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Open Access
Featured
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News & Views |
Rules of selective condensation in cells
Liquid droplets form in cells to concentrate specific biomolecules (while excluding others) in order to perform specific functions. The molecular mechanisms that determine whether different macromolecules undergo co-partitioning or exclusion has so far remained elusive. Now, two studies uncover key principles underlying this selectivity.
- Michael Phillips
- & Kingshuk Ghosh
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Review Article |
Homogeneous multi-payload antibody–drug conjugates
Multi-payload antibody–drug conjugates (ADCs) are an emerging class of targeted therapeutics. Comprising a monoclonal antibody with multiple unique payloads attached, these constructs have the potential to produce synergistic anticancer effects with reduced therapeutic resistance. In this Review, methods for generating multi-payload ADCs are discussed, highlighting some key preclinical results.
- Toby Journeaux
- & Gonçalo J. L. Bernardes
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Article
| Open AccessMachine learning designs new GCGR/GLP-1R dual agonists with enhanced biological potency
Engineering new ligands that specifically target multiple G protein-coupled receptors with desired activity profiles requires time-consuming and expensive cycles of design-make-test-analyse work. Now it has been shown that limited experimental data can be used to train sophisticated machine learning models to accurately predict the activity of previously uncharacterized peptide ligand variants.
- Anna M. Puszkarska
- , Bruck Taddese
- & Lucy J. Colwell
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Article
| Open AccessStructural basis of the Meinwald rearrangement catalysed by styrene oxide isomerase
Understanding how membrane-bound styrene oxide isomerase (SOI) catalyses the Meinwald rearrangement—a Lewis-acid-catalysed isomerization of an epoxide to a carbonyl compound—can be useful as SOI represents a green alternative to chemical synthesis. Here, the catalytic mechanism of SOI was determined using cryo-EM, EPR spectroscopy, mutagenesis, functional assays and docking experiments.
- Basavraj Khanppnavar
- , Joel P. S. Choo
- & Xiaodan Li
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In Your Element |
Deciding the future of adipic acid
John Steele and Stephen Wallace discuss recent advances in the chemical and biotechnological synthesis of the prolific platform chemical adipic acid.
- John F. C. Steele
- & Stephen Wallace
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Article
| Open AccessSelection of a promiscuous minimalist cAMP phosphodiesterase from a library of de novo designed proteins
Evolution separates complex modern enzymes from their hypothetical simpler early ancestors, which raises the question of how unevolved sequences can develop new functions. Here a library of non-natural protein sequences was subjected to ultrahigh-throughput screens in microfluidic droplets, leading to the isolation of a phosphodiesterase enzyme capable of hydrolysing the biological second messenger, cyclic AMP.
- J. David Schnettler
- , Michael S. Wang
- & Michael H. Hecht
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News & Views |
Organic solvent enhances oxidative folding of disulfide-rich proteins
Natural protein folding takes place in aqueous cell environments. Now, it has been found that proteins in a water-free environment undergo faster and more efficient folding.
- Shay Laps
- & Norman Metanis
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Article |
Stereodivergent photobiocatalytic radical cyclization through the repurposing and directed evolution of fatty acid photodecarboxylases
Despite their intriguing photochemical activities, natural photoenzymes have not yet been repurposed for new-to-nature activities. Now, by leveraging the strongly oxidizing excited-state flavoquinone cofactor, fatty acid photodecarboxylases were engineered to catalyse unnatural decarboxylative radical cyclization with excellent chemo-, enantio- and diastereoselectivities.
- Shuyun Ju
- , Dian Li
- & Yang Yang
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Research Briefing |
Masked acid chlorides for proximity labelling of RNA
A non-radical proximity labelling platform — BAP-seq — is presented that uses subcellular-localized BS2 esterase to convert unreactive enol-based probes into highly reactive acid chlorides in situ to label nearby RNAs. When paired with click-handle-mediated enrichment and sequencing, this chemistry enables high-resolution spatial mapping of RNAs across subcellular compartments.
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Article |
Bioorthogonal masked acylating agents for proximity-dependent RNA labelling
RNA localization is key to regulating cellular function but is challenging to measure in an unbiased manner. Now a combination of enol-masked acylating probes with a bioorthogonal esterase to locally unmask them provides a non-radical RNA proximity labelling platform—termed BAP-seq—that enables the generation of high-resolution spatial maps of RNA.
- Shubhashree Pani
- , Tian Qiu
- & Bryan C. Dickinson
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In Your Element |
Call me serotonin
Serotonin is known by many names — in science as 5-hydroxytryptamine (5-HT) or enteramine, and in popular culture as the ‘feel good’ chemical or the ‘happy hormone’. Cameron Movassaghi and Anne Andrews discuss the knowns and unknowns of this well-studied yet elusive neurotransmitter.
- Cameron S. Movassaghi
- & Anne Milasincic Andrews
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Article |
Radiotherapy activates picolinium prodrugs in tumours
Photoinduced electron transfer (PET) occurs in many chemical processes and has various applications. Here ionizing radiation was used to trigger PET for controlled drug release from an antibody–drug conjugate using a picolinium cage. The radiotherapy-activated prodrug system demonstrated high antitumour efficacy and minimal side effects.
- Qunfeng Fu
- , Zhi Gu
- & Zhibo Liu
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Article |
Expanding the molecular language of protein liquid–liquid phase separation
Key molecular features that drive protein liquid–liquid phase separation (LLPS) for biomolecular condensate have been reported. A spectrum of additional interactions that influence protein LLPS and material properties have now been characterized. These interactions extend beyond a limited set of residue types and can be modulated by environmental factors such as temperature and salt concentration.
- Shiv Rekhi
- , Cristobal Garcia Garcia
- & Jeetain Mittal
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Article
| Open AccessDeciphering functional roles of protein succinylation and glutarylation using genetic code expansion
Negatively charged lysine acylations—malonylation, succinylation and glutarylation—impact protein structure and function, which can affect cellular processes. Now temporarily masked thioester derivatives of succinylation and glutarylation can be used for site-specific modification of diverse bacterial and mammalian proteins, which can facilitate the study of how these lysine modifications impact enzymatic activity and control protein–protein and protein–DNA interactions.
- Maria Weyh
- , Marie-Lena Jokisch
- & Kathrin Lang
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Article |
Non-modular fatty acid synthases yield distinct N-terminal acylation in ribosomal peptides
Ribosomally synthesized and post-translationally modified peptides (RiPPs) can have vast structural diversity and biological functions enabled by disparate post-translational modifications (PTMs). However, unconventional PTMs derived from non-RiPP biosynthesis are rarely reported. Now a class of lipopeptides featuring a distinct fatty-acyl-modified N terminus and the responsible RiPP/fatty-acid hybrid biosynthetic machinery have been characterized.
- Hengqian Ren
- , Chunshuai Huang
- & Huimin Zhao
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Research Briefing |
Identifying phase-separating biomolecular condensates in cells
We developed a high-throughput, unbiased strategy for the identification of endogenous biomolecular condensates by merging cell volume compression, sucrose density gradient centrifugation and quantitative mass spectrometry. We demonstrated the performance of this strategy by identifying both global condensate proteins and those responding to specific biological processes on a proteome-wide scale.
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Article |
High-throughput and proteome-wide discovery of endogenous biomolecular condensates
High-throughput proteome-wide methods for identifying endogenous proteins that phase separate or partition into condensates during certain physiological events are needed but remain a challenge. Now, a high-throughput, unbiased and quantitative strategy can identify endogenous biomolecular condensates and screen proteins involved in phase separation on a proteome-wide scale.
- Pengjie Li
- , Peng Chen
- & Yiwei Li
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Article
| Open AccessRNA modulates hnRNPA1A amyloid formation mediated by biomolecular condensates
The underlying mechanism for how heterotypic protein–RNA interactions modulate the liquid to amyloid transition of hnRNPA1A, a protein involved in amyotrophic lateral sclerosis, has so far remained elusive. Now characterization of hnRNPA1A condensate formation and aggregation in vitro reveals that the RNA/protein stoichiometry affects the molecular pathways leading to amyloid formation.
- Chiara Morelli
- , Lenka Faltova
- & Paolo Arosio
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Review Article |
Nanopore DNA sequencing technologies and their applications towards single-molecule proteomics
Nanopore label-free sequencing of DNA and RNA at the single-molecule level offers rapid readout, high accuracy, low cost and portability. This Review surveys technologies underpinning commercial and academic nanopore sequencing, and examines how underlying biochemical advances can fuel future developments in nanopore-based protein sequencing.
- Adam Dorey
- & Stefan Howorka
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News & Views |
ATP hydrolysis captured in atomic detail
Single-particle cryo-electron microscopy and all-atom molecular dynamics simulations provide atomic details of ATP hydrolysis in the multimeric enzyme p97.
- Nadia Elghobashi-Meinhardt
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Article |
Genetically encoded bioorthogonal tryptophan decaging in living cells
Developing a generalizable method for blocking and rescuing tryptophan (Trp) interactions would enable the gain-of-function manipulation of various Trp-containing proteins but has so far been challenging. Now a genetically encoded N1-vinyl-caged Trp capable of rapid and bioorthogonal decaging enables site-specific activation of Trp on a protein of interest within living cells.
- Yuchao Zhu
- , Wenlong Ding
- & Peng R. Chen
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Article
| Open AccessAsymmetric oligomerization state and sequence patterning can tune multiphase condensate miscibility
The biomolecular principles underlying the formation of multiphasic condensates have been difficult to elucidate owing to a paucity of tools, especially within living cells. In this work synthetic orthogonal protein scaffolds alongside molecular simulations are used to highlight how the oligomerization of disordered proteins can asymmetrically drive miscibility–immiscibility transitions.
- Ushnish Rana
- , Ke Xu
- & Clifford P. Brangwynne
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Article |
Diazobutanone-assisted isobaric labelling of phospholipids and sulfated glycolipids enables multiplexed quantitative lipidomics using tandem mass spectrometry
Lipidomics aims to uncover lipid functions in biological systems and disease. Quantifying lipids is challenging due to highly diverse chemical structures. Here a diazobutanone-assisted isobaric labelling method is developed that relies on diazobutanone and isobaric mass tags to target phosphate- and sulfate-containing lipids, enabling multiplexed lipidomic quantification in complex mixtures.
- Ting-Jia Gu
- , Peng-Kai Liu
- & Lingjun Li
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Article
| Open AccessA divergent intermediate strategy yields biologically diverse pseudo-natural products
Design strategies that possess both biological relevance and structural diversity may lead to compound collections that are enriched in diverse bioactivities. Now a diverse pseudo-natural product design principle has been established to efficiently explore biologically relevant chemical space. Through dearomatization reactions, a compound collection enriched in both structural and biological diversity was rapidly generated.
- Sukdev Bag
- , Jie Liu
- & Herbert Waldmann
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Research Briefing |
A protein-templated selection approach for the identification of full ligands from DNA-encoded libraries
A protein-templated selection approach has been developed for the discovery of full ligands from dual-pharmacophore DNA-encoded libraries by incorporating fragment linking into the selection process. The performance of this method was demonstrated with selections against protein–protein interaction and protein–DNA interaction targets, through which potent and selective inhibitors were identified.
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Article
| Open AccessCharacterizing ATP processing by the AAA+ protein p97 at the atomic level
The human ATP-hydrolysing enzyme p97 populates a metastable reaction intermediate, the ADP·Pi state, which is poised between hydrolysis and product release. Now, molecular motions at the active site in the temporal window immediately before and after ATP hydrolysis have been elucidated by merging cryo-EM, NMR spectroscopy and molecular dynamics simulations.
- Mikhail Shein
- , Manuel Hitzenberger
- & Anne K. Schütz
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Article |
Protein-templated ligand discovery via the selection of DNA-encoded dynamic libraries
Dual-pharmacophore DNA-encoded chemical libraries enable the identification of two synergistic binders for a biological target, but subsequent linking of this pair is required to obtain a full ligand, which can be challenging. Here we report a protein-templated selection of DNA-encoded dynamic library that can identify full ligands from fragment libraries without the need for subsequent fragment linking.
- Yu Zhou
- , Wenyin Shen
- & Xiaoyu Li
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Article |
Determinants that enable disordered protein assembly into discrete condensed phases
Cells spatially organize biochemical reactions within membrane-bound and membraneless compartments. The extent to which intrinsically disordered proteins themselves can form discrete compartments or condensed phases is poorly understood. Now a pair of model IDRs that display orthogonality in condensation and the chain features governing selective assembly have been identified.
- Rachel M. Welles
- , Kandarp A. Sojitra
- & Matthew C. Good
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News & Views |
Discovering cryptic natural products by substrate manipulation
Cryptic halogenation reactions result in natural products with diverse structural motifs and bioactivities. However, these halogenated species are difficult to detect with current analytical methods because the final products are often not halogenated. An approach to identify products of cryptic halogenation using halide depletion has now been discovered, opening up space for more effective natural product discovery.
- Ludek Sehnal
- , Libera Lo Presti
- & Nadine Ziemert
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Article |
Mirror-image trypsin digestion and sequencing of D-proteins
The lack of effective methods for mirror-image (d-) protein sequencing hampers the development of mirror-image biology systems and related applications. Now, total chemical synthesis of mirror-image trypsin enables the sequencing of long d-peptides and d-proteins, which may facilitate applications of d-peptides and d-proteins as potential therapeutic and informational tools.
- Guanwei Zhang
- & Ting F. Zhu
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Article
| Open AccessDirected ultrafast conformational changes accompany electron transfer in a photolyase as resolved by serial crystallography
Photoinduced electron transfer forms the basis for photosynthesis and DNA repair. Ultrafast structural changes recorded for a DNA-repairing photolyase now reveal specific and directed protein motions accompanying the electron transfer.
- Andrea Cellini
- , Madan Kumar Shankar
- & Sebastian Westenhoff
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Article
| Open AccessAccelerating the discovery of alkyl halide-derived natural products using halide depletion
Natural products discovery remains an ongoing challenge. Now, halide depletion offers a complementary approach to discover natural products whose biosynthesis requires halides, including products of cryptic halogenation. Halide depletion reveals that nostochlorosides, the products of an orphan biosynthetic gene cluster in Nostoc punctiforme, are polymerized by a halide-displacing etherifying enzyme.
- Nathaniel R. Glasser
- , Dongtao Cui
- & Emily P. Balskus
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News & Views |
How membranes influence intracellular phase separation
Liquid–liquid phase separation (LLPS) within cells is a captivating phenomenon known to aid the organization of cellular components; however, its complex kinetics have remained a puzzle. Now, a new study elucidates the crosstalk between the phase state of an encapsulating membrane and LLPS dynamics.
- Rumiana Dimova
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Thesis |
WT19F
Given the fraught history of fluorine, Michelle Francl wonders what made medicinal chemists consider fluorine derivatives?
- Michelle Francl
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Article |
Molecular jackhammers eradicate cancer cells by vibronic-driven action
In contrast to photothermal therapy requiring high powers over extended times and photodynamic therapy being abrogated by inhibitors of reactive oxygen species, actuation of vibronic modes in single molecules—molecular jackhammers—can now induce efficient cancer cell death. Here, the mechanical disassembly of cell membranes is characterized as the underlying mechanism by which this vibronic-driven action promotes necrotic cell death.
- Ciceron Ayala-Orozco
- , Diego Galvez-Aranda
- & James M. Tour
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News & Views |
Engineering cyanine cyclizations for new fluorogenic probes
As the need for specific fluorescent probes that enable high sensitivity and super-resolution imaging experiments continues to grow, it is imperative to develop new, well-characterized methods to modulate the emission of fluorophores. Now, a general platform affords visible-to-NIR fluorogenic fluorophores by engineering a simple cyclization event into cyanine dyes.
- Quintashia D. Wilson
- & Ellen M. Sletten
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Article |
Electrochemical labelling of hydroxyindoles with chemoselectivity for site-specific protein bioconjugation
Current electrochemical-based protein labelling methods suffer from limited site-selectivity and off-target reactivity owing to required radical/electrophilic reagents. Now an electrochemical strategy enables chemoselective labelling of proteins at a site-specifically incorporated 5-hydroxytryptophan residue using aromatic amines as coupling partners. This approach works on various proteins, including a full-length antibody, and is compatible with established click reactions.
- Conor Loynd
- , Soumya Jyoti Singha Roy
- & Abhishek Chatterjee
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Article |
Subdomain dynamics enable chemical chain reactions in non-ribosomal peptide synthetases
Many natural products are produced by non-ribosomal peptide synthetases in an assembly-line fashion. How these molecular machines orchestrate the biochemical sequences has remained elusive. It is now understood that an extended-conformation ensemble is needed to coordinate chemical-transformation steps whereas the biosynthesis directionality is driven by the enzyme’s innate conformational free energies.
- Xun Sun
- , Jonas Alfermann
- & Haw Yang
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Article
| Open AccessArtificial cell synthesis using biocatalytic polymerization-induced self-assembly
Enzyme-initiated polymerization-induced self-assembly has been used to generate various biomimetic structures. Now, myoglobin’s activity is used for biocatalytic polymerization-induced self-assembly to generate vesicular artificial cells. As various cargoes can be encapsulated during polymerization, these artificial cells are capable of protein expression and can act as microreactors for distinct enzymatic reactions.
- Andrea Belluati
- , Sètuhn Jimaja
- & Nico Bruns
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News & Views |
Using symmetry to drive new protein assemblies
Recent improvements in de novo protein design are likely to support a broad range of applications, but larger complexes will be easier to create if a building block approach is adopted. Now protein filaments with tunable geometry can be made using assemblies that have both cyclic and superhelical symmetries aligned along the same axis.
- Jeremy R. H. Tame
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Article
| Open AccessA general strategy to develop fluorogenic polymethine dyes for bioimaging
Polymethine dyes are bright and red-shifted fluorophores that lack an intrinsic turn-on mechanism, which leads to non-specific staining when applied to biological samples. Now the fluorescence of polymethine dyes was masked through an intracellular cyclization strategy that gets reversed upon binding an intended macromolecular target, providing specificity for live-cell imaging.
- Annabell Martin
- & Pablo Rivera-Fuentes
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Article
| Open AccessEnabling late-stage drug diversification by high-throughput experimentation with geometric deep learning
Late-stage functionalization of complex drug molecules is challenging. To address this problem, a discovery platform based on geometric deep learning and high-throughput experimentation was developed. The computational model predicts binary reaction outcome, reaction yield and regioselectivity with low error margins, enabling the functionalization of complex molecules without de novo synthesis.
- David F. Nippa
- , Kenneth Atz
- & Gisbert Schneider
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Research Briefing |
Phase-separation behaviour of RNAs
Ribonucleoprotein granules are ubiquitous in living organisms with the protein and RNA components having distinct roles. In the absence of proteins, RNAs are shown to undergo phase separation upon heating. This transition is driven by desolvation entropy and ion-mediated crosslinking and is tuned by the chemical specificity of the RNA nucleobases.
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Article |
Remote stereocontrol with azaarenes via enzymatic hydrogen atom transfer
The inherent rigidity of the azaarene ring structure has made it challenging to achieve remote stereocontrol through asymmetric catalysis on these substrates. Now, through a photoenzymatic process, an ene-reductase system facilitates the production of diverse azaarenes with distant γ-stereocentres, highlighting the potential of biocatalysts for stereoselectivity at remote sites.
- Maolin Li
- , Wesley Harrison
- & Huimin Zhao
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Research Briefing |
In vitro selection of covalent aptamers with sulfur(VI) fluoride exchange chemistry
To develop covalent inhibitors with high potency and low off-target effects, combinatorial approaches that search for candidates from large libraries are desired. Here, sulfur(VI) fluoride exchange (SuFEx) in vitro selection is established for the evolution of covalent aptamers from trillions of SuFEx-modified oligonucleotides. Through this technique, covalent aptamers with optimally balanced selectivity and reactivity are identified.
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Article |
RNAs undergo phase transitions with lower critical solution temperatures
The physicochemical driving forces of protein-free, RNA-driven phase transitions were previously unclear, but it is now shown that RNAs undergo entropically driven liquid–liquid phase separation upon heating in the presence of magnesium ions. In the condensed phase, RNAs can undergo an enthalpically favourable percolation transition that leads to arrested condensates.
- Gable M. Wadsworth
- , Walter J. Zahurancik
- & Priya R. Banerjee
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News & Views |
Ribozyme for stabilized SAM analogue modifies RNA in cells
Site-specific modification of RNA in cells is crucial for analysis and functional investigations. Natural enzymes that promote RNA methylation using S-adenosyl-l-methionine (SAM) exist, but leveraging these proteins for RNA modification is limited by cell permeability, stability and specificity of their substrates. Now, a de novo ribozyme that acts on a stabilized and cell-permeable SAM analogue enables site-specific RNA modification with a click handle in living cells.
- Nicolas V. Cornelissen
- & Andrea Rentmeister
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Article |
Heteromultivalency enables enhanced detection of nucleic acid mutations
Detecting genetic mutations, such as single nucleotide polymorphisms (SNPs), is essential for disease diagnostics but can be difficult using homomultivalent DNA hybridization-based approaches. Now, heteromultivalent hybridization is used to fine-tune binding specificity for the detection of one or two SNPs in a single target, enabling straightforward discrimination between adjacent and distant mutations and different viral strains.
- Brendan R. Deal
- , Rong Ma
- & Khalid Salaita
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Article
| Open AccessThe interface of condensates of the hnRNPA1 low-complexity domain promotes formation of amyloid fibrils
Understanding of the molecular mechanisms underlying the maturation of protein condensates into amyloid fibrils associated with neurodegenerative diseases has so far remained elusive. Now it has been shown that in condensates formed by the low-complexity domain of the amyotrophic lateral sclerosis-associated protein hnRNPA1, fibril formation is promoted at the interface, which provides a potential therapeutic target for counteracting aberrant protein aggregation.
- Miriam Linsenmeier
- , Lenka Faltova
- & Paolo Arosio
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