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Article
| Open AccessIdiosyncratic Mòjiāng virus attachment glycoprotein directs a host-cell entry pathway distinct from genetically related henipaviruses
The attachment glycoprotein (HNV-G) of henipaviruses interacts with host receptors at the cell surface and is a major determinant of species tropism. Here the authors provide structural and functional evidence that the emergent henipavirus, Mòjiang virus, uses an entry mechanism that is independent of known paramyoxviral cellular receptors.
- Ilona Rissanen
- , Asim A. Ahmed
- & Thomas A. Bowden
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Article
| Open AccessNucleolin directly mediates Epstein-Barr virus immune evasion through binding to G-quadruplexes of EBNA1 mRNA
Cells infected with Epstein-Barr virus (EBV) express the virus-encoded EBNA1, which is essential for viral genome maintenance but also highly antigenic. Here the authors implicate nucleolin as a host factor that mediates the repression of EBNA1-derived antigenic peptides through binding of the G4-quadruplex structure present within the EBNA1 mRNA.
- María José Lista
- , Rodrigo Prado Martins
- & Marc Blondel
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Article
| Open AccessThe E3 ubiquitin ligase and RNA-binding protein ZNF598 orchestrates ribosome quality control of premature polyadenylated mRNAs
Translation of aberrant mRNAs causes ribosome stalling and translation arrest, followed by recycling of the stalled ribosome complex. Here the authors show that the Zinc Finger Protein 598 (ZNF598/Hel2) is implicated in sensing faulty translation of prematurely polyadenylated mRNAs through the recognition of AAA codons.
- Aitor Garzia
- , Seyed Mehdi Jafarnejad
- & Nahum Sonenberg
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Article
| Open AccessEngineered botulinum neurotoxin B with improved efficacy for targeting human receptors
Humans are less sensitive to the therapeutic effects of botulinum neurotoxin B (BoNT/B) than the animal models it is tested on due to differences between the human and the mouse receptors. Here, the authors engineer BoNT/B to improve its affinity to human receptors and enhance its therapeutic efficacy.
- Liang Tao
- , Lisheng Peng
- & Min Dong
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Article
| Open AccessA dynamic and adaptive network of cytosolic interactions governs protein export by the T3SS injectisome
Bacterial type III secretion systems (T3SS) play important roles in pathogenesis. Here, Diepoldet al. show the dynamic nature of complexes formed of essential T3SS components in live bacteria, and that extracellular calcium concentrations influence these cytosolic complexes likely via SctK/YscK.
- Andreas Diepold
- , Erdinc Sezgin
- & Judith P. Armitage
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Article
| Open AccessStructural insights into the function of ZRANB3 in replication stress response
ZRANB3 (Zinc-finger, RAN-Binding domain containing 3) is a structure-specific endonuclease that is recruited to DNA breaks and stressed replication forks. Here the authors present the crystal structure of the ZRANB3 endonuclease domain and analyse how ZRANB3 is regulated by the DNA clamp PCNA.
- Marek Sebesta
- , Christopher D. O. Cooper
- & Dragana Ahel
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Article
| Open AccessStructure of the Rpn13-Rpn2 complex provides insights for Rpn13 and Uch37 as anticancer targets
In the proteasome, Rpn2 provides the docking site for substrate receptor Rpn13. Here the authors present the structure of human Rpn13 Pru domain bound to its binding site in Rpn2 and provide insights into the mode of action for Rpn13-targeting molecule RA190, which has anticancer properties.
- Xiuxiu Lu
- , Urszula Nowicka
- & Kylie J. Walters
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Article
| Open AccessVariation in auxin sensing guides AUX/IAA transcriptional repressor ubiquitylation and destruction
The phytohormone auxin is sensed by SCFTIR1-AUX/IAA receptors leading to AUX/IAA repressor ubiquitylation and turnover. Here the authors show that IAA6 and IAA19 differ in their ubiquitylation and turnover dynamics, differentially contributing to auxin sensing and enabling discrimination of auxin concentrations.
- Martin Winkler
- , Michael Niemeyer
- & Luz Irina A. Calderón Villalobos
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Article
| Open AccessStructural basis of HypK regulating N-terminal acetylation by the NatA complex
N-terminal acetylation is a common eukaryotic protein modification that is primarily catalysed by the N-acetyl transferase complex A (NatA). Here, the authors present the crystal structure of NatA bound to Huntingtin yeast two-hybrid protein K (HypK) and show that HypK is a negative regulator of NatA.
- Felix Alexander Weyer
- , Andrea Gumiero
- & Irmgard Sinning
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Article
| Open AccessRegulated membrane remodeling by Mic60 controls formation of mitochondrial crista junctions
The MICOS complex has an essential role in crista junction formation and mitochondrial inner membrane morphology. Here, the authors show that one of its components, Mic60, known to form contact sites between inner and outer membranes, also displays membrane-shaping activity.
- Manuel Hessenberger
- , Ralf M. Zerbes
- & Oliver Daumke
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Review Article
| Open AccessExploring chemoselective S-to-N acyl transfer reactions in synthesis and chemical biology
The conversion of thioesters to amides via acyl transfer has become one of the most important synthetic techniques for the chemical synthesis and modification of proteins. This review discusses this S-to-N acyl transfer process, and highlights some of the key applications across chemistry and biology.
- Helen M. Burke
- , Lauren McSweeney
- & Eoin M. Scanlan
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Article
| Open AccessRules of engagement between αvβ6 integrin and foot-and-mouth disease virus
Foot-and-mouth disease virus binds αvβ6 integrin, via a conserved RGD motif in the flexible, exposed GH loop of capsid protein VP1, for cell entry. Here Kotechaet al.visualize this interaction with the VP1 GH loop extending away from the viral surface, engaging αvβ6 in an open, active state.
- Abhay Kotecha
- , Quan Wang
- & David I. Stuart
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Article
| Open AccessStructural basis for perception of diverse chemical substances by T1r taste receptors
Nutrients taste perception is mediated by T1r receptors that discriminate specific tastes among their wide diversity. Here the authors present crystal structures of the ligand-binding domains of the fish T1r2-T1r3 receptor, providing a structural framework for its ligand recognition.
- Nipawan Nuemket
- , Norihisa Yasui
- & Atsuko Yamashita
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Article
| Open AccessAnti-platelet factor 4/polyanion antibodies mediate a new mechanism of autoimmunity
Antibodies against the platelet factor 4 (PF4) support bacterial host defence but in some cases may lead to heparin-induced thrombocytopenia (HIT). Nguyenet al.show that in autoimmune HIT a subset of antibodies binds strongly to PF4 causing its conformational change that leads to association of non-pathogenic PF4 antibodies and thrombotic platelet activation.
- Thi-Huong Nguyen
- , Nikolay Medvedev
- & Andreas Greinacher
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Article
| Open AccessStructure of the quaternary complex between SRP, SR, and translocon bound to the translating ribosome
Membrane proteins are inserted co-transnationally through the association between ribosome, the signal recognition particle and its receptor, and the membrane-bound translocon. Here the authors present a cryo-EM reconstruction of this quaternary complex in the activated state and propose a model for signal sequence transfer to the translocon.
- Ahmad Jomaa
- , Yu-Hsien Hwang Fu
- & Nenad Ban
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Article
| Open AccessSignal recognition particle prevents N-terminal processing of bacterial membrane proteins
Bacterial proteins are synthesized with formyl-methionine in their N-terminus, but most of them are co-translationally deformylated. Here, the authors show that inner-membrane proteins are protected from deformylation by the binding of the signal recognition particle (SRP) during translation.
- Amitabh Ranjan
- , Evan Mercier
- & Wolfgang Wintermeyer
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Article
| Open AccessAn optimized strategy to measure protein stability highlights differences between cold and hot unfolded states
Crowding effects—important when considering cellular environments—greatly influence protein stability. Here the authors study the impact of macromolecular crowders on high and low temperature protein unfolding, and show that volume exclusion effects are larger when the protein and crowder volumes are similar.
- Caterina Alfano
- , Domenico Sanfelice
- & Piero Andrea Temussi
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Article
| Open AccessProtein-protein interactions and metabolite channelling in the plant tricarboxylic acid cycle
A metabolon is a complex of sequential metabolic enzymes that channels substrates directly between enzymes, thus optimizing metabolic flux. Here Zhanget al. provide protein interaction and isotope dilution data that support the existence of a metabolon that channels both citrate and fumarate in the plant TCA cycle.
- Youjun Zhang
- , Katherine F. M. Beard
- & Toshihiro Obata
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Article
| Open AccessStructural heterogeneity in the intrinsically disordered RNA polymerase II C-terminal domain
The C-terminal domain (CTD) of RNA polymerase II is composed of a series of heptad repeats that exhibit some degree of sequence variation and that are subject to extensive phosphorylation. Here the authors provide evidence that local structural variations within the CTD are functionally important.
- Bede Portz
- , Feiyue Lu
- & David S. Gilmour
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Article
| Open AccessISCA1 is essential for mitochondrial Fe4S4 biogenesis in vivo
The mitochondrial proteins ISCA1 and ISCA2 form a complex that is involved in the biogenesis of Fe–S clusters. Here the authors report that ISCA1 and ISCA2 interact differently with proteins of the Fe–S machinery and that under certain conditions, ISCA2 seems dispensable for Fe–S biogenesis.
- Lena Kristina Beilschmidt
- , Sandrine Ollagnier de Choudens
- & Alain Martelli
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Article
| Open AccessMolecular basis for blue light-dependent phosphorylation of Arabidopsis cryptochrome 2
Plant cryptochromes are regulated by blue-light dependent phosphorylation. Here the authors map thein vivo phosphorylation sites of Arabidopsiscryptochrome 2 and identify four closely related kinases that act to both activate and destabilize the receptor in response to blue light.
- Qing Liu
- , Qin Wang
- & Chentao Lin
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Article
| Open AccessSubnanometre-resolution structure of the doublet microtubule reveals new classes of microtubule-associated proteins
Cilia are hair-like appendages involved in cell motility and sensory reception. Here, the authors report a high resolution cryo-EM structure of the microtubule doublet from motile cilia and identify microtubule inner proteins (MIPs) bound to the inner surface of the doublet that appear to stabilize its structure.
- Muneyoshi Ichikawa
- , Dinan Liu
- & Khanh Huy Bui
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Article
| Open AccessMechanism of SOS PR-domain autoinhibition revealed by single-molecule assays on native protein from lysate
The guanine nucleotide exchange factor SOS is a critical intermediary that transduces receptor tyrosine kinase stimulation into Ras activation. Here the authors develop a single molecule assay in which SOS is captured from raw lysates using Ras-functionalized membrane microarrays and uncover an autoinhibitory mechanism of SOS regulation.
- Young Kwang Lee
- , Shalini T. Low-Nam
- & Jay T. Groves
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Article
| Open AccessA multi-crystal method for extracting obscured crystallographic states from conventionally uninterpretable electron density
Building a ligand into a weak region of an electron density map of a protein is a subjective process. Here, the authors present a new method to obtain a clear electron density for a bound ligand based on multi-crystal experiments and 3D background correction.
- Nicholas M. Pearce
- , Tobias Krojer
- & Frank von Delft
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Article
| Open AccessGating of TonB-dependent transporters by substrate-specific forced remodelling
Bacterial outer membrane TonB-dependent transporters (TBDTs) mediate the influx of several nutrients. Here the authors use single-molecule force spectroscopy to show that the interaction between TonB andEscherichia coliTBDT BtuB is mechanically resistant to the pulling that gates the BtuB channel.
- Samuel J. Hickman
- , Rachael E. M. Cooper
- & David J. Brockwell
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Article
| Open AccessThermogenic adipocytes promote HDL turnover and reverse cholesterol transport
Activation of brown adipose tissue (BAT) reduces the development of atherosclerosis in animal models. Here the authors show that BAT activation also increases reverse cholesterol transport and turnover of high-density lipoprotein, which likely contributes to the anti-atherosclerotic effect of BAT activation.
- Alexander Bartelt
- , Clara John
- & Joerg Heeren
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Article
| Open AccessA new inhibitor of the β-arrestin/AP2 endocytic complex reveals interplay between GPCR internalization and signalling
Beta-arrestins play central roles in the mechanisms regulating GPCR signalling and trafficking. Here the authors identify a selective inhibitor of the interaction between β-arrestin and the β2-adaptin subunit of the clathrin adaptor protein AP-2, which they use to dissect the role of the β-arrestin/β2-adaptin interaction in GPCR signalling.
- Alexandre Beautrait
- , Justine S. Paradis
- & Michel Bouvier
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Article
| Open AccessKinetic CRAC uncovers a role for Nab3 in determining gene expression profiles during stress
Protein RNA interactions are dynamic and regulated in response to environmental changes. Here the authors describe ‘kinetic CRAC’, an approach that allows time resolved analyses of protein RNA interactions with minute time point resolution and apply it to gain insight into the function of the RNA-binding protein Nab3.
- Rob van Nues
- , Gabriele Schweikert
- & Sander Granneman
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Article
| Open AccessThe Pu.1 target gene Zbtb11 regulates neutrophil development through its integrase-like HHCC zinc finger
Neutrophils are increased in response to injury and infection but how they form from a common granulocyte-macrophage progenitor is unclear. Here, the authors identify a role for the transcriptional repressor ZBTB11 in zebrafish, which is regulated by master myeloid regulators and repressesTP53.
- Maria-Cristina Keightley
- , Duncan P. Carradice
- & Graham J. Lieschke
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Article
| 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 AccessMolecular level detection and localization of mechanical damage in collagen enabled by collagen hybridizing peptides
Collagen denaturation is thought to occur during tissue mechanical damage, but its role in damage initiation is still unclear. Here, the authors use a collagen hybridizing peptide to provide insights into the molecular mechanisms leading to collagen unfolding during tendon mechanical stretch.
- Jared L. Zitnay
- , Yang Li
- & Jeffrey A. Weiss
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Article
| Open AccessAllosteric modulation of peroxisomal membrane protein recognition by farnesylation of the peroxisomal import receptor PEX19
PEX19 is a chaperone and import receptor for peroxisomal membrane proteins (PMPs). Here the authors present the structure of the farnesylated C-terminal domain of PEX19, and its interaction with PMPs reveals how the farnesyl moiety allosterically reshapes the PMP binding surface and modulates PEX19 function.
- Leonidas Emmanouilidis
- , Ulrike Schütz
- & Michael Sattler
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Article
| Open AccessStructural basis of homo- and heterotrimerization of collagen I
Heterotrimers of collagen I (two α1 chains, one α2 chain) are crucial for the normal function of multiple tissues and organs. Here the authors show the molecular basis of both homotrimerization (three α1 chains) and heterotrimerization of collagen I through specific intermolecular interactions.
- Urvashi Sharma
- , Loïc Carrique
- & David J. S. Hulmes
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Article
| Open AccessRapid self-assembly of complex biomolecular architectures during mussel byssus biofabrication
Mussels attach to rocks using a byssus, which possesses unique properties of adhesion, toughness and self-healing. Here, the authors explore the fabrication process of mussel byssus demonstrating the self-assembly of specific proteins into multi-scale organized structures using artificially induced byssus threads.
- Tobias Priemel
- , Elena Degtyar
- & Matthew J. Harrington
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Article
| Open AccessDynamic regulation of GDP binding to G proteins revealed by magnetic field-dependent NMR relaxation analyses
Heterotrimeric guanine-nucleotide-binding proteins (G proteins) act as molecular switches. Here the authors use NMR relaxation analyses, which reveal the dynamics of G protein alpha subunit binding to GDP on a microsecond timescale.
- Yuki Toyama
- , Hanaho Kano
- & Ichio Shimada
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Article
| Open AccessC-edge loops of arrestin function as a membrane anchor
The activity of G-protein-coupled receptors is regulated by their interaction with arrestins. Here the authors show that loops located on C-edge of arrestin-1 serve as a membrane anchor during the multi-step binding process that leads to a stable receptor–arrestin complex.
- Ciara C M. Lally
- , Brian Bauer
- & Martha E Sommer
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Article
| Open AccessMembrane cholesterol access into a G-protein-coupled receptor
G-protein-coupled receptors trigger several signalling pathways and their activity was proposed to be allosteric modulated by cholesterol. Here the authors use molecular dynamics simulations and ligand binding assays to show that membrane cholesterol can bind to adenosine A2Areceptor orthosteric site.
- Ramon Guixà-González
- , José L. Albasanz
- & Jana Selent
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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 AccessArrestin-biased AT1R agonism induces acute catecholamine secretion through TRPC3 coupling
Angiotensin II type 1 receptor (AT1R)-mediated acute catecholamine release is modulated by β-arrestin. Here the authors show that β-arrestin-1 recruits the Ca2+channel TRPC3 and the PLCγ to the AT1R-β-arrestin complex, triggering G protein-independent calcium influx and catecholamine secretion.
- Chun-Hua Liu
- , Zheng Gong
- & Jin-Peng Sun
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Article
| Open AccessMolecular basis for protection of ribosomal protein L4 from cellular degradation
Acl4 is a dedicated assembly chaperone for ribosomal protein RpL4 that recognizes RpL4 in the cytoplasm to facilitate its nuclear import. Here the authors reveal the mechanism whereby Acl4 recognizes RpL4 and functions to protect it from Tom1-mediated degradation until RpL4 incorporation into the maturing 60S pre-ribosomal subunit.
- Ferdinand M. Huber
- & André Hoelz
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Article
| Open AccessSpecialized interfaces of Smc5/6 control hinge stability and DNA association
Structural Maintenance of Chromosomes (SMC) complexes maintain genome integrity by regulating the segregation of chromosomes. Here, Altet al. describe the structure of the heterodimeric Smc5/6-hinge from fission yeast and define functional features critical for Smc5/6’s cellular function.
- Aaron Alt
- , Hung Q. Dang
- & Antony W. Oliver
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Article
| Open AccessPortal protein functions akin to a DNA-sensor that couples genome-packaging to icosahedral capsid maturation
Tailed bacteriophages assemble empty precursor capsids known as procapsids that are subsequently filled with viral DNA by a genome-packaging motor. Here the authors present a structure-based analysis that suggests the signal for termination of genome packaging is achieved through a DNA-dependent symmetrization of portal protein.
- Ravi K. Lokareddy
- , Rajeshwer S. Sankhala
- & Gino Cingolani
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Review Article
| Open AccessAccelerating the search for the missing proteins in the human proteome
The Human Proteome Project aims to catalogue the ∼20,000 proteins encoded by the human genome. In this review, Bakeret al. focus on the missing proteins, proteins that lack high stringency proteomic evidence, and launch MissingProteinPedia, a database aimed at accelerating the search for missing proteins.
- Mark S. Baker
- , Seong Beom Ahn
- & Shoba Ranganathan
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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 AccessUncovering the SUMOylation and ubiquitylation crosstalk in human cells using sequential peptide immunopurification
Ubiquitylation and SUMOylation are two important related post-translational modifications. Here the authors present an approach for the simultaneous identification and quantification of protein-wide SUMO and ubiquitin sites from a single sample, uncovering widespread crosstalk between the two modifications.
- Frédéric Lamoliatte
- , Francis P. McManus
- & Pierre Thibault
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Article
| Open AccessStructural basis of ligand interaction with atypical chemokine receptor 3
The atypical chemokine receptor 3 (ACKR3) is important for cell migration in development and cancer. Here the authors combine radiolytic footprinting, disulfide trapping, mutagenesis and molecular modelling to characterize the ligand interactions and ligand-induced conformational changes in ACKR3.
- Martin Gustavsson
- , Liwen Wang
- & Tracy M. Handel
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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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