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Article
| Open AccessMERTK mediated novel site Akt phosphorylation alleviates SAV1 suppression
Hyperactivation of Akt promotes tumorigenesis. Here, the authors show that SAV1, a member of Hippo signalling, interacts with Akt to suppress Akt activity and MERTK-mediated Akt phosphorylation relieves this suppression to facilitate Akt oncogenic activity in clear cell renal carcinomas.
- Yao Jiang
- , Yanqiong Zhang
- & Pengda Liu
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Article
| Open AccessCa2+-dependent regulation of sodium channels NaV1.4 and NaV1.5 is controlled by the post-IQ motif
Skeletal muscle voltage-gated Na+ channel (NaV1.4) activity is subject to calmodulin (CaM) mediated Ca2 +-dependent inactivation while cardiac NaV1.5 is not. Here authors use structural biology, binding and electrophysiology to parse the Ca2 +-dependent changes of CaM when bound to the NaV1.4.
- Jesse B. Yoder
- , Manu Ben-Johny
- & L. Mario Amzel
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Article
| Open AccessSynthetic ligands for PreQ1 riboswitches provide structural and mechanistic insights into targeting RNA tertiary structure
RNA sensors—Riboswitches—respond to the binding of small molecules ligands through structure modification. Here the authors identify synthetic small molecules that bind and regulate the activity of PreQ1 Riboswitches despite having no obvious chemical similarity to the cognate ligand.
- Colleen M. Connelly
- , Tomoyuki Numata
- & John S. Schneekloth Jr.
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Article
| Open AccessStructural and biochemical evidence supporting poly ADP-ribosylation in the bacterium Deinococcus radiodurans
Poly-ADP-ribosylation (PARylation) is a well-known regulatory event in eukaryotes but has not yet been observed in bacteria. Here, the authors solve the structure of a bacterial PAR-glycohydrolase and provide evidence for a prokaryotic PARylation machinery involved in the response to genotoxic stress.
- Chao-Cheng Cho
- , Chia-Yu Chien
- & Chun-Hua Hsu
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Article
| Open AccessIdentification of human D lactate dehydrogenase deficiency
D-lactic acidosis typically occurs in the context of short bowel syndrome; excess D-lactate is produced by intestinal bacteria. Here, the authors identify two point mutations in the human lactate dehydrogenase D (LDHD) gene that cause enzymatic loss of function and are associated with elevated plasma D-lactate.
- Glen R. Monroe
- , Albertien M. van Eerde
- & Judith J. Jans
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Article
| Open AccessIdentification of serum metabolites associating with chronic kidney disease progression and anti-fibrotic effect of 5-methoxytryptophan
Accurate monitoring of chronic kidney disease (CKD) progression is essential for efficient disease management. Here Chen et al. identify five serum metabolites in patients with stage 1–5 CKD whose levels associate with disease progression, and find that 5-methoxytryptophan and its regulatory enzyme TPH-1 exert anti-fibrotic effects in mouse models of kidney injury.
- Dan-Qian Chen
- , Gang Cao
- & Ying-Yong Zhao
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Article
| Open AccessA study of the extraordinarily strong and tough silk produced by bagworms
Spider silk is widely studied for its structural properties; however, other creatures produce silk that could be of interest. Here, the authors study the properties and structure of Bagworm silk and report it as being extraordinarily strong and tough compared to other known silks.
- Taiyo Yoshioka
- , Takuya Tsubota
- & Tsunenori Kameda
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Article
| Open AccessPhosphatidylethanolamine made in the inner mitochondrial membrane is essential for yeast cytochrome bc1 complex function
Phosphatidylethanolamine (PE) is synthesized by four separate pathways, although surprisingly, perturbing mitochondrial PE synthesis compromises mitochondrial function. Here, the authors show that mitochondrial PE synthesis is required for Complex III function and challenge PE trafficking dogma.
- Elizabeth Calzada
- , Erica Avery
- & Steven M. Claypool
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Article
| Open AccessCoordination of capsule assembly and cell wall biosynthesis in Staphylococcus aureus
The cell wall of Gram-positive bacteria consists of peptidoglycan modified with other polymers, such as the capsular polysaccharide. Here, the authors reconstitute the biosynthesis of capsular polysaccharide and elucidate its interplay with the cell wall biosynthetic machinery.
- Marvin Rausch
- , Julia P. Deisinger
- & Tanja Schneider
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Article
| Open AccessNucleoside analogue activators of cyclic AMP-independent protein kinase A of Trypanosoma
Protein kinase A (PKA) is typically activated by cAMP. Here, Bachmaier et al. show that PKA of Trypanosoma is activated by nucleoside-related ligands, explain the ligand selectivity swap by a co-crystal structure of trypanosome PKAR, and identify potential downstream targets by phosphoproteomics.
- Sabine Bachmaier
- , Yuri Volpato Santos
- & Michael Boshart
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Article
| Open AccessProminence of the tropics in the recent rise of global nitrogen pollution
Nitrogen pollution is influenced by many stressors, and their combined effects are poorly constrained. Here the authors used a global land biosphere model to analyse the past two and a half centuries of land N pollution budgets and fluxes to the ocean and atmosphere and found that land sequesters 11% of global annual reactive N inputs.
- Minjin Lee
- , Elena Shevliakova
- & P. C. D. Milly
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Article
| Open AccessX-ray structures of the high-affinity copper transporter Ctr1
Copper (Cu) is an essential trace element for growth and development and the Cu+ transporter Ctr1 is crucial for both dietary Cu uptake and peripheral distribution. Here authors solve Cu+ -free and Cu+ -bound Ctr1 structures which adopt a homo-trimeric Cu+ -selective ion channel-like architecture
- Feifei Ren
- , Brandon L. Logeman
- & Peng Yuan
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Article
| Open AccessA TonB-dependent transporter is required for secretion of protease PopC across the bacterial outer membrane
TonB-dependent transporters (TBDTs) are outer membrane proteins that import nutrients and bacteriocins in bacteria. Here, Gómez-Santos et al. show that a TBDT is required for secretion of a protease in Myxococcus xanthus, suggesting that some TBDTs may be involved in protein secretion.
- Nuria Gómez-Santos
- , Timo Glatter
- & Lotte Søgaard-Andersen
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Article
| Open AccessSelective binding of a toxin and phosphatidylinositides to a mammalian potassium channel
G-protein-gated inward rectifying potassium channels (GIRKs) require Gβγ subunits and phosphorylated phosphatidylinositides (PIPs) for gating. Here authors use native ion mobility mass spectrometry to monitor small molecule binding events to GIRK2 and shed light on the selectivity of GIRK2 towards PIPs.
- Yang Liu
- , Catherine E. LoCaste
- & Arthur Laganowsky
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Article
| Open AccessComplex formation of APP with GABAB receptors links axonal trafficking to amyloidogenic processing
The mechanisms that control the presynaptic abundance of GABAB receptors (GBRs) remains unclear. This study shows that sequence-related epitopes in APP, AJAP-1 and PIANP bind with nanomolar affinities to the N-terminal sushi-domain of presynaptic GBRs, and that selective loss of APP impaired GBR-mediated presynaptic inhibition and axonal GBR expression
- Margarita C. Dinamarca
- , Adi Raveh
- & Bernhard Bettler
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Article
| Open AccessSMARCAD1 ATPase activity is required to silence endogenous retroviruses in embryonic stem cells
Tight regulation of retrotransposons such as endogenous retroviruses (ERVs) is essential for genome and transcriptome integrity. Here, the authors show that the ATPase function of the chromatin remodeler SMARCAD1 facilitates the binding of KAP1 to ERVs and is required for their repression in embryonic stem cells.
- Parysatis Sachs
- , Dong Ding
- & Jacqueline E. Mermoud
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Article
| Open AccessTG-interacting factor 1 (Tgif1)-deficiency attenuates bone remodeling and blunts the anabolic response to parathyroid hormone
Parathyroid hormone (PTH) is used to treat osteoporosis, but its therapeutic mechanism remains unclear. Here, the authors show that Tgif1 is a PTH target gene, and that its deletion impairs the function of osteoblasts and PTH-induced bone formation in mice.
- Hiroaki Saito
- , Andreas Gasser
- & Eric Hesse
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Article
| Open AccessCapturing site-specific heterogeneity with large-scale N-glycoproteome analysis
Mass spectrometry facilitates large-scale glycosylation profiling but in-depth analysis of intact glycopeptides is still challenging. Here, the authors show that activated ion electron transfer dissociation is suitable for glycopeptide fragmentation and improves glycoproteome coverage.
- Nicholas M. Riley
- , Alexander S. Hebert
- & Joshua J. Coon
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Article
| Open AccessA post-translational modification of human Norovirus capsid protein attenuates glycan binding
Attachment of human noroviruses to histo blood group antigens (HBGAs) is essential for infection. Here the authors report that an asparagine residue located near the HBGA-attachment site can convert into an iso-aspartate residue through spontaneous deamidation and influence HBGA recognition.
- Alvaro Mallagaray
- , Robert Creutznacher
- & Thomas Peters
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Article
| Open AccessThe Arabidopsis H3K27me3 demethylase JUMONJI 13 is a temperature and photoperiod dependent flowering repressor
Jumonji domain-containing histone demethylases regulate flowering in plants. Here Zheng et al. show that Arabidopsis JMJ13 is an H3K27me3 demethylase that recognizes H3K27me3 via hydrogen bonding and hydrophobic interactions and affects both photoperiod and temperature-dependent flowering responses.
- Shuzhi Zheng
- , Hongmiao Hu
- & Jiamu Du
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Article
| Open AccessThe conserved NxNNWHW motif in Aha-type co-chaperones modulates the kinetics of Hsp90 ATPase stimulation
Hsp90 is a molecular chaperone that acts together with co-chaperones to ensure folding and activation of many client proteins. Here authors show that a N-terminal motif in Aha-type co-chaperones modulates the apparent affinity of Hsp90 for nucleotide substrates.
- Rebecca Mercier
- , Annemarie Wolmarans
- & Paul LaPointe
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Article
| Open AccessCryo-EM structure of cardiac amyloid fibrils from an immunoglobulin light chain AL amyloidosis patient
Immunoglobulin Light Chain Amyloidosis (AL) is the most common systemic amyloidosis occurring in Western countries. Here the authors present the 4.0 Å cryo-EM structure of light chain AL55 fibrils that were isolated from the heart of an AL systemic amyloidosis patient.
- Paolo Swuec
- , Francesca Lavatelli
- & Martino Bolognesi
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Article
| Open AccessCryo-EM structure of a light chain-derived amyloid fibril from a patient with systemic AL amyloidosis
Systemic AL amyloidosis is caused by misfolding of immunoglobulin light chains and is one of the most frequently occurring forms of systemic amyloidosis. Here the authors present the 3.3 Å cryo-EM structure of a λ1 AL amyloid fibril that was isolated from an explanted human heart.
- Lynn Radamaker
- , Yin-Hsi Lin
- & Marcus Fändrich
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Article
| Open AccessReversible histone glycation is associated with disease-related changes in chromatin architecture
Proteins continuously undergo non-enzymatic modifications such as glycation, which accumulate under physiological conditions but can be enhanced in disease. Here the authors characterise histone glycation, provide evidence that it affects chromatin, particularly in breast cancer, and identify DJ-1 as a deglycase.
- Qingfei Zheng
- , Nathaniel D. Omans
- & Yael David
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Article
| Open AccessUnusual substrate and halide versatility of phenolic halogenase PltM
Halogenase enzymes are of interest as halogenating tools for organic synthesis. Here the authors show that the bacterial FAD-dependent phenolic halogenase PltM chlorinates, brominates and iodinates a variety of substrates and reveal the structural basis for its substrate versatility and provide insights into the FAD recycling mechanism of PltM.
- Shogo Mori
- , Allan H. Pang
- & Oleg V. Tsodikov
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Article
| Open AccessDistinct G protein-coupled receptor phosphorylation motifs modulate arrestin affinity and activation and global conformation
The cellular functions of arrestins are determined in part by the pattern of phosphorylation on the G protein-coupled receptors (GPCRs) to which arrestins bind. Here, authors use a library of synthetic phosphopeptide analogues of the GPCR rhodopsin C-terminus and determine the ability of these peptides to bind and activate arrestins using a variety of biochemical and biophysical methods.
- Daniel Mayer
- , Fred F. Damberger
- & Dmitry B. Veprintsev
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Article
| Open AccessUFL1 promotes histone H4 ufmylation and ATM activation
Ufmylation is a ubiquitylation-like protein modification but only a few ufmylation substrates and functions have been discovered so far. Here, the authors demonstrate ufmylation of histone H4 upon DNA damage and show that this modification is involved in the amplification of ATM activation.
- Bo Qin
- , Jia Yu
- & Zhenkun Lou
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Article
| Open AccessDietary fatty acids fine-tune Piezo1 mechanical response
Piezo channels are mechanosensitive and rely on membrane composition to transduce physical stimuli into electrical signals. Here authors analyse the membrane components that modulate Piezo1 function using lipid profiling which shows that fatty acid metabolism can modulate ion channel activity.
- Luis O. Romero
- , Andrew E. Massey
- & Valeria Vásquez
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Review Article
| Open AccessEmerging roles of eraser enzymes in the dynamic control of protein ADP-ribosylation
ADP-ribose erasing enzymes are increasingly recognized as critical regulators of protein ADP-ribosylation dynamics in living systems. Here, the authors review recent advances in the discovery and characterization of ADP-ribose erasers and discuss their role within the cellular ADP-ribosylation machinery.
- Julia O’Sullivan
- , Maria Tedim Ferreira
- & Guy G. Poirier
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Article
| Open AccessQuantifying protein dynamics and stability in a living organism
Studying protein kinetics and stability in living organisms is challenging and most studies are performed in cell culture. Here the authors combine meganuclease-mediated transformation and fluorescence-detected temperature-jump microscopy to quantify protein stability in different tissues of living zebrafish.
- Ruopei Feng
- , Martin Gruebele
- & Caitlin M. Davis
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Article
| Open AccessCryoEM structure of adenovirus type 3 fibre with desmoglein 2 shows an unusual mode of receptor engagement
Human adenoviruses (HAd) cause respiratory, gastrointestinal and ocular infections. Here, the authors provide insights into the early stages of adenovirus infection by determining the cryo-EM structure of the trimeric HAd type 3 fibre knob bound to its cellular receptor human desmoglein 2, which reveals residues critical for HAd-receptor interactions.
- Emilie Vassal-Stermann
- , Gregory Effantin
- & Pascal Fender
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Article
| Open AccessMolecular architecture of a cylindrical self-assembly at human centrosomes
The centrosome is a membraneless organelle composed of two centrioles and an amorphous pericentriolar material but the overall centrosome organizations remains unknown. Here authors show that two scaffold proteins, Cep63 and Cep152, self-assemble into a higher-order cylindrical architecture capable of recruiting downstream components, including Plk4.
- Tae-Sung Kim
- , Liang Zhang
- & Kyung S. Lee
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Article
| Open AccessProteome-wide solubility and thermal stability profiling reveals distinct regulatory roles for ATP
ATP can function as a biological hydrotrope, but its global effects on protein solubility have not yet been characterized. Here, the authors quantify the effect of ATP on the thermal stability and solubility of the cellular proteome, providing insights into protein solubility regulation by ATP.
- Sindhuja Sridharan
- , Nils Kurzawa
- & Mikhail M. Savitski
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Article
| Open AccessStructural basis for transcription initiation by bacterial ECF σ factors
Extra-cytoplasmic function (ECF) σ factors allow bacteria to rapidly respond to stress conditions. Here the authors provide insights into the mechanism of bacterial stress-induced transcription by determining the crystal structures of the M. tuberculosis ECF σ factor bound RNA Polymerase (RNAP) holoenzyme and the ECF σ factor-RNAP transcription initiation complex.
- Lingting Li
- , Chengli Fang
- & Yu Zhang
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Article
| Open AccessApoptotic tumor cell-derived microRNA-375 uses CD36 to alter the tumor-associated macrophage phenotype
The mode of miRNA transfer between tumour-immune cells is usually via exosomes. Here, the authors show that an alternative mode of transfer whereby miR-375 from apoptotic tumour cells can be transferred to tumour-associated macrophages via CD36 receptor, which induces macrophage migration and infiltration to the tumours.
- Ann-Christin Frank
- , Stefanie Ebersberger
- & Bernhard Brüne
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Article
| Open AccessA Ca2+-regulated deAMPylation switch in human and bacterial FIC proteins
In many AMPylating FIC proteins a structurally conserved glutamate represses AMPylation. Here, the authors show that this glutamate supports deAMPylation in Enterococcus faecalis FIC (EfFIC), and that EfFIC switches from AMPylation to deAMPylation by binding Ca2+ at distinct sites.
- Simon Veyron
- , Giulia Oliva
- & Jacqueline Cherfils
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Article
| Open AccessCryo-EM structure of the human ferritin–transferrin receptor 1 complex
The human transferrin receptor 1 (CD71) is a transmembrane protein responsible for iron uptake. Here the authors present the 3.9 Å resolution cryo-EM structure of the CD71 ectodomain-human ferritin (H-Ft) complex and find that H-Ft binds a CD71 region different from the transferrin one that overlaps with the surface recognized by select pathogens.
- Linda Celeste Montemiglio
- , Claudia Testi
- & Beatrice Vallone
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Article
| Open AccessStructural determinants of lipid specificity within Ups/PRELI lipid transfer proteins
The Ups/PRELI family mediates intramitochondrial lipid distribution and synthesis by shuttling phospholipids between both mitochondrial membranes. Here the authors combine X-ray crystallography, MD simulations and yeast genetic screens and identify residues that are important for Ups/PRELI lipid specificity and reveal a dual lipid recognition mechanism in Ups/PRELI family members.
- Xeni Miliara
- , Takashi Tatsuta
- & Thomas Langer
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Article
| Open AccessInner lumen proteins stabilize doublet microtubules in cilia and flagella
Microtubules in cilia are sufficiently stable to withstand the beating motion, but how they are stabilized while serving as tracks for intraflagellar transport and axonemal dyneins remains unknown. Here authors identify two microtubule inner proteins, FAP45 and FAP52, which stabilize the ciliary axonemes in Chlamydomonas.
- Mikito Owa
- , Takayuki Uchihashi
- & Masahide Kikkawa
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Article
| Open AccessCryo-EM fibril structures from systemic AA amyloidosis reveal the species complementarity of pathological amyloids
Systemic AA amyloidosis is caused by misfolding of the acute phase protein serum amyloid A1. Here the authors present the cryo-EM structures of murine and human AA amyloid fibrils that were isolated from tissue samples and describe how the fibrils differ in their fundamental structural properties.
- Falk Liberta
- , Sarah Loerch
- & Matthias Schmidt
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Article
| Open AccessA widely distributed diheme enzyme from Burkholderia that displays an atypically stable bis-Fe(IV) state
The diheme enzyme MauG forms a bis-Fe(IV) state. Here the authors identify and determine the structure of BthA, a diheme peroxidase conserved in all Burkholderia and show that BthA also forms a bis-Fe(IV) species but mechanistically differs from MauG by combining magnetic resonance, near-IR and Mössbauer spectroscopies and electrochemical methods.
- Kimberly Rizzolo
- , Steven E. Cohen
- & Sean J. Elliott
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Article
| Open AccessLocal unfolding of the HSP27 monomer regulates chaperone activity
The small heat-shock protein HSP27 occurs predominantly in oligomeric forms, which makes its structural characterisation challenging. Here the authors employ CPMG and high-pressure NMR with native mass spectrometry and biophysical assays to show that the active monomeric form of HSP27 is substantially disordered and highly chaperone-active.
- T. Reid Alderson
- , Julien Roche
- & Andrew J. Baldwin
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Article
| Open AccessAnalysis of human acetylation stoichiometry defines mechanistic constraints on protein regulation
Many human proteins are regulated by lysine acetylation, but the degree of acetylation at individual sites is poorly characterized. Here, the authors measure acetylation stoichiometry in the HeLa cell proteome, providing a resource to assess mechanistic constraints on acetylation-mediated protein regulation.
- Bogi Karbech Hansen
- , Rajat Gupta
- & Brian T. Weinert
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Article
| Open AccessHelical antimicrobial peptides assemble into protofibril scaffolds that present ordered dsDNA to TLR9
Amphihelical antimicrobial peptides (AMPs) are bactericidal host defense factors, but their function as immunomodulators is emerging. Here the authors show that several AMPs organize DNA into periodic nanocrystals by self-assembling into superhelical protofibril scaffolds, which potentiates DNA sensing by TLR9.
- Ernest Y. Lee
- , Changsheng Zhang
- & Gerard C. L. Wong
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Article
| Open AccessHigh-resolution structure determination of sub-100 kDa complexes using conventional cryo-EM
Despite many recent advances in cryo-EM, imaging smaller macromolecules (below 100 kDa) has remained a challenge. Here the authors show that biological specimens amassing <100 kDa can be resolved to better than 3 Å resolution using conventional defocus-based single-particle analysis methods.
- Mark A. Herzik Jr.
- , Mengyu Wu
- & Gabriel C. Lander
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Article
| Open AccessSynthetic energy sensor AMPfret deciphers adenylate-dependent AMPK activation mechanism
AMP-activated protein kinase AMPK senses and regulates cellular energy state. Here the authors engineer a synthetic sensor, AMPfret, that allows direct, real-time readout of the AMPK conformational state by fluorescence resonance energy transfer (FRET).
- Martin Pelosse
- , Cécile Cottet-Rousselle
- & Uwe Schlattner
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Article
| Open AccessPurification of cross-linked RNA-protein complexes by phenol-toluol extraction
RNA binding proteins are important regulators of RNA function. Here the authors describe a method for isolation of RNA-protein complexes that does not rely on a specific RNA sequence or motif, and demonstrate the approach by providing the global RNA-bound proteomes of human HEK293 cells and Salmonella Typhimurium.
- Erika C. Urdaneta
- , Carlos H. Vieira-Vieira
- & Benedikt M. Beckmann
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Article
| Open AccessDynamic pigmentary and structural coloration within cephalopod chromatophore organs
Chromatophores in cephalopod skin are known for fast changes in coloration due to light-scattering pigment granules. Here, authors demonstrate structural coloration facilitated by reflectin in sheath cells and offer insights into the interplay between structural and pigmentary coloration elements.
- Thomas L. Williams
- , Stephen L. Senft
- & Leila F. Deravi
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Article
| Open AccessIon mobility conformational lipid atlas for high confidence lipidomics
The biological functions of lipids critically depend on their highly diverse molecular structures. Here, the authors determine the mass-resolved collision cross sections of 456 sphingolipid and glycerophospholipid species, providing a reference for future structural lipidomics studies.
- Katrina L. Leaptrot
- , Jody C. May
- & John A. McLean
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