Featured
-
-
Article
| Open AccessTopological barrier to Cas12a activation by circular DNA nanostructures facilitates autocatalysis and transforms DNA/RNA sensing
The authors find that small circular DNA nanostructures which partially match gRNA sequences only minimally activate Cas12a. They report AutoCAR (Autocatalytic Cas12a Circular DNA Amplification Reaction) which allows a single nucleic acid target to activate multiple ribonucleoproteins, and increases reporter cleavage rates.
- Fei Deng
- , Yi Li
- & Ewa M. Goldys
-
Article
| Open AccessDJ-1 protects proteins from acylation by catalyzing the hydrolysis of highly reactive cyclic 3-phosphoglyceric anhydride
Human protein DJ-1 displays neuroprotective properties. Here, the authors demonstrate that DJ-1 hydrolyzes cyclic 3-phosphoglyceric anhydride (cPGA), thereby protecting proteins from acylation by this highly reactive metabolite spontaneously forming in glycolysis.
- Aizhan Akhmadi
- , Adilkhan Yeskendir
- & Darkhan Utepbergenov
-
Article
| Open AccessCentrosome amplification and aneuploidy driven by the HIV-1-induced Vpr•VprBP•Plk4 complex in CD4+ T cells
People living with HIV-1 are at an increased risk of developing various cancers. Here, the authors suggest that HIV-1-encoded Vpr can promote oncogenesis by forming a ternary complex with VprBP and Plk4 and inducing Plk4-dependent centriole overduplication and aneuploidy.
- Jung-Eun Park
- , Tae-Sung Kim
- & Kyung S. Lee
-
Article
| Open AccessSpecific pharmacological and Gi/o protein responses of some native GPCRs in neurons
G protein responses mediated by GPCRs may differ depending on their environment. Here, using highly sensitive Gi/o sensors, the authors reveal the specific pharmacological and Gi/o protein responses of some native GPCRs in neurons, and the influence of G protein composition.
- Chanjuan Xu
- , Yiwei Zhou
- & Jianfeng Liu
-
Article
| Open AccessA non-canonical nucleophile unlocks a new mechanistic pathway in a designed enzyme
The authors previously showed that a histidine nucleophile and a flexible arginine can work in synergy to accelerate the Morita Baylis-Hillman (MBH) reaction. Here, they report another efficient MBHase that employs a non-canonical Nδ-methylhistidine nucleophile paired with a catalytic glutamate, providing an alternative mechanistic solution for MBH catalysis.
- Amy E. Hutton
- , Jake Foster
- & Anthony P. Green
-
Article
| Open AccessStructural basis for the modulation of MRP2 activity by phosphorylation and drugs
The ABC transporter MRP2/ABCC2 is a polyspecific efflux transporter of organic anions expressed in hepatocyte canalicular membranes. Dysfunction leads to Dubin-Johnson syndrome. Here the authors provide structural and biochemical evidence on the modulation of MRP2 by intracellular kinases and inhibition by therapeutic drugs.
- Tiziano Mazza
- , Theodoros I. Roumeliotis
- & Konstantinos Beis
-
Article
| Open AccessFilament formation drives catalysis by glutaminase enzymes important in cancer progression
Mitochondrial enzymes, collectively known as glutaminase, satisfy the metabolic requirements of cancer cells. Here the authors show that glutaminases form filamentous structures necessary for their catalytic activity.
- Shi Feng
- , Cody Aplin
- & Richard A. Cerione
-
Article
| Open AccessStructure-guided engineering of biased-agonism in the human niacin receptor via single amino acid substitution
GPR109A is a prototypical GPCR and a key drug target for dyslipidemia. Here, the authors present cryo-EM structures of this receptor to elucidate agonist-binding and activation, and design receptor mutants with transducer-coupling-bias.
- Manish K. Yadav
- , Parishmita Sarma
- & Arun K. Shukla
-
Article
| Open AccessA structural and dynamic visualization of the interaction between MAP7 and microtubules
Integrated structural data show that the MAP7 microtubule binding domain stabilizes the microtubule lattice through binding along protofilaments. Both strong and weak interactions between MAP7 and the lattice extend beyond a single tubulin dimer and include the tubulin C-terminal tails.
- Agnes Adler
- , Mamata Bangera
- & Marc Baldus
-
Article
| Open AccessStructural insight into an Arl1–ArfGEF complex involved in Golgi recruitment of a GRIP-domain golgin
Arl1 is a GTP-binding protein that interacts with the guanine nucleotide exchange factor Gea2 to recruit the golgin Imh1 to the Golgi. Here, the authors report structures of the full-length Gea2 and the Arl1–Gea2 complex, with insights into the mechanism of their function in membrane trafficking.
- H. Diessel Duan
- , Bhawik K. Jain
- & Huilin Li
-
Article
| Open AccessAlternative low-populated conformations prompt phase transitions in polyalanine repeat expansions
Here, the authors show that pathogenic mutations in the polyalanine expansions of PHOX2B promote nascent structural conformations that trigger irreversible phase transitions that arrest wild-type PHOX2B, disrupting function.
- Rosa Antón
- , Miguel Á. Treviño
- & Javier Oroz
-
Article
| Open AccessSpecificity, synergy, and mechanisms of splice-modifying drugs
Two small-molecule drugs, risdiplam and branaplam, have been developed for treating spinal muscular atrophy. Here the authors develop quantitative modeling methods for the sequence-specific and concentration-dependent effects of these and other splice-modifying drugs.
- Yuma Ishigami
- , Mandy S. Wong
- & Justin B. Kinney
-
Article
| Open AccessOrthoID: profiling dynamic proteomes through time and space using mutually orthogonal chemical tools
Proteomics at the organelle contact site remains challenging due to the spatial and temporal dynamics of proteins. Here, the authors developed OrthoID, a mutually orthogonal dual enzymatic proteomics approach to explore the proteome at the contact site of the endoplasmic reticulum and mitochondria.
- Ara Lee
- , Gihyun Sung
- & Kimoon Kim
-
Article
| Open AccessAltered receptor binding, antibody evasion and retention of T cell recognition by the SARS-CoV-2 XBB.1.5 spike protein
New variants of SARS-CoV-2 virus can evolve such that antibodies that recognised previous versions are not able to recognise newer versions. Here the authors characterise antibody binding to the XBB.1.5 variant and how antibodies and T cells from persons infected with earlier versions of SARS-CoV-2 are able to recognise and/or bind to the XBB.1.5 spike protein.
- Dhiraj Mannar
- , James W. Saville
- & Sriram Subramaniam
-
Article
| Open AccessUnderstanding activity-stability tradeoffs in biocatalysts by enzyme proximity sequencing
Understanding the complex relationships between enzyme sequence, folding stability and catalytic activity is essential for applications, but current technologies cannot simultaneously resolve both stability and activity phenotypes and couple these to gene sequences at large scale. Here, the authors report Enzyme Proximity Sequencing (EP-Seq), a deep mutational scanning method to assay both expression level and catalytic activity of thousands of oxidoreductase variants from a cellular pool in a single experiment.
- Rosario Vanella
- , Christoph Küng
- & Michael A. Nash
-
Article
| Open AccessCryo-EM structure of cell-free synthesized human histamine 2 receptor/Gs complex in nanodisc environment
The study describes the molecular structure of the human histamine 2 receptor in active conformation and in complex with Gs heterotrimer, synthesized in a cell-free system and co-translationally inserted into preformed nanodiscs.
- Zoe Köck
- , Kilian Schnelle
- & Frank Bernhard
-
Article
| Open AccessStructure-function analysis of the cyclic β-1,2-glucan synthase from Agrobacterium tumefaciens
Here, the authors present the structure of cyclic β-1,2-glucan synthase from Agrobacterium tumefaciens, revealing a distinct mechanism that uses a tyrosine-linked oligosaccharide intermediate in cycles of polymerization and processing of the glucan chain.
- Jaroslaw Sedzicki
- , Dongchun Ni
- & Christoph Dehio
-
Article
| Open AccessStructure of the p53 degradation complex from HPV16
HPV’s E6 protein promotes cancer by degrading p53. This study reveals the cryoEM structure of HPV16 E6 in complex with E6AP and p53, highlighting their picomolar affinity and large protein-protein interaction interface.
- John C. K. Wang
- , Hannah T. Baddock
- & Aaron H. Nile
-
Article
| Open AccessFunctional regulation of aquaporin dynamics by lipid bilayer composition
Membrane proteins depend on their lipid environments. Using aquaporin as a model, the authors show that the choice of lipid bilayer fundamentally affects membrane protein structure, thermodynamics, kinetic, and function, even to the point of lipid-based inhibition.
- Anh T. P. Nguyen
- , Austin T. Weigle
- & Diwakar Shukla
-
Article
| Open AccessA release of local subunit conformational heterogeneity underlies gating in a muscle nicotinic acetylcholine receptor
Authors show that agonist binding to the muscle acetylcholine receptor releases local conformational heterogeneity transitioning all subunits into a symmetric open state. A release of conformational heterogeneity underlies allosteric communication.
- Mackenzie J. Thompson
- , Farid Mansoub Bekarkhanechi
- & John E. Baenziger
-
Article
| Open AccessTopBP1 utilises a bipartite GINS binding mode to support genome replication
Effective and regulated activation of the Mcm2-7 helicase underlies faithful genome replication. Here the authors reveal mechanistic detail how the pre-loading complex proteins TopBP1 and GINS interact and, thus, how the helicase activator GINS loads on Mcm2-7 during replication origin firing.
- Matthew Day
- , Bilal Tetik
- & Dominik Boos
-
Article
| Open AccessBicarbonate signalling via G protein-coupled receptor regulates ischaemia-reperfusion injury
The acid–base balance regulates cellular responses, but little has been known about its molecular mechanism. Here, the authors unveil a bicarbonate-sensing GPCR, GPR30, that underlies cerebral ischemia–reperfusion injury by regulating blood flow recovery.
- Airi Jo-Watanabe
- , Toshiki Inaba
- & Takehiko Yokomizo
-
Article
| Open AccessDeciphering the mechanism of glutaredoxin-catalyzed roGFP2 redox sensing reveals a ternary complex with glutathione for protein disulfide reduction
Fusion proteins between roGFP2 and glutaredoxins are used for intracellular redox measurements. Here, the authors determined all rate constants of the reaction cycle for roGFP2 measurements and identified an alternative glutaredoxin mechanism.
- Fabian Geissel
- , Lukas Lang
- & Marcel Deponte
-
Article
| Open AccessReducing the metabolic burden of rRNA synthesis promotes healthy longevity in Caenorhabditis elegans
Synthesis of ribosomal RNA (rRNA) by Pol I sustains cell growth but is highly energy demanding. Here the authors show that curbing of Pol I activity lowers systemic energy utilization and delays metabolic aging by reducing triglyceride lipolysis and mitochondrial oxygen consumption.
- Samim Sharifi
- , Prerana Chaudhari
- & Maria Ermolaeva
-
Article
| Open AccessSingle-molecule RNA sizing enables quantitative analysis of alternative transcription termination
The development of RNA technologies demands accurate assessment of transcript size and heterogeneity. Here, authors report a nanopore-based approach to study full-length RNA transcripts at the single-molecule level, identify premature transcription termination and study rolling-circle transcription.
- Gerardo Patiño-Guillén
- , Jovan Pešović
- & Ulrich Felix Keyser
-
Article
| Open AccessNAAA-regulated lipid signaling in monocytes controls the induction of hyperalgesic priming in mice
Circulating monocytes contribute to the transition to pain chronicity but the molecular events that cause their deployment are still unclear. Using a mouse model of hyperalgesic priming, here the authors show that blood monocytes contribute to the emergence of chronic pain via a mechanism that requires a transient disruption of NAAA-regulated lipid signaling.
- Yannick Fotio
- , Alex Mabou Tagne
- & Daniele Piomelli
-
Article
| Open AccessA co-assembly platform engaging macrophage scavenger receptor A for lysosome-targeting protein degradation
Targeted degradation of proteins has emerged as a powerful method for modulating protein homeostasis. Here, the authors develop LYTACAs, a modular supramolecular lysosome-targeting co-assembly system, as an effective platform for lysosomal degradation of extracellular and membrane proteins.
- Qian Wang
- , Xingyue Yang
- & Suwei Dong
-
Article
| Open AccessSubstrate binding and catalytic mechanism of the Se-glycosyltransferase SenB in the biosynthesis of selenoneine
SenB is a Se-glycosyltransferase in the microbial biosynthesis pathway of selenoneine. Here, the authors perform the structure-function investigation, providing mechanistic insights into a two-step catalytic reaction of SenB.
- Wei Huang
- , Jun Song
- & Feng Long
-
Article
| Open AccessMotility of an autonomous protein-based artificial motor that operates via a burnt-bridge principle
Inspired by biology, great progress has been made in creating artificial molecular motors. Here the authors report the synthesis and characterization of the Lawnmower, an autonomous, protein-based artificial molecular motor and show their design is capable of track-guided motion.
- Chapin S. Korosec
- , Ivan N. Unksov
- & Nancy R. Forde
-
Article
| Open AccessEuglena’s atypical respiratory chain adapts to the discoidal cristae and flexible metabolism
Euglena gracilis is a model organism of the eukaryotic supergroup Discoba, single-celled organisms containing mitochondria with discoid cristae. Here, the authors report structures of Euglena’s transport chain supercomplex to reveal their distinctive architecture and working mechanisms.
- Zhaoxiang He
- , Mengchen Wu
- & Long Zhou
-
Perspective
| Open AccessAnnexins—a family of proteins with distinctive tastes for cell signaling and membrane dynamics
Annexins are calcium-regulated membrane binding proteins with an array of cellular activities. Here, Gerke et al. describe recent research highlighting the many functions of annexins and provide a view on directions for the future.
- Volker Gerke
- , Felicity N. E. Gavins
- & Ursula Rescher
-
Article
| Open AccessAccurate global and local 3D alignment of cryo-EM density maps using local spatial structural features
Density map alignment is a fundamental step in Cryo-EM data postprocessing. Here, authors propose an accurate global and local density map alignment method using local density features.
- Bintao He
- , Fa Zhang
- & Renmin Han
-
Article
| Open AccessLarge dynamics of a phase separating arginine-glycine-rich domain revealed via nuclear and electron spins
The authors show the RNA-induced droplet formation by a component of Cajal bodies and reveal the large nanoseconds mobility of glycine residues inside droplets as a molecular factor potentially contributing to the large dynamics of Cajal bodies.
- Giuseppe Sicoli
- , Daniel Sieme
- & Nasrollah Rezaei-Ghaleh
-
Article
| Open AccessImputation of plasma lipid species to facilitate integration of lipidomic datasets
Advancements in plasma lipidomic profiling increase specificity of measurements but pose challenges in aligning datasets created at different times or platforms. Here the authors present a predictive framework for harmonising such datasets with different levels of granularity in their lipid measurements.
- Aleksandar Dakic
- , Jingqin Wu
- & Peter J. Meikle
-
Article
| Open AccessA mutational atlas for Parkin proteostasis
Gene variants can affect folding and stability of the encoded protein. Here, the authors apply deep mutational scanning to provide genotype-phenotype information for 99% of the possible PRKN variants and reveal mechanistic details on how some variants cause loss-of-function and Parkinsons disease.
- Lene Clausen
- , Vasileios Voutsinos
- & Rasmus Hartmann-Petersen
-
Article
| Open AccessEvolutionarily related host and microbial pathways regulate fat desaturation in C. elegans
Fatty acid desaturation is central to metazoan lipid metabolism. Here, using C. elegans as a model, the authors show that both endogenous and microbiota-dependent small molecule signals converge to promote lipid desaturation via the nuclear receptor NHR-49/PPARα.
- Bennett W. Fox
- , Maximilian J. Helf
- & Frank C. Schroeder
-
Article
| Open AccessGenetic influences on circulating retinol and its relationship to human health
Retinol, a form of vitamin A, plays an essential role in many biological processes throughout the human lifespan. Here the authors identify genetic variants that influence the level of circulating retinol and use this information to better understand how retinol impacts human health.
- William R. Reay
- , Dylan J. Kiltschewskij
- & Murray J. Cairns
-
Article
| Open AccessA SPLICS reporter reveals \({{{{{\boldsymbol{\alpha }}}}}}\)-synuclein regulation of lysosome-mitochondria contacts which affects TFEB nuclear translocation
Mitochondria-lysosome interactions are fundamental to cellular physiology. Here, the authors describe a genetically-encoded SPLICS reporter to study short- and long-juxtapositions between mitochondria and lysosomes.
- Flavia Giamogante
- , Lucia Barazzuol
- & Marisa Brini
-
Article
| Open AccessSubstrate promiscuity of inositol 1,4,5-trisphosphate kinase driven by structurally-modified ligands and active site plasticity
InsP3 3-kinase phosphorylates 1,4,5-trisphosphate (InsP3) specifically at its secondary 3-hydroxyl group to generate a tetrakisphosphate. Here, the authors used a combination of methods to survey InsP3 3-kinase ligand specificity and determined that IP3K specificity surpasses that of its natural substrate, allowing it to bind diverse ligands with a primary hydroxyl in the reactive position and based on a carbohydrate moiety.
- María Ángeles Márquez-Moñino
- , Raquel Ortega-García
- & Beatriz González
-
Article
| Open AccessAn alpha-helical lid guides the target DNA toward catalysis in CRISPR-Cas12a
CRISPR-Cas12a is a powerful RNA-guided genome-editing system. Saha et al. show that an alpha-helical lid plays the central role in guiding the target DNA toward the single RuvC nuclease domain, resulting in a double-stranded DNA break.
- Aakash Saha
- , Mohd Ahsan
- & Giulia Palermo
-
Article
| Open AccessDistinct functional constraints driving conservation of the cofilin N-terminal regulatory tail
Here the authors screen a saturation mutagenesis library of the disordered N-terminal tail of the actin severing protein cofilin. Their results reveal how a key phosphorylation site can balance competing sequence constraints on function and regulation.
- Joel A. Sexton
- , Tony Potchernikov
- & Benjamin E. Turk
-
Article
| Open AccessDNA binding redistributes activation domain ensemble and accessibility in pioneer factor Sox2
The function of transcription factors is conveyed through intrinsically disordered regions (IDRs) containing activation or repression domains, but the lack of quantitative structural ensemble models prevents their mechanistic decoding. Here, the authors use several methods to demonstrate that DNA binding can lead to complex changes in the IDR ensemble and accessibility on the example of the C-terminal IDR of pioneer factor Sox2.
- Sveinn Bjarnason
- , Jordan A. P. McIvor
- & Pétur O. Heidarsson
-
Article
| Open AccessAggregation of rhodopsin mutants in mouse models of autosomal dominant retinitis pigmentosa
Mutations in rhodopsin can cause the receptor to aggregate, however, it is unclear whether this molecular defect underlies the retinal degeneration in autosomal dominant retinitis pigmentosa. Here, the authors show the potential for rhodopsin aggregates to play a role in retinal degeneration.
- Sreelakshmi Vasudevan
- , Subhadip Senapati
- & Paul S.–H. Park
-
Article
| Open AccessSEL1L-HRD1 interaction is required to form a functional HRD1 ERAD complex
The importance of the SEL1L-HRD1 interaction in vivo was unclear. Here, authors reported that SEL1L-HRD1 interaction is required to form a functional HRD1 ERAD complex by recruiting the E2 enzyme UBE2J1 and DERLIN to HRD1.
- Liangguang Leo Lin
- , Huilun Helen Wang
- & Ling Qi
-
Article
| Open AccessReduced progranulin increases tau and α-synuclein inclusions and alters mouse tauopathy phenotypes via glucocerebrosidase
Neurodegenerative diseases often co-accumulate several disease-associated proteins. Here, the authors show that reduction of progranulin, a protein associated with TDP-43, also increases accumulation of tau and a-synuclein via glucocerebrosidase.
- Hideyuki Takahashi
- , Sanaea Bhagwagar
- & Stephen M. Strittmatter
-
Article
| Open AccessPro-ferroptotic signaling promotes arterial aging via vascular smooth muscle cell senescence
Ferroptosis is a novel form of regulated cell death associated with lipid oxidation. Here, the authors demonstrate that the proferroptosis signal is activated and drives vascular aging by inducing senescence in vascular smooth muscle cells.
- Di-Yang Sun
- , Wen-Bin Wu
- & Pei Wang
-
Article
| Open AccessComputational redesign of a hydrolase for nearly complete PET depolymerization at industrially relevant high-solids loading
The application of the LCC variant of polyethylene terephthalate (PET) hydrolase for industrial degradation of PET has been hindered by the 10% of nonbiodegradable PET. Here, the authors use a computational strategy to engineer TurboPETase which outperforms other PETase variants and achieves nearly complete depolymerization of the postconsumer PET bottles at a high, industrially relevant, level of solids loading.
- Yinglu Cui
- , Yanchun Chen
- & Bian Wu
-
Article
| Open AccessDynamics of activation in the voltage-sensing domain of Ciona intestinalis phosphatase Ci-VSP
Understanding the molecular basis of voltage-sensing is of great importance in biology. Here, the authors use computational analysis and simulations to reveal atomic level insights into the mechanism of an isolated voltage-sensing domain.
- Spencer C. Guo
- , Rong Shen
- & Aaron R. Dinner
-
Article
| Open AccessReconstitution of early paclitaxel biosynthetic network
Paclitaxel is an important anticancer drug whose biosynthetic pathway reconstruction is hindered by the propensity of heterologously expressed pathway cytochromes P450, including taxadiene 5α-hydroxylase (T5αH), to form multiple products. Here, the authors tune the promoter strength for T5αH expression in Nicotiana plants to increase the levels of paclitaxel precursor taxadien-5α-ol by three-fold and reconstitute the six step early biosynthetic pathway of paclitaxel.
- Jack Chun-Ting Liu
- , Ricardo De La Peña
- & Elizabeth S. Sattely
Browse broader subjects
Browse narrower subjects
- Biocatalysis
- Biogeochemistry
- Bioinorganic chemistry
- Biophysical chemistry
- Carbohydrates
- Chemical modification
- Cytokines
- DNA
- Enzyme mechanisms
- Enzymes
- Glycobiology
- Glycomics
- Histocytochemistry
- Hormones
- Immunochemistry
- Ion channels
- Isoenzymes
- Kinases
- Lipidomics
- Lipids
- Metabolomics
- Metals
- Neurochemistry
- Peptides
- Prions
- Proteases
- Protein folding
- Proteins
- Proteolysis
- Proteomics
- RNA
- Structural biology