Featured
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Article
| Open AccessSubstrate recognition mechanism of the endoplasmic reticulum-associated ubiquitin ligase Doa10
Doa10/MARCHF6 is a conserved E3 ubiquitin ligase in the endoplasmic reticulum (ER) membrane in eukaryotes, but its molecular mechanism was unknown. The authors combine cryo-EM, computational and biochemical analyses to reveal how Doa10 recognizes its substrate proteins for ER-associated degradation.
- Kevin Wu
- , Samuel Itskanov
- & Eunyong Park
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Article
| Open AccessLipoarabinomannan mediates localized cell wall integrity during division in mycobacteria
Mycobacteria have a unique cell envelope that includes characteristic lipoglycans, such as lipoarabinomannan. Here, Sparks et al. show that this lipoglycan plays roles in maintenance of local cell envelope integrity and septal placement during cell division.
- Ian L. Sparks
- , Takehiro Kado
- & Yasu S. Morita
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Article
| Open AccessSimultaneous proteome localization and turnover analysis reveals spatiotemporal features of protein homeostasis disruptions
Protein function depends on their subcellular location and turnover rate. Here, the authors report a method to measure spatial and temporal proteome dynamics simultaneously, revealing compartment-specific protein turnover and translocation in cardiac cells under ER stress and carfilzomib treatment.
- Jordan Currie
- , Vyshnavi Manda
- & Edward Lau
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Article
| Open AccessAn organism-wide atlas of hormonal signaling based on the mouse lemur single-cell transcriptome
Endocrinologists have traditionally focused on studying one hormone or organ system at a time. Here the authors use transcriptomic data from the mouse lemur to globally characterize primate hormonal signaling, describing hormone sources and targets, identifying conserved and primate specific regulation, and elucidating principles of the network.
- Shixuan Liu
- , Camille Ezran
- & James E. Ferrell Jr.
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Article
| Open AccessAutomating data analysis for hydrogen/deuterium exchange mass spectrometry using data-independent acquisition methodology
Manual data mining for HDX-MS restricts the use of this biophysical technique to a small number of samples run by specialty labs. Enabled by data-independent acquisition methodology, the authors describe an approach that fully automates and standardizes the information extraction process, opening the door to new and challenging applications.
- Frantisek Filandr
- , Vladimir Sarpe
- & David C. Schriemer
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Article
| Open AccessAlphaPept: a modern and open framework for MS-based proteomics
Mass spectrometry-based proteomics faces the challenge of processing vast data amounts. Here, the authors introduce AlphaPept, an open-source, Python-based framework that offers high speed analysis and easy integration for large-scale proteome analysis.
- Maximilian T. Strauss
- , Isabell Bludau
- & Matthias Mann
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Article
| Open AccessFUS unveiled in mitochondrial DNA repair and targeted ligase-1 expression rescues repair-defects in FUS-linked motor neuron disease
Dysfunction of Fused in Sarcoma (FUS) leads to increased mitochondrial DNA (mtDNA) damage, mutations, and mitochondrial dysfunction. This study shows that FUS collaborates with mtDNA Ligase IIIα to maintain mtDNA repair and integrity.
- Manohar Kodavati
- , Haibo Wang
- & Muralidhar L. Hegde
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Article
| Open AccessA three-level regulatory mechanism of the aldo-keto reductase subfamily AKR12D
Here, the authors characterise an aldo-keto reductase AKRtyl, which belongs to a previously unidentified subfamily AKR12D. They uncover a complex mechanism of allosteric regulation that is mediated by 3 distinct states.
- Zhihong Xiao
- , Jinyin Zha
- & Shaobo Dai
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Article
| Open AccessDeficiency of ASGR1 promotes liver injury by increasing GP73-mediated hepatic endoplasmic reticulum stress
The genetic factors involved in liver injury remain largely unknown. Here, the authors show that ASGR1 deficiency induces liver injury by activating the GP73-mediated ER stress pathway, suggesting its role as a genetic determinant influencing susceptibility to liver injury.
- Zhe Zhang
- , Xiang Kai Leng
- & Jiang Wei Wu
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Article
| Open AccessViscosity-dependent control of protein synthesis and degradation
Xenopus egg extracts constitute a cell-like system for studying biochemical reactions. Here Chen and co-workers show that extract protein synthesis and degradation are differently affected by cytoplasmic concentration and viscosity.
- Yuping Chen
- , Jo-Hsi Huang
- & James E. Ferrell Jr.
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Article
| Open AccessStructural basis for self-discrimination by neoantigen-specific TCRs
Neoantigen-specific T cells recognise neoantigen-MHC complexes on target tumour cells. Here, the authors describe a molecular mechanism by which the neoantigen Hsf2 p.K72N is recognised by a corresponding high affinity Hsf2 p.K72N-reactive T cell receptor, 47BE7, from the mouse melanoma line B16F10.
- John P. Finnigan
- , Jenna H. Newman
- & Nina Bhardwaj
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Article
| Open AccessA Protein Misfolding Shaking Amplification-based method for the spontaneous generation of hundreds of bona fide prions
To study neurodegenerative prion diseases, a method (PMSA) for generating prions spontaneously is presented. Applied to 380+ different prion proteins, their tendency to become pathogenic was ranked, illuminating their formation process.
- Hasier Eraña
- , Cristina Sampedro-Torres-Quevedo
- & Joaquín Castilla
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Article
| Open AccessMachine learning predictor PSPire screens for phase-separating proteins lacking intrinsically disordered regions
Here the authors report a machine learning model, PSPire, which integrates both residue-level and structure-level features and outperforms tools in identifying phase-separating proteins lacking intrinsically disordered regions.
- Shuang Hou
- , Jiaojiao Hu
- & Yong Zhang
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Article
| Open AccessPMI-controlled mannose metabolism and glycosylation determines tissue tolerance and virus fitness
Glucose metabolism is crucial for cellular energy regulation and affects the immune response. Here the authors show that nutritional supplementation of mannose may be beneficial during virus infections by rewiring glucose metabolic dysregulation and alleviating inflammatory tissue damage.
- Ronghui Liang
- , Zi-Wei Ye
- & Shuofeng Yuan
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Article
| Open AccessBioengineered amyloid peptide for rapid screening of inhibitors against main protease of SARS-CoV-2
The main protease (Mpro) plays a crucial role in the replication of SARS-CoV-2, thereby making it an attractive target for COVID-19 treatment. Here, the authors develop a colorimetric screening platform for discovering Mpro inhibitors using engineered amyloid peptide-based nanocomplexes.
- Dongtak Lee
- , Hyo Gi Jung
- & Dae Sung Yoon
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Article
| Open AccessChloride intracellular channel (CLIC) proteins function as fusogens
The Chloride Intracellular Channel (CLIC) protein family is highly conserved, yet their function remains a matter of ongoing research. Here, authors reveal their ability to facilitate membrane fusion, shedding light on their physiological role.
- Bar Manori
- , Alisa Vaknin
- & Yoni Haitin
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Article
| Open AccessPla2g12b drives expansion of triglyceride-rich lipoproteins
Thierer and colleagues identify PLA2G12B as a key gene driving triglyceride incorporation into lipoproteins and show that disruption of this activity provides protection from atherosclerosis.
- James H. Thierer
- , Ombretta Foresti
- & Steven A. Farber
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Article
| Open AccessProTInSeq: transposon insertion tracking by ultra-deep DNA sequencing to identify translated large and small ORFs
Identifying small proteins is challenging. ProTInSeq uses modified transposons to express markers inserted in-frame to protein-coding genes. This method identifies 153 unannotated small proteins in M. pneumoniae and additional proteomic information.
- Samuel Miravet-Verde
- , Rocco Mazzolini
- & Luis Serrano
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Article
| Open AccessDimerization-dependent serine protease activity of FAM111A prevents replication fork stalling at topoisomerase 1 cleavage complexes
FAM111A is a serine protease important for DNA replication and antiviral defense. Here, the authors report that the FAM111A dimerization is crucial for its proteolytic activity and for promoting DNA replication at trapped topoisomerase I.
- Sowmiya Palani
- , Yuka Machida
- & Yuichi J. Machida
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Article
| Open AccessRNA compaction and iterative scanning for small RNA targets by the Hfq chaperone
Small RNAs (sRNAs) turn bacterial genes on or off by base pairing with mRNAs. Here the authors employ single molecule fluorescence to show how sRNAs and their chaperone Hfq quickly locate the proper target by repeatedly scanning an mRNA until a stable match is found.
- Ewelina M. Małecka
- & Sarah A. Woodson
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Article
| Open AccessAn artificial protein modulator reprogramming neuronal protein functions
Direct modulation of protein by artificial catalysts as enzyme mimetics remains hindered by the lack of highly efficient catalytic centers. Here, the authors present the development of artificial protein modulators (APROMs) with protein phosphatase-like characteristics, catalytically reprogram the biological function of α-synuclein.
- Peihua Lin
- , Bo Zhang
- & Daishun Ling
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Article
| Open AccessMicrotubule damage shapes the acetylation gradient
Microtubules are acetylated on the inside of their hollow lumen, a modification linked to their lifespan. Here, the authors show that damage holes act as entry points for a deacetylase to access the lumen, thereby locally counteracting acetylation.
- Mireia Andreu-Carbó
- , Cornelia Egoldt
- & Charlotte Aumeier
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Article
| Open AccessCryo-EM structures reveal how phosphate release from Arp3 weakens actin filament branches formed by Arp2/3 complex
Arp2/3 complex forms branched actin filaments for cell movements. Here, the authors report cryo-EM structures of branch junctions with ADP or ADPBeFx (to mimic γ-phosphate) bound to Arp3 to explain why γ-phosphate dissociation destabilizes branches.
- Sai Shashank Chavali
- , Steven Z. Chou
- & Charles V. Sindelar
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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