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| 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
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Article
| Open AccessStructural basis for lysophosphatidylserine recognition by GPR34
GPR34 is a GPCR which has an immunomodulatory role and recognizes lysophosphatidylserine (LysoPS) as a putative endogenous ligand. Here, authors report two cryo-EM structures of human GPR34-Gi complex with one of two ligands bound: either the LysoPS analogue S3E-LysoPS, or its derivative M1.
- Tamaki Izume
- , Ryo Kawahara
- & Osamu Nureki
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Article
| Open AccessASPSCR1-TFE3 reprograms transcription by organizing enhancer loops around hexameric VCP/p97
VCP/p97 is identified as a co-factor to the fusion oncoprotein ASPSCR1::TFE3. They co-localize on chromatin, co-dependent for enhancer looping and transcriptional regulation in alveolar soft part sarcomas and Xp11- rearranged renal cell carcinomas.
- Amir Pozner
- , Li Li
- & Kevin B. Jones
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Article
| Open AccessCryo-EM structure of the extracellular domain of murine Thrombopoietin Receptor in complex with Thrombopoietin
The haematopoietic cytokine thrombopoietin (Tpo) is the primary regulator of megakaryocyte and platelet numbers. Here authors present a structural and biochemical characterization of how Tpo binds to its receptor to induce signaling.
- Kaiseal T. G. Sarson-Lawrence
- , Joshua M. Hardy
- & Nadia J. Kershaw
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Article
| Open AccessStructural basis for the oligomerization-facilitated NLRP3 activation
NLRP3 is a critical intracellular inflammasome sensor and an important clinical target against inflammation-driven human diseases. Here, the authors determined Cryo-EM structures of human NLRP3 in its closed and open states, elucidating the mechanism of NLRP3 inflammasome activation.
- Xiaodi Yu
- , Rosalie E. Matico
- & Sujata Sharma
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Article
| Open AccessThe host RNA polymerase II C-terminal domain is the anchor for replication of the influenza virus genome
The cellular RNA polymerase II C-terminal domain is known to support transcription of influenza virus mRNAs. Here, Krischuns et al. use cell-based and in vitro approaches to demonstrate that it also plays a role in replication of the viral genome.
- Tim Krischuns
- , Benoît Arragain
- & Nadia Naffakh
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Article
| Open AccessTransport mechanism of human bilirubin transporter ABCC2 tuned by the inter-module regulatory domain
Human ABC transporter ABCC2 transports conjugated bilirubin from hepatocyte to bile duct, dysfunction of which causes Dubin-Johnson syndrome. Here, the authors provide structural insights into the substrate specificity of ABCC2 and the transport mechanism regulated by the R domain.
- Yao-Xu Mao
- , Zhi-Peng Chen
- & Yuxing Chen
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Article
| Open AccessLocal structural preferences in shaping tau amyloid polymorphism
In this work, using a combination of Cryo-EM, in-cell experiments and biophysical analysis, the authors decoded the aggregation propensity of tau, revealing 5 central hot spots in its primary sequence and identify PAM4 as short segment that determines both the structure, as well as the cellular propagation of tau aggregates extracted from Alzheimer’s disease, corticobasal degeneration, and progressive supranuclear palsy patients.
- Nikolaos Louros
- , Martin Wilkinson
- & Joost Schymkowitz
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Article
| Open AccessMolecular-level architecture of Chlamydomonas reinhardtii’s glycoprotein-rich cell wall
Chlamydomonas reinhardtii produces a glycoprotein-rich cell wall. Using nuclear magnetic resonance and mass spectrometry approaches, this study reveals unprecedented details on its protein and carbohydrate content, and provide an atomic-level architecture model.
- Alexandre Poulhazan
- , Alexandre A. Arnold
- & Isabelle Marcotte
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Article
| Open AccessAsymmetric nucleosome PARylation at DNA breaks mediates directional nucleosome sliding by ALC1
Bacic et al. demonstrate that PARP1/HPF1 preferentially modify histone tails closest to the DNA break, directing ALC1-catalyzed nucleosome sliding. These findings suggest a mechanism for rendering DNA breaks more accessible to repair factors.
- Luka Bacic
- , Guillaume Gaullier
- & Sebastian Deindl
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| Open AccessA structural vista of phosducin-like PhLP2A-chaperonin TRiC cooperation during the ATP-driven folding cycle
Proper cellular proteostasis requires a network of the chaperonin TRiC/CCT with cochaperones prefoldin (PFD) and phosducin-like proteins (PhLPs) to facilitate the folding of essential eukaryotic proteins. Here, the authors characterized the ATP-driven cycle of TRiC-PFD-PhLP2A interaction using cryoEM and biochemical analyses.
- Junsun Park
- , Hyunmin Kim
- & Soung-Hun Roh
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Article
| Open AccessIdentification of potential aggregation hotspots on Aβ42 fibrils blocked by the anti-amyloid chaperone-like BRICHOS domain
This study identifies potential aggregation hotspots on the fibril surface of Alzheimer’s disease associated Aβ42 fibrils, which are blocked by the anti-amyloid chaperone-like domain BRICHOS.
- Rakesh Kumar
- , Tanguy Le Marchand
- & Axel Abelein
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Article
| Open AccessMolecular mechanisms underlying the BIRC6-mediated regulation of apoptosis and autophagy
The balance between apoptosis and autophagy is critical for normal development, proper tissue function, and disease pathogenesis. Here, the authors show previously unannotated BIRC6 domains, including a ubiquitin-like domain, and how it utilizes its ubiquitylation function to regulate both apoptosis and autophagy.
- Shuo-Shuo Liu
- , Tian-Xia Jiang
- & Xiao-Bo Qiu
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Article
| Open AccessStructural and biochemical insights into the mechanism of the Gabija bacterial immunity system
The Gabija system is a newly discovered bacterial immune system. Here, the authors report the EM structure of the Gabija complex at 3.6 Å. Here, the authors show that when invading phages depletes cellular NTP and dNTP, the nuclease activity of Gabija complex is activated and cleaves the circular DNA to prevent phage DNA replication.
- Yanwu Huo
- , Lingfei Kong
- & Taotao Wei
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Article
| Open AccessThe cryo-EM structure of homotetrameric attachment glycoprotein from langya henipavirus
In this work, the authors report the full-length structure of the attachment glycoprotein from Langya Henipavirus, which could enhance the understanding of emerging Henipavirus and provide important clues for vaccine development in the future.
- Yingying Guo
- , Songyue Wu
- & Renhong Yan
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Article
| Open AccessStructural and functional insights into the lipid regulation of human anion exchanger 2
Anion exchanger 2 (AE2), a widely expressed Cl- /HCO3 - exchanger, participates in the regulation of intracellular pH. Here, the authors present the structures of AE2 and uncover the regulatory mechanism of PIP2.
- Weiqi Zhang
- , Dian Ding
- & Yuxin Yin
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Article
| Open AccessAn extensive disulfide bond network prevents tail contraction in Agrobacterium tumefaciens phage Milano
Sonani et al. report the cryo-EM structures of the Milano phage tail, unraveling the mechanism of its flexible-to-rigid transformation, the inter-chain disulfide network hindering tail contraction and the structural organization of receptor binding proteins.
- Ravi R. Sonani
- , Lee K. Palmer
- & Edward H. Egelman
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Article
| Open Access2.7 Å cryo-EM structure of human telomerase H/ACA ribonucleoprotein
Here the authors captured the structure of human telomerase H/ACA ribonucleoprotein (RNP) by cryo-EM. The structure rationalizes telomere-disorder disease mutations and reveals insights into the mechanism of pseudouridylation by eukaryotic H/ACA RNPs.
- George E. Ghanim
- , Zala Sekne
- & Thi Hoang Duong Nguyen
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Article
| Open AccessMethionine aminopeptidase 2 and its autoproteolysis product have different binding sites on the ribosome
The role of methionine aminopeptidase 2 (MAP2) at the ribosome goes beyond N-terminal methionine excision. Klein et al. use cryo-EM to identify a second MAP2 binding site on the ribosome, and describe the dynamic interactions of MAP2 at the ribosome.
- Marius A. Klein
- , Klemens Wild
- & Irmgard Sinning
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Article
| Open AccessFolding pathway of a discontinuous two-domain protein
Here, using single molecule FRET, the unfolding and folding of a discontinuous two-domain protein was studied. The authors find that a dynamic, intermediate population entropically limits the rate of folding while the order of domain folding is kept in a slow-folding mutant.
- Ganesh Agam
- , Anders Barth
- & Don C. Lamb
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Article
| Open AccessStructure of the M. tuberculosis DnaK−GrpE complex reveals how key DnaK roles are controlled
Cryo-EM analysis reveals that the GrpE dimer of M. tuberculosis undergoes ratcheting motions when bound to an intact DnaK, thereby allosterically regulating DnaK’s nucleotide exchange and substrate release.
- Xiansha Xiao
- , Allison Fay
- & Huilin Li
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Article
| Open AccessCryo- EM structure of the mycobacterial 70S ribosome in complex with ribosome hibernation promotion factor RafH
Ribosome hibernation is a key survival strategy bacteria adapt under stress. Here, cryo- EM structure of mycobacterial 70S ribosome with hypoxia stress-induced factor RafH suggests the molecular mechanism of RafH-induced ribosome hibernation.
- Niraj Kumar
- , Shivani Sharma
- & Prem S. Kaushal
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Article
| Open AccessOrigin of the multi-phasic quenching dynamics in the BLUF domains across the species
Here the authors combine 19 F NMR and femtosecond transient absorption to characterise the structural origin of the multiphasic quenching dynamics in various species of BLUF domains, highlighting the importance of the heterogeneous active-site H-bond network.
- Yalin Zhou
- , Siwei Tang
- & Dongping Zhong
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Article
| Open AccessMolecular switching in transcription through splicing and proline-isomerization regulates stress responses in plants
Transcription factor DREB2A interacts with Med25 to regulate stress responses. Here, the authors show that DREB2A uses splicing and proline-isomerization for this regulation and that proline cis-trans switching introduces structural frustration facilitating regulator exchange.
- Frederik Friis Theisen
- , Andreas Prestel
- & Karen Skriver
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Article
| Open AccessStructural polymorphism of amyloid fibrils in ATTR amyloidosis revealed by cryo-electron microscopy
In this work, the authors report Cryo-EM imaging revealing diversity in amyloid fibril structures among ATTR patients with the same genetic mutation I84S. Further study is warranted to grasp the implications in ATTR amyloidosis pathology.
- Binh An Nguyen
- , Virender Singh
- & Lorena Saelices
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Article
| Open AccessSelective CK1α degraders exert antiproliferative activity against a broad range of human cancer cell lines
Here, the authors describe a potent and selective CK1a molecular glue degrader with a broad antiproliferative potency. Crystallographic data provide rationale for the high degradation efficacy displayed by this compound.
- Gisele Nishiguchi
- , Lauren G. Mascibroda
- & Zoran Rankovic
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Article
| Open AccessStructural differences between the closely related RNA helicases, UAP56 and URH49, fashion distinct functional apo-complexes
UAP56 is an important factor in the TREX complex, which is responsible for mRNA export. Here the authors show that the closely related RNA helicases, UAP56 and URH49, exhibit different three-dimensional structures due to one amino acid change. Accordingly, they form distinct apo-complexes and function in the nuclear export of specific target mRNAs.
- Ken-ichi Fujita
- , Misa Ito
- & Seiji Masuda
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Article
| Open AccessCryo-EM observation of the amyloid key structure of polymorphic TDP-43 amyloid fibrils
This study presents the cryo-EM structures of polymorphic TDP-43-derived amyloid fibrils that share a common fibril protein conformation constituting an amyloid key motif. The obtained results provide a possible mechanistic explanation for the formation of this motif in amyloid fibrils.
- Kartikay Sharma
- , Fabian Stockert
- & Marcus Fändrich
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Article
| Open AccessDisordered-to-ordered transitions in assembly factors allow the complex II catalytic subunit to switch binding partners
Here, the authors investigate the maturation of human respiratory Complex II, uncovering two metastable intermediates of maturation which suggest changes in intrinsic disorder ensure that the assembly steps occur in the correct sequence.
- Pankaj Sharma
- , Elena Maklashina
- & T. M. Iverson
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Article
| Open AccessLigand coupling mechanism of the human serotonin transporter differentiates substrates from inhibitors
The serotonin transporter, targeted by several medications, terminates neurotransmission by clearing serotonin from the synaptic cleft. Combining biochemical results with in silico data, the authors show the key interactions that initiate substrate transport.
- Ralph Gradisch
- , Katharina Schlögl
- & Thomas Stockner
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Article
| Open AccessCryo-EM structure and B-factor refinement with ensemble representation
Cryo-EM is the go-to method for visualizing large, flexible biomolecules. Here, authors introduce a new Gaussian mixture modelling method for cryo-EM modelling tasks, including refinement, composite map generation and ensemble representation.
- Joseph G. Beton
- , Thomas Mulvaney
- & Maya Topf
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Article
| Open AccessEpstein-Barr virus-driven B cell lymphoma mediated by a direct LMP1-TRAF6 complex
Epstein-Barr virus causes lymphoma. Here the authors describe a direct complex of the viral oncoprotein LMP1 with the cellular TRAF6 protein as a critical virus-host interface for lymphoma survival and validate this complex as a potential therapeutic target.
- Fabian Giehler
- , Michael S. Ostertag
- & Arnd Kieser
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Article
| Open AccessOvercoming resolution attenuation during tilted cryo-EM data collection
Here, the authors quantify the effect of cryo-EM data acquisition with stage-tilt on the global resolution of reconstructions and present a tool for predicting an optimal stage-tilt angle to ameliorate the effects of preferred specimen orientation.
- Sriram Aiyer
- , Philip R. Baldwin
- & Dmitry Lyumkis
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Article
| Open AccessDoa10/MARCH6 architecture interconnects E3 ligase activity with lipid-binding transmembrane channel to regulate SQLE
Transmembrane E3 ligases are crucial in cellular homeostasis and metabolic regulation. Here, the authors provide the structural details of the ER-resident E3 ligase MARCH6/Doa10, uncovering its unique circular membrane structure and its role in ubiquitylation processes, essential for protein quality control.
- J. Josephine Botsch
- , Roswitha Junker
- & Bastian Bräuning
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Article
| Open AccessMultiple redox switches of the SARS-CoV-2 main protease in vitro provide opportunities for drug design
Here the authors demonstrate that the SARS-CoV-2 main protease (Mpro) is subject to redox regulation in vitro, reversibly switching between the enzymatically active dimer and the functionally dormant monomer through redox modifications of cysteine residues.
- Lisa-Marie Funk
- , Gereon Poschmann
- & Kai Tittmann
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Article
| Open AccessMulti-scale structures of the mammalian radial spoke and divergence of axonemal complexes in ependymal cilia
Radial spokes (RS) are crucial in coordinating ciliary motility. Here, authors use cryo-EM and cryo-ET to gain insight into mammalian RS divergence in ependymal cilia, RS assembly mechanism and the structure-function relationships of ciliary and flagellar axonemes.
- Xueming Meng
- , Cong Xu
- & Yao Cong
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Article
| Open AccessConformational coupling of the sialic acid TRAP transporter HiSiaQM with its substrate binding protein HiSiaP
Tripartite ATP-independent periplasmic (TRAP) transporters use an extra substrate binding protein to transport a variety of substrates in bacteria and archaea. Here the authors use a disulfide engineering approach to lock the TRAP transporter HiSiaPQM from H. influenzae in different conformational states for characterisation.
- Martin F. Peter
- , Jan A. Ruland
- & Gregor Hagelueken
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Article
| Open AccessMechanism of anion exchange and small-molecule inhibition of pendrin
Here the authors report structures of pendrin, an anion exchanger, in complex with its substrate Cl−, I−, or HCO3−, which reveal two anion binding sites in each protomer. The authors also identify binding sites of a pendrin inhibitor, niflumic acid.
- Lie Wang
- , Anthony Hoang
- & Ming Zhou
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Article
| Open AccessTon motor conformational switch and peptidoglycan role in bacterial nutrient uptake
Gram-negative bacteria rely on the Ton system for nutrient uptake. Here, authors uncover how the ExbD protein acts as a conformational switch and the function of peptidoglycan in order to energize this transport process across the outer membrane.
- Maximilian Zinke
- , Maylis Lejeune
- & Nadia Izadi-Pruneyre
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Article
| Open AccessTail-tape-fused virion and non-virion RNA polymerases of a thermophilic virus with an extremely long tail
The authors describe the structure and function of two evolutionarily diverged RNA polymerases of a thermophilic phage. One of the polymerases is fused to the phage tape measure protein, a virion component dictating the length of the phage tail.
- Anastasiia Chaban
- , Leonid Minakhin
- & Maria L. Sokolova
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Article
| Open AccessCleavage-intermediate Lassa virus trimer elicits neutralizing responses, identifies neutralizing nanobodies, and reveals an apex-situated site-of-vulnerability
Gorman et al. designed a Lassa virus prefusion-stabilized soluble glycoprotein complex trimer (GPC), with which they identified a Lassa virus-neutralizing nanobody that bound the GPC apex and elicited neutralizing antibody responses in guinea pigs.
- Jason Gorman
- , Crystal Sao-Fong Cheung
- & Peter D. Kwong
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Article
| Open AccessHelical reconstruction of VP39 reveals principles for baculovirus nucleocapsid assembly
Baculoviruses are used as insecticides, gene therapy tools, and protein production vectors. Here, the authors report the structure of the Autographa californica MNPV nucleocapsid and its fold conservation across all baculoviruses.
- Friederike M. C. Benning
- , Simon Jenni
- & Luke H. Chao
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Article
| Open AccessPetascale pipeline for precise alignment of images from serial section electron microscopy
Segmentation accuracy of serial section electron microscopy (ssEM) images can be limited by the step of aligning 2D section images to create a 3D image stack. Here the authors report a computational pipeline for aligning ssEM images and apply this to a whole fly brain dataset.
- Sergiy Popovych
- , Thomas Macrina
- & H. Sebastian Seung
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Article
| Open AccessDiverse array of neutralizing antibodies elicited upon Spike Ferritin Nanoparticle vaccination in rhesus macaques
An adjuvanted SARS-CoV-2 spike-ferritin nanoparticle vaccine can elicit antibodies with relatively broad sarbecovirus activity in non-human primates. Here, the authors isolate and structurally characterize several monoclonal antibodies providing insights into the targeted epitopes and broad reactivity.
- Rajeshwer S. Sankhala
- , Kerri G. Lal
- & M. Gordon Joyce
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Article
| Open AccessMolecular mechanism of antihistamines recognition and regulation of the histamine H1 receptor
Histamine receptor H1R has been extensively targeted in the development of antihistamines. Here, Wang et al. determine structures of H1R alone and bound to different antihistamines, providing insights into the structure-based design of next-generation drugs.
- Dandan Wang
- , Qiong Guo
- & Yuyong Tao
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Article
| Open AccessStructural heterogeneity of the ion and lipid channel TMEM16F
TMEM16F is a transmembrane protein that facilitates passive phospholipid transbilayer movement and ion conduction across membranes. Here, authors reveal a structural heterogeneity which is possibly linked to TMEM16F unique dual function.
- Zhongjie Ye
- , Nicola Galvanetto
- & Arin Marchesi
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Article
| Open AccessCompetition between inside-out unfolding and pathogenic aggregation in an amyloid-forming β-propeller
Here, the relationship between unfolding and amyloid aggregation of glaucoma-associated myocilin is probed, showing that myocilin is not at equilibrium and pathogenic aggregation competes directly with unfolding.
- Emily G. Saccuzzo
- , Mubark D. Mebrat
- & Raquel L. Lieberman
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Article
| Open AccessLipid nanodisc scaffold and size alter the structure of a pentameric ligand-gated ion channel
The authors show that lipid nanodiscs of different scaffold type and size alter the structure of the pentameric ligand-gated ion channel, ELIC. The results suggest that nanodisc selection is an important consideration for structural studies of membrane proteins.
- Vikram Dalal
- , Mark J. Arcario
- & Wayland W. L. Cheng
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Article
| Open AccessAvapritinib-based SAR studies unveil a binding pocket in KIT and PDGFRA
Avapritinib, a potent inhibitor, offers hope for D842V-mutant GIST patients with high response rates; however, resistance and side effects remain challenges. Here, crystal structures shed light on this and reveal a Gα-pocket for drug development.
- A. Teuber
- , T. Schulz
- & D. Rauh