
- & Jae-Sung Woo
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Article
| Open AccessBarrier properties of Nup98 FG phases ruled by FG motif identity and inter-FG spacer length
The permeability barrier of the nuclear pore assembles from cohesive FG repeats. By systematic engineering and testing repeat variants, the authors pinpointed the sequence features that rule barrier assembly and transport selectivity.
- Sheung Chun Ng
- , Abin Biswas
- & Dirk Görlich
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Article
| Open AccessMolecular insights into the gating mechanisms of voltage-gated calcium channel CaV2.3
The CaV2.3 channel is involved in synaptic plasticity and neurological disorders. Here, authors resolve the human CaV2.3 structure to explore functional heterogeneity of VSDs and elucidated the closed- and open-state inactivation mechanisms of the channel.
- Yiwei Gao
- , Shuai Xu
- & Yan Zhao
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Article
| Open AccessLigand recognition mechanism of the human relaxin family peptide receptor 4 (RXFP4)
Relaxin family peptide receptor 4 (RXFP4) regulates pleiotropic biological processes. Here, authors report cryo-EM structures revealing the ligand-binding modes and key determinants of peptidomimetic agonism and subtype selectivity
- Yan Chen
- , Qingtong Zhou
- & Ming-Wei Wang
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Article
| Open AccessStructural insights into the elevator-type transport mechanism of a bacterial ZIP metal transporter
The ZIP family (SLC39A) is involved in transition metal homeostasis. Here, authors use integrated approaches to conclude that the ZIP from Bordetella bronchiseptica (BbZIP) utilizes the elevator-type transport mechanism to achieve alternating access.
- Yao Zhang
- , Yuhan Jiang
- & Jian Hu
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Article
| Open AccessA gain-of-function TPC2 variant R210C increases affinity to PI(3,5)P2 and causes lysosome acidification and hypopigmentation
TPC2 is an important organellar Na+/Ca2+ release channel which regulates function of lysosomes and lysosome-related organelles. Here, Wang et al. demonstrate that a gain-of-function mutation (R210C) in TPC2 leads to hypopigmentaion, enlarged endolysosomes, enhanced lysosomal Ca2+ release and hyper-acidification.
- Qiaochu Wang
- , Zengge Wang
- & Wei Li
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Article
| Open AccessConformational plasticity of NaK2K and TREK2 potassium channel selectivity filters
The potassium channel selectivity filter is responsible for conduction and selectivity of K + over other cations. Here, the authors use a combination of single molecule FRET, non-canonical fluorescent amino acid incorporation, and single channel patch-clamp electrophysiology, to establish the generality of K + -induced SF conformational stability across the K + channel superfamily.
- Marcos Matamoros
- , Xue Wen Ng
- & Colin G. Nichols
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Article
| Open AccessVertebrate OTOP1 is also an alkali-activated channel
pH sensation is critical for survival of vertebrates. Here, authors found six vertebrate OTOP1 channels that were highly conserved and directly activated by extracellular alkali. Key mutations of OTOP1 reduced alkali affinity without affecting acid activation.
- Lifeng Tian
- , Hao Zhang
- & Ren Lai
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Article
| Open AccessCalcium-permeable channelrhodopsins for the photocontrol of calcium signalling
To date, no Ca2 + -selective channelrhodopsins have been characterized. In this study, Fernandez Lahore et al. report two calcium-permeable channelrhodopsins (CapChR1 and 2) for the photocontrol of calcium signalling in excitable tissue.
- Rodrigo G. Fernandez Lahore
- , Niccolò P. Pampaloni
- & Peter Hegemann
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Article
| Open AccessWood structure explained by complex spatial source-sink interactions
The authors present a wood formation model to explain multiple, hitherto poorly understood observations, related to carbon density, cell size, and temperature-growth relationships key for future carbon cycle simulations and past proxy interpretation.
- Andrew D. Friend
- , Annemarie H. Eckes-Shephard
- & Quinten Tupker
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Article
| Open AccessDetecting and quantifying liquid–liquid phase separation in living cells by model-free calibrated half-bleaching
It is currently debated how to reliably distinguish liquid–liquid phase separation (LLPS) from other mechanisms. Here the authors report model-free calibrated half-FRAP (MOCHA-FRAP) to probe the barrier at the condensate interface that is responsible for preferential internal mixing in LLPS.
- Fernando Muzzopappa
- , Johan Hummert
- & Fabian Erdel
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Article
| Open AccessActivating alternative transport modes in a multidrug resistance efflux pump to confer chemical susceptibility
Antibiotic resistance through multidrug efflux is a major hurdle in antibiotic development. Here, authors experimentally demonstrate that EmrE, a small multidrug resistance efflux pump from E. coli, can confer resistance or susceptibility depending on the small molecule substrate.
- Peyton J. Spreacker
- , Nathan E. Thomas
- & Katherine A. Henzler-Wildman
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Comment
| Open AccessRegulating voltage-gated ion channels with nanobodies
In this work, Morgenstern and colleagues describe an approach involving functionalized nanobodies which decrease the activity of voltage-gated Ca2+ channels associated with β1 subunits and promote their removal from the surface membrane of neurons and muscle.
- Declan Manning
- & L. Fernando Santana
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Article
| Open AccessSelective posttranslational inhibition of CaVβ1-associated voltage-dependent calcium channels with a functionalized nanobody
Auxiliary subunit molecular diversity is an unexploited target for developing ion channel inhibitors. Here, the authors develop a general approach to inhibit ion channels based on the resident auxiliary subunit isoform to elucidate unique functions of distinct ion channel macromolecular complexes.
- Travis J. Morgenstern
- , Neha Nirwan
- & Henry M. Colecraft
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Article
| Open AccessBackbone amides are determinants of Cl− selectivity in CLC ion channels
CLC-type channels selectively transport Cl− across biological membranes, but it is unclear how discrimination between anions is maintained. Here, authors use a combination of non-natural amino acid substitutions, electrophysiology, and molecular dynamics simulations to determine Cl− specificity within this family of ion channels.
- Lilia Leisle
- , Kin Lam
- & Alessio Accardi
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Article
| Open AccessCannabinoid non-cannabidiol site modulation of TRPV2 structure and function
TRPV2 is activated by temperature and cannabinoids. Here, the authors have used cryo-EM and electrophysiology to identify a cannabinoid binding site distinct from that of cannabidiol as a possible drug target for treatment of inflammation and immune-mediated diseases.
- Liying Zhang
- , Charlotte Simonsen
- & Peter M. Zygmunt
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Article
| Open AccessStructures of the R-type human Cav2.3 channel reveal conformational crosstalk of the intracellular segments
Voltage-gated Ca2+ channel subtype Cav2.3 represents a potential drug target for neurological diseases. Here, authors report cryo-EM structures of Cav2.3 and its mutant to reveal the crosstalk of intracellular segments, which may facilitate future drug discovery.
- Xia Yao
- , Yan Wang
- & Nieng Yan
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Article
| Open AccessGating and ion selectivity of Channelrhodopsins are critical for photo-activated orientation of Chlamydomonas as shown by in vivo point mutation
Channelrhodopsin photoreceptors are responsible for phototaxis in C. reinhardtii. Here, authors introduce point mutations in the channel which modify photocycle kinetics and ion selectivity, resulting in a deeper understanding of phototaxis in low light conditions.
- Olga Baidukova
- , Johannes Oppermann
- & Peter Hegemann
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Article
| Open AccessUptake mechanism of iron-phytosiderophore from the soil based on the structure of yellow stripe transporter
Iron is an essential mineral in plant physiology. YS1 transporter imports iron–phytosiderophore complex (Fe(III)–DMA) from the soil. Here, the authors describe the cryo-EM structures of barley YS1 in complex with substrate, and a synthetic substrate analog.
- Atsushi Yamagata
- , Yoshiko Murata
- & Mikako Shirouzu
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Article
| Open AccessGating intermediates reveal inhibitory role of the voltage sensor in a cyclic nucleotide-modulated ion channel
Visualizing conformational changes during ion channel gating is crucial to understand their regulation. Here, Gao et al. capture multiple gating intermediates in a CNG channel as well as subtle, lateral voltage sensor movements necessary for channel opening.
- Xiaolong Gao
- , Philipp A. M. Schmidpeter
- & Crina M. Nimigean
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Article
| Open AccessStructural basis for the activation of the lipid scramblase TMEM16F
TMEM16F is a dual ion channel and lipid scramblase that is involved in blood coagulation and cell fusion. Here, authors elucidate how the protein is activated by Ca2+ to accomplish both functions in a single protein conformation.
- Melanie Arndt
- , Carolina Alvadia
- & Raimund Dutzler
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Article
| Open AccessStructural mechanism of SGLT1 inhibitors
SGLT1 is essential for glucose, galactose and water uptake from the intestine, and its inhibitors have broad therapeutic potential. Here, the authors describe the cryo-EM structure of human SGLT1 in complex with an inhibitor.
- Yange Niu
- , Wenhao Cui
- & Lei Chen
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Article
| Open AccessPurification and structural characterization of the Na+-translocating ferredoxin: NAD+ reductase (Rnf) complex of Clostridium tetanomorphum
Rnf reversibly reduces NAD+ by ferredoxin coupled with Na+/H+ pumping for microbial ion gradient or reduced ferredoxin formation. Here, a cryo-EM structure provides information about the participating iron and flavin cofactors, the electron transfer route and the putative Na+ passage.
- Stella Vitt
- , Simone Prinz
- & Wolfgang Buckel
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Article
| Open AccessA simple thermodynamic description of phase separation of Nup98 FG domains
The nuclear pore complex (NPC) barrier is a selective phase assembled from disordered but cohesive FG domains. The authors provide a thermodynamic description of an FG phase that is ultimately simplified and yet closely recapitulates NPC transport selectivity.
- Sheung Chun Ng
- & Dirk Görlich
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Article
| Open AccessDispersive transport dynamics in porous media emerge from local correlations
Dispersive transport through complex media, relevant for semiconductors, liquid crystals, and biological soft matter, is influenced by their microscopic, porous structure. The authors consider the statistics of pore-junction units, in contrast to individual pores, to link morphology and macroscopic transport characteristics.
- Felix J. Meigel
- , Thomas Darwent
- & Karen Alim
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Article
| Open AccessThe lysosomal transporter TAPL has a dual role as peptide translocator and phosphatidylserine floppase
In this work, the authors report an ATP-dependent phosphatidylserine floppase activity for the lysosomal ATP-binding cassette transporter TAPL. In addition, they report the cryo-EM structures of mouse TAPL complexed with (i) phospholipid, (ii) cholesteryl hemisuccinate (CHS) and 9-mer peptide, and (iii) ADP·BeF3. Together, their results suggest that TAPL uses different mechanisms to function as a peptide translocase and a phosphatidylserine floppase.
- Jun Gyou Park
- , Songwon Kim
- & Mi Sun Jin
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Article
| Open AccessStructural basis for the activity regulation of a potassium channel AKT1 from Arabidopsis
Arabidopsis thaliana potassium channel AKT1 is responsible for primary K + uptake from soil, which is functionally activated through phosphorylation and negatively regulated by an α-subunit AtKC1. Here, the authors report the structures of AKT1 at different states, revealing a 2- fold to 4-fold symmetry switch at cytoplasmic domain associated with AKT1 activity regulation.
- Yaming Lu
- , Miao Yu
- & Guanghui Yang
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Article
| Open AccessProton-driven alternating access in a spinster lipid transporter
The Spns lipid transporters use ion gradients to drive substrate transport, including bioactive sphingolipids. Here, Dastvan et al. investigated how binding of protons powers the conformational changes that enable broad transport by a bacterial Spns.
- Reza Dastvan
- , Ali Rasouli
- & Emad Tajkhorshid
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Article
| Open AccessPercolation transition prescribes protein size-specific barrier to passive transport through the nuclear pore complex
Combining realistic coarse-grained simulations with a percolation transition theory, this study elucidates the microscopic mechanism that governs the selectivity of passive, unassisted transport through the nuclear pore complex.
- David Winogradoff
- , Han-Yi Chou
- & Aleksei Aksimentiev
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Article
| Open AccessStructural basis of ion uptake in copper-transporting P1B-type ATPases
P1B-type ATPases export excess transition metals from cells. Here, the authors report a molecular structure of CopA, a coppertransporting P1B-ATPase from A. fulgidus, in an inward-facing E1 conformation.
- Nina Salustros
- , Christina Grønberg
- & Pontus Gourdon
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Article
| Open AccessABCA1 is an extracellular phospholipid translocase
ATP-binding cassette transporter A1 (ABCA1) drives phospholipid (PL) from the plasma membrane into extracellular apolipoprotein A-I, for the production of high density lipoprotein (HDL). Here, the authors use simulations to assess the mechanism of ABCA1 function and show that ABCA1 extracts lipid from the outer face of the plasma membrane.
- Jere P. Segrest
- , Chongren Tang
- & Jay W. Heinecke
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Article
| Open AccessStructural insights into inhibitory mechanism of human excitatory amino acid transporter EAAT2
EAAT2 is an amino acid transporter implicated in glutamate homeostasis in brain and therapy resistance of cancer cells. Here, the authors report cryo-EM structures and reveal inhibitory mechanisms via selective inhibitor WAY213613.
- Takafumi Kato
- , Tsukasa Kusakizako
- & Osamu Nureki
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Article
| Open AccessStructural and mechanistic analysis of a tripartite ATP-independent periplasmic TRAP transporter
Tripartite ATP-independent periplasmic (TRAP) transporters are widespread in bacteria and archaea. Here, the authors used cryo-EM and a range of biophysical techniques to study the structure of function of the sialic acid TRAP transporter HiSiaQM.
- Martin F. Peter
- , Jan A. Ruland
- & Gregor Hagelueken
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Article
| Open AccessStructures of Atm1 provide insight into [2Fe-2S] cluster export from mitochondria
Mitochondrial Atm1 proteins play important roles in the maturation of certain cytosolic proteins. Here, the authors exploit cryo-EM to capture several structures of an Atm1. The findings shed new light on the molecular function of Atm1 transporters.
- Ping Li
- , Amber L. Hendricks
- & Pontus Gourdon
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Article
| Open AccessCryo-EM structures of recombinant human sodium-potassium pump determined in three different states
Sodium-Potassium Pump (Na+/K+-ATPase, NKA) generates an electrochemical gradient of sodium and potassium ions across the plasma membrane by hydrolyzing ATP. Here, the authors report structures of human NKA providing insight into the cytoplasmic Na+ entrance and the cytoplasmic gate closure coupled to ATP hydrolysis.
- Yingying Guo
- , Yuanyuan Zhang
- & Qiang Zhou
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Article
| Open AccessSubstrate binding in the mitochondrial ADP/ATP carrier is a step-wise process guiding the structural changes in the transport cycle
The mitochondrial ADP/ATP carrier transports adenine nucleotides. Here, authors identify the residues involved in substrate binding. One set forms the central substrate binding site and two asparagine/arginine pairs help to guide the substrates during the transport cycle.
- Vasiliki Mavridou
- , Martin S. King
- & Edmund R. S. Kunji
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Article
| Open AccessStructures of a mammalian TRPM8 in closed state
The mechanism of cold-activated TRPM8 channel activation remains unclear. Here, authors have determined structures of mouse TRPM8 in apo or ligand-bound states, providing insights into the activation of TRPM8 structures in different states.
- Cheng Zhao
- , Yuan Xie
- & Jiangtao Guo
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Article
| Open AccessVanilloid-dependent TRPV1 opening trajectory from cryoEM ensemble analysis
Cryo-EM often yields multiple protein conformations within a single dataset. Using the thermal titration methods and cryo-EM, Do Hoon Kwon et al. elucidate the conformational trajectory of the TRPV1 with resiniferatoxin (RTx) bound.
- Do Hoon Kwon
- , Feng Zhang
- & Seok-Yong Lee
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Article
| Open AccessMolecular basis for gating of cardiac ryanodine receptor explains the mechanisms for gain- and loss-of function mutations
Ryanodine receptor 2 (RyR2) is a Ca2+ release channel essential for cardiac excitation-contraction coupling. Here, the authors use structural and functional analysis to reveal RyR2 gating mechanism and its alterations by pathogenic mutations.
- Takuya Kobayashi
- , Akihisa Tsutsumi
- & Haruo Ogawa
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Article
| Open AccessStructural mechanism of TRPV3 channel inhibition by the anesthetic dyclonine
TRPV3 mediates cutaneous sensations such as itch and pain. Here authors present the cryo-EM structure of TRPV3 bound with local anesthetic which binds the channel in membrane portals that connect the membrane environment to the channel pore.
- Arthur Neuberger
- , Kirill D. Nadezhdin
- & Alexander I. Sobolevsky
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Article
| Open AccessInhibition mechanism of the chloride channel TMEM16A by the pore blocker 1PBC
TMEM16A, a calcium-activated chloride channel involved in multiple cellular processes, is implicated in various diseases, but its pharmacology remains poorly understood. Here, the authors combine cryo-EM and electrophysiology to elucidate the mechanism of TMEM16A inhibition by the pore blocker 1PBC.
- Andy K. M. Lam
- , Sonja Rutz
- & Raimund Dutzler
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Article
| Open AccessStructural basis for inhibition of the Cation-chloride cotransporter NKCC1 by the diuretic drug bumetanide
Loop diuretics including bumetanide inhibit Na+-K+-Cl−-cotransporters (NKCCs) and are used for the treatment of edema and hypertension. Here, Zhao et. al. report structures of NKCC1 with bumetanide bound, revealing its mechanism of action that would facilitate design of novel diuretics.
- Yongxiang Zhao
- , Kasturi Roy
- & Erhu Cao
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Article
| Open AccessStructural identification of vasodilator binding sites on the SUR2 subunit
SUR2-containing KATP channels are drug targets for certain vasodilators. Here, the authors determine high-resolution cryo-EM structures of SUR2 in complex with two vasodilators, P1075 and levcromakalim, uncovering the mechanisms of these drugs.
- Dian Ding
- , Jing-Xiang Wu
- & Lei Chen
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Article
| Open AccessStructural basis of ion – substrate coupling in the Na+-dependent dicarboxylate transporter VcINDY
DASS carboxylate transporters linked to metabolic diseases couple the Na+ gradient to nutrient uptake. Here, the authors unravel the structural basis by which Na+ binding coordinates substrate interactions, revealing a distinct coupling mechanism.
- David B. Sauer
- , Jennifer J. Marden
- & Da-Neng Wang
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Article
| Open AccessTMEM16 scramblases thin the membrane to enable lipid scrambling
Lipid scrambling is required for many cellular processes but the lipid-protein interactions that occur during transport are unknown. Using cryoEM and biochemical assays the authors show that membrane thinning is critical for lipid flipping.
- Maria E. Falzone
- , Zhang Feng
- & Alessio Accardi
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Article
| Open AccessThe dopamine transporter antiports potassium to increase the uptake of dopamine
The dopamine transporter, DAT, controls dopamine signaling by facilitating its reuptake using the Na+ gradient as driving force. Here, the authors uncover that an antiport of K+ ions also contributes to setting the rate of DAT-mediated dopamine clearance.
- Solveig G. Schmidt
- , Mette Galsgaard Malle
- & Claus J. Loland
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Article
| Open AccessKidney epithelial cells are active mechano-biological fluid pumps
How mechanical forces drive fluid transport in the kidney remains unclear. Here, the authors use a microfluidic platform to show that kidney epithelial cells generate hydraulic pressure gradients across the epithelium, and that the fluid flux is from apical to basal for normal cells, and inverted in autosomal dominant polycystic kidney disease cells.
- Mohammad Ikbal Choudhury
- , Yizeng Li
- & Sean X. Sun
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Article
| Open AccessAtomic resolution dynamics of cohesive interactions in phase-separated Nup98 FG domains
The permeability barrier of nuclear pores is formed by disordered and yet self-interacting FG repeat domains, whose sequence heterogeneity is a challenge for mechanistic insights. Here the authors overcome this challenge and characterize the protein’s dynamics by applying NMR techniques to an FG phase system that has been simplified to its essentials.
- Eszter E. Najbauer
- , Sheung Chun Ng
- & Loren B. Andreas
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Article
| Open AccessStructural basis for activation and gating of IP3 receptors
IP3 receptors are intracellular calcium channels involved in numerous signaling pathways. Here, the authors present the cryo-EM structures of type-3 IP3 receptors in multiple gating conformations, including the active state revealing the molecular mechanism of the receptor activation.
- Emily A. Schmitz
- , Hirohide Takahashi
- & Erkan Karakas