Article
Multidisciplinary Sciences
Jingyuan Cong, Xiaoying Feng, Huiling Kang, Wangjun Fu, Lei Wang, Chenlong Wang, Xuemei Li, Yutao Chen, Zihe Rao
Summary: This study investigates the structure-function relationship of the L-P complex of Newcastle disease virus (NDV) using cryo-EM and enzymatic assays. The research reveals distinct conformations and interactions between L and P proteins, advancing our understanding of Paramyxoviridae RNA synthesis and providing potential therapeutic targets.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Stefania Dispinseri, Massimiliano Secchi, Maria Franca Pirillo, Monica Tolazzi, Martina Borghi, Cristina Brigatti, Maria Laura De Angelis, Marco Baratella, Elena Bazzigaluppi, Giulietta Venturi, Francesca Sironi, Andrea Canitano, Ilaria Marzinotto, Cristina Tresoldi, Fabio Ciceri, Lorenzo Piemonti, Donatella Negri, Andrea Cara, Vito Lampasona, Gabriella Scarlatti
Summary: The study reveals that antibody responses to SARS-CoV-2 spike protein play a significant role in neutralization and protection against severe COVID-19, unaffected by heterologous boosting or common cold immunity, and can last for up to 8 months.
NATURE COMMUNICATIONS
(2021)
Article
Immunology
Daisy A. Hoagland, Rasmus Moller, Skyler A. Uhl, Kohei Oishi, Justin Frere, Ilona Golynker, Shu Horiuchi, Maryline Panis, Daniel Blanco-Melo, David Sachs, Knarik Arkun, Jean K. Lim, Benjamin R. tenOever
Summary: This study investigated the systemic response to SARS-CoV-2 infection in hamsters and found that inflammation was present in all tissues but not enough to prevent disease progression. Bolstering the antiviral response with intranasal administration of recombinant IFN-I reduced viral disease, prevented transmission, and lowered inflammation in vivo. This suggests that intranasal IFN-I could be an effective early treatment for SARS-CoV-2 infection.
Article
Multidisciplinary Sciences
Julien Sourimant, Carolin M. Lieber, Jeong-Joong Yoon, Mart Toots, Mugunthan Govindarajan, Venkata Udumula, Kaori Sakamoto, Michael G. Natchus, Joseph Patti, John Vernachio, Richard K. Plemper
Summary: Respiratory syncytial virus (RSV) is a major cause of lower respiratory infections in infants and the immuno-compromised. A study has identified a compound called AVG that can inhibit RSV RNA synthesis, potentially providing a therapeutic solution for RSV disease.
Article
Biology
Aayush Gupta, Souvik Dey, Alan Hicks, Huan-Xiang Zhou
Summary: This study developed generative autoencoders that can learn from short molecular dynamics simulations and generate full conformational ensembles of intrinsically disordered proteins.
COMMUNICATIONS BIOLOGY
(2022)
Article
Biology
Shih-Hui Chiu, Wen-Lin Ho, Yung-Chen Sun, Jean-Cheng Kuo, Jie-rong Huang
Summary: The intrinsically disordered regions (IDRs) among paralogs have different physicochemical properties but converge on the same biophysical function. The diversity of IDRs can lead to different traits, but they ultimately evolve to achieve a converged function.
COMMUNICATIONS BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Xi Wang, Harry M. Greenblatt, Lavi S. Bigman, Binhan Yu, Channing C. Pletka, Yaakov Levy, Junji Iwahara
Summary: This study investigates how D/E repeats cause autoinhibition of HMGB1 and its specific binding to cisplatin-modified DNA. By varying ionic strength, the conformational equilibrium between autoinhibited and uninhibited states can be shifted, revealing fuzzy interactions of D/E repeats with other intrinsically disordered regions. Mutations mimicking post-translational modifications relevant to nuclear export of HMGB1 can moderately modulate DNA-binding affinity, possibly by impacting the autoinhibition.
JOURNAL OF MOLECULAR BIOLOGY
(2021)
Article
Immunology
Delphine C. Malherbe, Drishya Kurup, Christoph Wirblich, Adam J. Ronk, Chad Mire, Natalia Kuzmina, Noor Shaik, Sivakumar Periasamy, Matthew A. Hyde, Julie M. Williams, Pei-Yong Shi, Matthias J. Schnell, Alexander Bukreyev
Summary: The study developed a SARS-CoV-2 ConVac vaccine which, through animal experiments, showed that a single dose of the vaccine could rapidly control viral replication after disease challenge, protecting animals from weight loss and lung virus replication, with some inflammation still detected.
Article
Biochemistry & Molecular Biology
Christopher M. Furman, Ting-Yi Wang, Qiuye Zhao, Kumar Yugandhar, Haiyuan Yu, Eric Alani
Summary: This study demonstrated that dynamic and coordinated rearrangements of the MLH IDRs regulate the function of the MLH complex positively and negatively in MMR.
NUCLEIC ACIDS RESEARCH
(2021)
Article
Biology
Raghavendar R. Sanganna Gari, Grigory Tagiltsev, Ruth A. Pumroy, Yining Jiang, Martin Blackledge, Vera Y. Moiseenkova-Bell, Simon Scheuring
Summary: This study used high-speed atomic force microscopy to image TRPV2 channels in membranes and found that the N-terminal intrinsically disordered regions (IDRs) were involved in intermolecular interactions. The results provide evidence about the 'structure' of TRPV2 IDRs and suggest their potential role in mediating protein-protein interactions.
COMMUNICATIONS BIOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Stephan J. Sigrist, Volker Haucke
Summary: Membrane compartmentalization is important for controlling cellular physiology, and it involves the exchange of material through vesicles and membrane contact sites. This process is mediated by proteins with intrinsically disordered regions, and dysfunction of these proteins can lead to disease.
Article
Multidisciplinary Sciences
Gil Koren, Sagi Meir, Lennard Holschuh, Haydyn D. T. Mertens, Tamara Ehm, Nadav Yahalom, Adina Golombek, Tal Schwartz, Dmitri I. Svergun, Omar A. Saleh, Joachim Dzubiella, Roy Beck
Summary: Short-range interactions and long-range contacts drive the folding of proteins. The structure of proteins directly affects their biological function. Nearly 40% of eukaryotes proteome is composed of intrinsically disordered proteins (IDPs) and protein regions that fluctuate between ensembles of numerous conformations. Polymer physics can, to some level, relate the IDP's sequence to its ensemble conformations, but long-range contacts between distant amino acids play a crucial role in determining intramolecular structures.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Biochemistry & Molecular Biology
Samuel R. Witus, Lisa M. Tuttle, Wenjing Li, Alex Zelter, Meiling Wang, Klaiten E. Kermoade, Damien B. Wilburn, Trisha N. Davis, Peter S. Brzovic, Weixing Zhao, Rachel E. Klevit
Summary: BRCA1/BARD1 is a tumor suppressor gene with functions in DNA damage repair and transcriptional regulation. It interacts with nucleosomes and facilitates ubiquitylation of histone H2A. Our study reveals novel interactions involving an intrinsically disordered DNA-binding region of BARD1 that support H2A ubiquitylation and recruitment to chromatin and DNA damage sites. These interactions contribute to cell survival and identify a network of BARD1-nucleosome interactions on chromatin.
Article
Biochemical Research Methods
Balint Meszaros, Andras Hatos, Nicolas Palopoli, Federica Quaglia, Edoardo Salladini, Kim Van Roey, Haribabu Arthanari, Zsuzsanna Dosztanyi, Isabella C. Felli, Patrick D. Fischer, Jeffrey C. Hoch, Cy M. Jeffries, Sonia Longhi, Emiliano Maiani, Sandra Orchard, Rita Pancsa, Elena Papaleo, Roberta Pierattelli, Damiano Piovesan, Iva Pritisanac, Luiggi Tenorio, Thibault Viennet, Peter Tompa, Wim Vranken, Silvio C. E. Tosatto, Norman E. Davey
Summary: This Perspective introduces the Minimum Information About Disorder Experiments guidelines, which provide a community consensus on the minimum information required to appropriately describe metadata on experimentally and computationally derived structural state(s) of intrinsically disordered proteins or regions. An unambiguous description of an experiment, and the subsequent biological observation, is vital for accurate data interpretation.
Review
Chemistry, Multidisciplinary
Matti Mar, Kateryna Nitsenko, Petur O. Heidarsson
Summary: Eukaryotic transcription factors play a crucial role in integrating molecular feedback and regulating gene expression. They consist of structured DNA-binding domains and long intrinsically disordered regions (IDRs). The dynamic multifunctionality of IDRs is essential for their functions in genome regulation. This review analyzes the chemical features of TF IDRs and their involvement in protein interactions, DNA binding, chromatin opening, and phase separation. Suggestions are given for future research to integrate experiments and simulations in understanding TF functions.
CHEMISTRY-A EUROPEAN JOURNAL
(2023)
Article
Multidisciplinary Sciences
Laura Marino Perez, Francesco S. Ielasi, Luiza M. Bessa, Damien Maurin, Jaka Kragelj, Martin Blackledge, Nicola Salvi, Guillaume Bouvignies, Andres Palencia, Malene Ringkjobing Jensen
Summary: This study uncovers the structural rearrangements that occur during ring flipping of a buried tyrosine residue. The results provide insights into protein breathing motions associated with ring flipping and have implications for protein design and structure prediction.
Article
Multidisciplinary Sciences
Luiza Mamigonian Bessa, Serafima Guseva, Aldo R. Camacho-Zarco, Nicola Salvi, Damien Maurin, Laura Marino Perez, Maiia Botova, Anas Malki, Max Nanao, Malene Ringkjobing Jensen, Rob W. H. Ruigrok, Martin Blackledge
Summary: The genome replication and transcription processes of SARS-CoV-2 are important targets for inhibiting the virus. The interaction between the nucleoprotein (N) and the amino-terminal ubiquitin-like domain of nsp3 (Ubl1), which is a cofactor of the replication-transcription complex, has been described at the atomic level. This interaction involves two linear motifs in the linker domain of N, which fold N around Ubl1 to regulate binding to RNA. The identification of these motifs provides future targets for developing innovative strategies against COVID-19.
Review
Chemistry, Multidisciplinary
Aldo R. Camacho-Zarco, Vincent Schnapka, Serafima Guseva, Anton Abyzov, Wiktor Adamski, Sigrid Milles, Malene Ringkjobing Jensen, Lukas Zidek, Nicola Salvi, Martin Blackledge
Summary: This review introduces the applications of nuclear magnetic resonance (NMR) in understanding the structure, dynamic behavior, and interaction trajectories of intrinsically disordered proteins. NMR provides ensemble averaged structural and dynamic parameters for each assigned resonance, revealing the importance of these parameters in the kinetics and thermodynamics of cellular and extracellular reactions. Furthermore, NMR can uncover the mechanistic basis of functional disordered molecular assemblies that are crucial for human health.
Article
Biochemistry & Molecular Biology
Jean-Marie Bourhis, Filip Yabukarski, Guillaume Communie, Robert Schneider, Valentina A. Volchkova, Mickael Freneat, Francine C. Gerard, Corinne Ducournau, Caroline Mas, Nicolas Tarbouriech, Malene Ringkjobing Jensen, Viktor E. Volchkov, Martin Blackledge, Marc Jamin
Summary: The study investigated the interactions between the phosphoprotein (P) and the nucleoprotein (N) in the Paramyxoviridae's transcription/replication complex. The structural properties of the C-terminal X domain (P-XD) of Nipah (NiV) and Hendra virus (HeV) P protein were characterized. The experiments demonstrated that NiV P-XD adopted different conformations in solution, formed dimers, and played a possible role in viral replication.
JOURNAL OF MOLECULAR BIOLOGY
(2022)
Article
Biology
Paul Lambey, Omolade Otun, Xiaojing Cong, Francois Hoh, Luc Brunel, Pascal Verdie, Claire M. Grison, Fanny Peysson, Sylvain Jeannot, Thierry Durroux, Cherine Bechara, Sebastien Granier, Cedric Leyrat
Summary: The study characterized the interaction of LukE with chemokine receptors ACKR1, CCR2, and CCR5, revealing the location of receptor sulfotyrosine binding sites in the toxins. This work provides new insights into chemokine receptor recognition by leukotoxins and suggests that the conserved sulfotyrosine binding pocket could be a target for future drug development.
Article
Biochemistry & Molecular Biology
Giuseppe Sicoli, Albert Konijnenberg, Jeremy Guerin, Steve Hessmann, Elise Del Nero, Oscar Hernandez-Alba, Sophie Lecher, Guillaume Rouaut, Linn Mueggenburg, Herve Vezin, Sarah Cianferani, Frank Sobott, Robert Schneider, Francoise Jacob-Dubuisson
Summary: This study explores the transient conformers of the TpsB transporter FhaC, revealing spontaneous conformational changes and their role in substrate secretion. The findings provide insights into the mechanism of protein secretion mediated by TpsB transporters and highlight the importance of intrinsic protein dynamics in this process.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Chemistry, Multidisciplinary
Guillaume Hoffmann, Madalen Le Gorrec, Emeline Mestdach, Stephen Cusack, Loic Salmon, Malene Ringkjobing Jensen, Andres Palencia
Summary: This study reveals a novel enzyme-independent prodrug activation mechanism by boron-based compounds targeting leucyl-tRNA synthetase. These benzoxaboroles act as prodrugs that activate their bioconversion by forming a specific and reversible inhibition adduct with ATP, AMP, or the terminal adenosine of the tRNALeu. This adenosine-dependent activation mechanism explains the good druglike properties and broad efficacy of benzoxaboroles against different human pathogens.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Virology
Francine C. A. Gerard, Jean-Marie Bourhis, Caroline Mas, Anais Branchard, Duc Duy Vu, Sylvia Varhoshkova, Cedric Leyrat, Marc Jamin
Summary: This study reconstituted a soluble heterodimeric complex between the nucleoprotein and phosphoprotein of rabies virus and solved the crystal structure of the complex. The results showed that the chaperone module undergoes a disordered-order transition during assembly and that the chaperone module and RNA-mediated polymerization reduce the ability of the RNA binding cavity to open and close.
Article
Multidisciplinary Sciences
Mingxi Yao, Ajay Tijore, Delfine Cheng, Jinyuan Vero Li, Anushya Hariharan, Boris Martinac, Guy Tran Van Nhieu, Charles D. Cox, Michael Sheetz
Summary: Mechanosensing is crucial for various physiological processes, and two major mechanosensing systems, focal adhesions and mechanosensitive ion channels, can convert mechanical features of the microenvironment into biochemical signals. Interestingly, it has been discovered that the mechanosensitive calcium-permeable channel Piezo1, previously thought to be diffusive on plasma membranes, binds to matrix adhesions in a force-dependent manner, thereby promoting cell spreading, adhesion dynamics, and calcium entry in normal cells but not in most cancer cells.
Article
Biochemistry & Molecular Biology
Ada Roy, Emeric Chan Mine, Lorenzo Gaifas, Cedric Leyrat, Valentina A. Volchkova, Florence Baudin, Luis Martinez-Gil, Viktor E. Volchkov, David G. Karlin, Jean-Marie Bourhis, Marc Jamin
Summary: The study found that despite low sequence similarity, the Tupaia paramyxovirus (TupV) C protein is structurally similar to the Sendai virus C protein. This suggests that all Orthoparamyxovirine C proteins are homologous. Additionally, the study also discovered that a STAT1-binding site is encoded by the same RNA region of the P/C gene across Paramyxovirinae, but in different reading frames (P or C), depending on the cluster they belong to.
Article
Chemistry, Multidisciplinary
Robert D. Healey, Louise Couillaud, Francois Hoh, Assia Mouhand, Aurelien Fouillen, Pierre Couvineau, Sebastien Granier, Cedric Leyrat
Summary: In this study, the crystal structure of a single-chain Fv antibody with a stable polyhistidine motif stabilized by cobalt ions was obtained. This finding has implications for biomaterial design and cryo-EM studies.
COMMUNICATIONS CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Robert D. Healey, Essa M. Saied, Xiaojing Cong, Gergely Karsai, Ludovic Gabellier, Julie Saint-Paul, Elise Del Nero, Sylvain Jeannot, Marion Drapeau, Simon Fontanel, Damien Maurel, Shibom Basu, Cedric Leyrat, Jerome Golebiowski, Guillaume Bossis, Cherine Bechara, Thorsten Hornemann, Christoph Arenz, Sebastien Granier
Summary: Sphingolipid metabolism is tightly regulated by enzymes, with recent attention on the discovery and mechanism of action of the first drug-like inhibitors of alkaline ceramidase 3 (ACER3). This discovery opens up a new paradigm for targeting ACER3 in drug discovery efforts.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Chemistry, Multidisciplinary
Robert D. Healey, Essa M. Saied, Xiaojing Cong, Gergely Karsai, Ludovic Gabellier, Julie Saint-Paul, Elise Del Nero, Sylvain Jeannot, Marion Drapeau, Simon Fontanel, Damien Maurel, Shibom Basu, Cedric Leyrat, Jerome Golebiowski, Guillaume Bossis, Cherine Bechara, Thorsten Hornemann, Christoph Arenz, Sebastien Granier
Summary: This study presents the discovery and mechanism of action of the first drug-like inhibitors of alkaline ceramidase 3 (ACER3), as well as the characterization of enzyme:inhibitor interactions using mass spectrometry and MD simulations. The use of novel fluorescent ceramide substrates enables screening of large compound libraries, offering a new paradigm for inhibition of lipid metabolizing enzymes with non-lipidic small molecules. The findings lay the groundwork for targeting ACER3 in drug discovery efforts.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Review
Chemistry, Multidisciplinary
Aldo R. Camacho-Zarco, Vincent Schnapka, Serafima Guseva, Anton Abyzov, Wiktor Adamski, Sigrid Milles, Malene Ringkjobing Jensen, Lukas Zidek, Nicola Salvi, Martin Blackledge
Summary: Intrinsically disordered proteins play essential roles in cellular and extracellular biochemistry. Nuclear magnetic resonance is a powerful tool for studying their structural and dynamic behavior, providing insights into reaction kinetics and thermodynamics essential for function. Recent applications of NMR have helped uncover the mechanistic basis of functional disordered molecular assemblies important for human health.
