Featured
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| 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 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 AccessDeepETPicker: Fast and accurate 3D particle picking for cryo-electron tomography using weakly supervised deep learning
Picking particles of biological macromolecules is critical for solving their structures in situ using cryo-electron tomograms. Here, authors develop DeepETPicker, a deep learning-based tool for fast, accurate, and automated picking of three-dimensional particles.
- Guole Liu
- , Tongxin Niu
- & Ge Yang
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Article
| Open AccessStructural insights into IL-11-mediated signalling and human IL6ST variant-associated immunodeficiency
IL-11 and IL-6 signal by binding gp130. Here, Gardner et al. use cryoEM to discover how IL-11 engages gp130 and co-receptor IL-11Rα. Together with MD simulations, they provide insight into gp130 mutations that cause human immunodeficiencies.
- Scott Gardner
- , Yibo Jin
- & Doryen Bubeck
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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 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 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 AccessIn-cell NMR suggests that DNA i-motif levels are strongly depleted in living human cells
I-Motifs (iM) are non-canonical DNA structures potentially forming in the accessible, single stranded, cytosine-rich genomic region, but the specific contributions of several factors involved in their formation are unknown. Using in-cell NMR, the authors examined DNA i-motif formation in human cells at body temperature, suggesting i-M occur in a small portion (<1%) of genomic sites predisposed to its formation.
- Pavlína Víšková
- , Eva Ištvánková
- & Lukáš Trantírek
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Article
| Open AccessMolecular basis of TMPRSS2 recognition by Paeniclostridium sordellii hemorrhagic toxin
Paeniclostridium sordellii hemorrhagic toxin (TcsH) targets TMPRSS2 to enter the host cells. Here, authors showed the cryo-EM structures of the TcsH-TMPRSS2 complex, providing a toxin-receptor interaction model for large clostridial toxins.
- Ruoyu Zhou
- , Liuqing He
- & Liang Tao
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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 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 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 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 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 AccessToxoplasma gondii actin filaments are tuned for rapid disassembly and turnover
Actin is critical to the survival of the parasite Toxoplasma gondii. In this study, Hvorecny and Sladewski et al. show that T. gondii actin forms intrinsically dynamic filaments in vitro due to differences in assembly contacts in the D-loop.
- Kelli L. Hvorecny
- , Thomas E. Sladewski
- & Aoife T. Heaslip
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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 AccessAn anti-CRISPR that represses its own transcription while blocking Cas9-target DNA binding
Anti-CRISPR proteins can help to evade bacterial immunity. Here, the authors elucidate the mechanism of AcrIIA15, which inhibits CRISPR-Cas9 system and also functions as a transcriptional repressor of itself as a fusion protein.
- Xieshuting Deng
- , Wei Sun
- & Yanli Wang
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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 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 AccessTransient disome complex formation in native polysomes during ongoing protein synthesis captured by cryo-EM
Direct visualization of short-lived intermediates during active protein synthesis remains challenging. Here, the authors structurally capture transient translation intermediates to uncover temporary disome formation during ribosome collisions.
- Timo Flügel
- , Magdalena Schacherl
- & Christian M. T. Spahn
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Article
| Open AccessA streamlined approach to structure elucidation using in cellulo crystallized recombinant proteins, InCellCryst
SX experiments require thousands of high-quality microcrystals. Here, authors present a pipeline for protein crystallization in insect cells, including compartment screening and identification of physiological ligands from data collection in cellulo.
- Robert Schönherr
- , Juliane Boger
- & Lars Redecke
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Article
| Open AccessBacteria employ lysine acetylation of transcriptional regulators to adapt gene expression to cellular metabolism
The mechanisms underlying adaptation of bacteria to changing environmental conditions remain poorly understood. Here, the authors show bacteria using lysine acetylation of transcriptional regulators to adjust gene expression to changing conditions.
- Magdalena Kremer
- , Sabrina Schulze
- & Michael Lammers
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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
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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
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Article
| Open AccessStructure of the recombinant RNA polymerase from African Swine Fever Virus
Pilotto and colleagues produce recombinant and catalytically active RNA polymerase (RNAP) from African Swine Fever Virus. Cryo-EM structures of RNAP with closed and open clamp conformations are presented along with in vitro transcription assays, yielding distinct functional conclusions.
- Simona Pilotto
- , Michal Sýkora
- & Finn Werner
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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
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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
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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
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Article
| Open AccessCyclic peptides discriminate BCL-2 and its clinical mutants from BCL-XL by engaging a single-residue discrepancy
Pro-survival B-cell lymphoma-2 (BCL-2) family proteins BCL-2 and BCL-XL are the targets of anti-tumour drugs, but resistance is emerging. The authors present cyclic peptides against BCL-2 and BCL-XL, with a distinct mechanism of targeting characterised.
- Fengwei Li
- , Junjie Liu
- & Dalei Wu
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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
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Article
| Open AccessUltrastructure of macromolecular assemblies contributing to bacterial spore resistance revealed by in situ cryo-electron tomography
Bacterial endospores are among the most resilient forms of life. Here, authors reveal ultrastructural details of the spore chromosome and the multiprotein, multilayered extracellular coat, shedding light on mechanisms contributing to spore resistance.
- Elda Bauda
- , Benoit Gallet
- & Cecile Morlot
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Article
| Open AccessCryo-EM structures of lipidic fibrils of amyloid-β (1-40)
Alzheimer’s plaques contain a high amount of Aβ fibrils and a high concentration of lipids. The authors determined structures of Aβ40 fibrils grown in the presence of lipids, revealing high-resolution details of potentially disease-relevant fibril-lipid interactions.
- Benedikt Frieg
- , Mookyoung Han
- & Gunnar F. Schröder
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Article
| Open AccessStructural basis for regulated assembly of the mitochondrial fission GTPase Drp1
Structural and functional studies highlight the molecular regulation of assembling the mitochondrial division machinery. The core unit is closed, and specific interactions open this unit to facilitate assembly at the right place and time in cells.
- Kristy Rochon
- , Brianna L. Bauer
- & Jason A. Mears
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Article
| Open AccessStructural and mechanistic characterization of bifunctional heparan sulfate N-deacetylase-N-sulfotransferase 1
Heparan sulfate biosynthesis is a complex process involving multiple reactions that extend and modify the polysaccharide. Here, the authors resolve structures of NDST1, responsible for the critical N-sulfoglucosamine modification of heparan sulfate.
- Courtney J. Mycroft-West
- , Sahar Abdelkarim
- & Liang Wu
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Article
| Open AccessBinding kinetics drive G protein subtype selectivity at the β1-adrenergic receptor
The authors show G protein subtype selectivity at the β1-adrenergic receptor is driven by the binding kinetics of ternary complex formation. Bound to G protein, the receptor adopts conformations that differ from its agonist-bound solution states.
- Andrew J. Y. Jones
- , Thomas H. Harman
- & Daniel Nietlispach
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Article
| Open AccessA general computational design strategy for stabilizing viral class I fusion proteins
The authors present a generalisable computational approach to stabilize class I fusion proteins in the prefusion state. The method was used to stabilize the fusion proteins of RSV, hMPV, and SARS-CoV-2 viruses, with the designs structurally validated and RSV F protein assessed in a neutralization assay.
- Karen J. Gonzalez
- , Jiachen Huang
- & Eva-Maria Strauch
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Article
| Open AccessA distinctive family of L,D-transpeptidases catalyzing L-Ala-mDAP crosslinks in Alpha- and Betaproteobacteria
The cell-wall peptidoglycan in model bacteria typically includes 4,3- and 3,3-crosslinks, catalysed by DD- and LD-transpeptidases, respectively. Here, the authors identify and characterise the activity and structure of an LD-transpeptidase that generates a new type of crosslink (1,3).
- Akbar Espaillat
- , Laura Alvarez
- & Felipe Cava
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Article
| Open AccessLiquid crystalline inverted lipid phases encapsulating siRNA enhance lipid nanoparticle mediated transfection
The authors display the bottom-up design, assembly, and in-depth characterization of defined lipid-RNA structures in the core of lipid nanoparticles. The inverted structures are thermostable and provide better transfection over lamellar structures.
- Roy Pattipeiluhu
- , Ye Zeng
- & Thomas H. Sharp
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Article
| Open AccessIn situ structure of actin remodeling during glucose-stimulated insulin secretion using cryo-electron tomography
Actin mediates insulin secretion in pancreatic β-cells through remodeling. Here, authors report the in situ structure of actin remodeling and quantify changes in architecture, alignment, and interactions during glucose-stimulated insulin secretion.
- Weimin Li
- , Angdi Li
- & Liping Sun
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Article
| Open AccessPoly-γ-glutamylation of biomolecules
Poly-γ-glutamate tails are a distinctive feature of folate and F420 cofactors, but it was unclear how these tails elongate while maintaining substrate specificity. Here, the authors discover that folylpolyglutamate synthase and γ-glutamyl ligase enzymes add successive L-glutamates to the termini of the growing γ-glutamyl chain in a processive mechanism.
- Ghader Bashiri
- , Esther M. M. Bulloch
- & Christopher J. Squire
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Article
| Open AccessDisordered regions in proteusin peptides guide post-translational modification by a flavin-dependent RiPP brominase
Here the authors use NMR, SAXS and MD simulations to characterise the structure of proteusin peptides, which are atypically long RiPP substrates. They show a small, unstructured region in the proteusin leader is sufficient for its interaction with a halogenase that brominates the terminal tryptophan residue.
- Nguyet A. Nguyen
- , F. N. U. Vidya
- & Vinayak Agarwal
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Article
| Open AccessThe acidic intrinsically disordered region of the inflammatory mediator HMGB1 mediates fuzzy interactions with CXCL12
Here, the authors utilise an integrative approach to characterise the fuzzy heterocomplex between CXCL12 and the fully reduced alarmin HMGB1, highlighting the importance of HMGB1’s acidic IDR to the interaction and with cell surface CXCR4.
- Malisa Vittoria Mantonico
- , Federica De Leo
- & Giovanna Musco
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Article
| Open AccessAutoinhibition and activation of myosin VI revealed by its cryo-EM structure
This study reveals the high-resolution cryo-EM structure of autoinhibited myosin VI, offering insights into cargo-mediated activation of this unique myosin motor and advancing our understanding of motor activity control in the myosin superfamily.
- Fengfeng Niu
- , Lingxuan Li
- & Zhiyi Wei
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Article
| Open AccessVirological characteristics of the SARS-CoV-2 Omicron XBB.1.5 variant
XBB.1.5 of SARS-CoV-2 is a descendant of XBB.1 and has mutations in spike and ORF8, making it more infectious to humans. Here, the authors examined in detail the differences in virological properties of the two variants.
- Tomokazu Tamura
- , Takashi Irie
- & Takasuke Fukuhara
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Article
| Open AccessMolecular basis of SAP05-mediated ubiquitin-independent proteasomal degradation of transcription factors
SAP05, a secreted effector of the obligate parasitic bacteria phytoplasma, bridges host SPL and GATA transcription factors (TFs) to the 26 S proteasome subunit RPN10 for ubiquitination-independent degradation. Here, the authors report the details on how SAP05 interacts with SPL5, GATA18 and RPN10.
- Xiaojie Yan
- , Xinxin Yuan
- & Cheng Dong