Structural Disorder within Viral Proteins: A Themed Issue Dedicated to Doctor Sonia Longhi

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Biomacromolecules: Proteins".

Deadline for manuscript submissions: closed (20 November 2023) | Viewed by 15324

Special Issue Editors


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Guest Editor
Department of Biochemistry & Biophysics, Oregon State University, Corvallis, OR, USA
Interests: structure; assembly; regulation of dynamic protein complexes

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Guest Editor
Centre de Biochimie Structurale (CBS), CNRS, INSERM, Univ Montpellier, Montpellier, France
Interests: intrinsically disordered proteins (IDPs); post-translational modifications (PTMs); signaling; nuclear magnetic resonance (NMR); small-angle X-ray scattering (SAXS)
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Guest Editor
Department of Molecular Medicine, USF Health Byrd Alzheimer’s Research Institute, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd, MDC07, Tampa, FL 33612, USA
Interests: intrinsically disordered proteins; protein folding; protein misfolding; partially folded proteins; protein aggregation; protein structure; protein function; protein stability; protein biophysics; protein bioinformatics; conformational diseases; protein–ligand interactions; protein–protein interactions; liquid-liquid phase transitions
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Over the past twenty years, the “structure–function” paradigm has been challenged by the discovery of intrinsically disordered proteins and regions (IDPs and IDRs, respectively), which are proteins/regions that are devoid of a unique tertiary structure under the conditions of physiological pH and salinity and that do not have binding partners. Among these IDPs or hybrid proteins with ordered domains and functional IDRs are viral proteins, such as the measles virus nucleoprotein and phosphoprotein, which possess long (>300 residues) IDRs. Since 2002, Longhi’s group has played a pioneering role in the discovery of disorders in these proteins and has extended these studies to show the prevalence of these intrinsic disorders  in a wide range of viruses, such as Nipah and Hendra, two biosafety level 4 human pathogens. This discovery opened the field to a new area of structural virology that is focused on elucidating the benefits of structural disorders. From the work of Sonia Longhi’s group, it has become clear that the functional role of structural disorders resides in enabling the virus to establish multiple interactions in spite of a small genome, allowing one single gene product to drive many different interactions, leading to multiple biological outcomes and functions. In addition, disorders allow the virus to handle overlapping reading frames, a common feature of viruses. More recently, it has become evident that disorders also mediate phase separation and liquid–liquid phase transition phenomena, which underlie the formation of viral factories in members of the Mononegavirales family as well as other viruses and membraneless organelles in cellular organisms. These condensates allow for the fine spatio-temporal regulation of cellular activities. They can undergo a “maturation” process to become gelified and/or solid condensates that are capable of nucleating amyloid-like fibers. The ability of viral proteins to undergo functional phase separation and fibrillation opens up the potential use of fibrillation inhibitors as antiviral therapeutics.

Dr. Sonia Longhi, one of the pioneers in the field of IDPs and of “unstructured” virology, received an HDR in Structural Virology from the University of Aix-Marseille I in 2003. Her scientific focus is on health-relevant IDPs and the mechanistic and functional aspects of their heterotypic and homotypic interactions. To date, she has authored 145 scientific publications and has edited a book on the nucleoprotein of the measles virus. She also co-edited (with Prof. Vladimir Uversky) a book on experimental approaches to characterize IDPs and a book on structural disorders within viral proteins (Wiley). Today, twenty years later, to celebrate her many contributions to IDP and the field of “unstructured” virology, we hope that Biomolecules publish this Special Issue in her honor. This Special Issue aims to present the state of the art and invites contributions, especially from those researchers who have known Dr. Sonia Longhi personally.

Prof. Dr. Elisar Barbar
Dr. Nathalie Sibille
Prof. Dr. Vladimir N. Uversky
Guest Editors

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Keywords

  • binding promiscuity
  • conformational ensemble
  • disorder in viral proteins
  • disorder in viruses
  • disorder-to-order transition
  • folding upon binding
  • innate immunity
  • intrinsic disorder in virus antigen
  • Intrinsically Disordered Proteins (IDPs)
  • Intrinsically Disordered Regions (IDPs)
  • Liquid-liquid phase separation
  • order-to-disorder transition
  • protein-protein interactions
  • reading frame
  • structural disorder
  • structural plasticity
  • unstructured virology
  • viral factories
  • virus-host interaction

Published Papers (5 papers)

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Research

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26 pages, 5962 KiB  
Article
Orthoparamyxovirinae C Proteins Have a Common Origin and a Common Structural Organization
by Ada Roy, Emeric Chan Mine, Lorenzo Gaifas, Cédric Leyrat, Valentina A. Volchkova, Florence Baudin, Luis Martinez-Gil, Viktor E. Volchkov, David G. Karlin, Jean-Marie Bourhis and Marc Jamin
Biomolecules 2023, 13(3), 455; https://doi.org/10.3390/biom13030455 - 1 Mar 2023
Cited by 2 | Viewed by 2017
Abstract
The protein C is a small viral protein encoded in an overlapping frame of the P gene in the subfamily Orthoparamyxovirinae. This protein, expressed by alternative translation initiation, is a virulence factor that regulates viral transcription, replication, and production of defective interfering RNA, [...] Read more.
The protein C is a small viral protein encoded in an overlapping frame of the P gene in the subfamily Orthoparamyxovirinae. This protein, expressed by alternative translation initiation, is a virulence factor that regulates viral transcription, replication, and production of defective interfering RNA, interferes with the host-cell innate immunity systems and supports the assembly of viral particles and budding. We expressed and purified full-length and an N-terminally truncated C protein from Tupaia paramyxovirus (TupV) C protein (genus Narmovirus). We solved the crystal structure of the C-terminal part of TupV C protein at a resolution of 2.4 Å and found that it is structurally similar to Sendai virus C protein, suggesting that despite undetectable sequence conservation, these proteins are homologous. We characterized both truncated and full-length proteins by SEC-MALLS and SEC-SAXS and described their solution structures by ensemble models. We established a mini-replicon assay for the related Nipah virus (NiV) and showed that TupV C inhibited the expression of NiV minigenome in a concentration-dependent manner as efficiently as the NiV C protein. A previous study found that the Orthoparamyxovirinae C proteins form two clusters without detectable sequence similarity, raising the question of whether they were homologous or instead had originated independently. Since TupV C and SeV C are representatives of these two clusters, our discovery that they have a similar structure indicates that all Orthoparamyxovirine C proteins are homologous. Our results also imply that, strikingly, a STAT1-binding site is encoded by exactly the same RNA region of the P/C gene across Paramyxovirinae, but in different reading frames (P or C), depending on which cluster they belong to. Full article
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28 pages, 3656 KiB  
Article
Looking at the Pathogenesis of the Rabies Lyssavirus Strain Pasteur Vaccins through a Prism of the Disorder-Based Bioinformatics
by Surya Dhulipala and Vladimir N. Uversky
Biomolecules 2022, 12(10), 1436; https://doi.org/10.3390/biom12101436 - 7 Oct 2022
Cited by 1 | Viewed by 5091
Abstract
Rabies is a neurological disease that causes between 40,000 and 70,000 deaths every year. Once a rabies patient has become symptomatic, there is no effective treatment for the illness, and in unvaccinated individuals, the case-fatality rate of rabies is close to 100%. French [...] Read more.
Rabies is a neurological disease that causes between 40,000 and 70,000 deaths every year. Once a rabies patient has become symptomatic, there is no effective treatment for the illness, and in unvaccinated individuals, the case-fatality rate of rabies is close to 100%. French scientists Louis Pasteur and Émile Roux developed the first vaccine for rabies in 1885. If administered before the virus reaches the brain, the modern rabies vaccine imparts long-lasting immunity to the virus and saves more than 250,000 people every year. However, the rabies virus can suppress the host’s immune response once it has entered the cells of the brain, making death likely. This study aimed to make use of disorder-based proteomics and bioinformatics to determine the potential impact that intrinsically disordered protein regions (IDPRs) in the proteome of the rabies virus might have on the infectivity and lethality of the disease. This study used the proteome of the Rabies lyssavirus (RABV) strain Pasteur Vaccins (PV), one of the best-understood strains due to its use in the first rabies vaccine, as a model. The data reported in this study are in line with the hypothesis that high levels of intrinsic disorder in the phosphoprotein (P-protein) and nucleoprotein (N-protein) allow them to participate in the creation of Negri bodies and might help this virus to suppress the antiviral immune response in the host cells. Additionally, the study suggests that there could be a link between disorder in the matrix (M) protein and the modulation of viral transcription. The disordered regions in the M-protein might have a possible role in initiating viral budding within the cell. Furthermore, we checked the prevalence of functional disorder in a set of 37 host proteins directly involved in the interaction with the RABV proteins. The hope is that these new insights will aid in the development of treatments for rabies that are effective after infection. Full article
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22 pages, 4209 KiB  
Article
The Role of Disordered Regions in Orchestrating the Properties of Multidomain Proteins: The SARS-CoV-2 Nucleocapsid Protein and Its Interaction with Enoxaparin
by Marco Schiavina, Letizia Pontoriero, Giuseppe Tagliaferro, Roberta Pierattelli and Isabella C. Felli
Biomolecules 2022, 12(9), 1302; https://doi.org/10.3390/biom12091302 - 15 Sep 2022
Cited by 4 | Viewed by 2403
Abstract
Novel and efficient strategies need to be developed to interfere with the SARS-CoV-2 virus. One of the most promising pharmaceutical targets is the nucleocapsid protein (N), responsible for genomic RNA packaging. N is composed of two folded domains and three intrinsically disordered regions [...] Read more.
Novel and efficient strategies need to be developed to interfere with the SARS-CoV-2 virus. One of the most promising pharmaceutical targets is the nucleocapsid protein (N), responsible for genomic RNA packaging. N is composed of two folded domains and three intrinsically disordered regions (IDRs). The globular RNA binding domain (NTD) and the tethered IDRs are rich in positively charged residues. The study of the interaction of N with polyanions can thus help to elucidate one of the key driving forces responsible for its function, i.e., electrostatics. Heparin, one of the most negatively charged natural polyanions, has been used to contrast serious cases of COVID-19 infection, and we decided to study its interaction with N at the molecular level. We focused on the NTR construct, which comprises the NTD and two flanking IDRs, and on the NTD construct in isolation. We characterized this interaction using different nuclear magnetic resonance approaches and isothermal titration calorimetry. With these tools, we were able to identify an extended surface of NTD involved in the interaction. Moreover, we assessed the importance of the IDRs in increasing the affinity for heparin, highlighting how different tracts of these flexible regions modulate the interaction. Full article
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22 pages, 2755 KiB  
Article
Shell Disorder Models Detect That Omicron Has Harder Shells with Attenuation but Is Not a Descendant of the Wuhan-Hu-1 SARS-CoV-2
by Gerard Kian-Meng Goh, A. Keith Dunker, James A. Foster and Vladimir N. Uversky
Biomolecules 2022, 12(5), 631; https://doi.org/10.3390/biom12050631 - 25 Apr 2022
Cited by 4 | Viewed by 2513
Abstract
Before the SARS-CoV-2 Omicron variant emergence, shell disorder models (SDM) suggested that an attenuated precursor from pangolins may have entered humans in 2017 or earlier. This was based on a shell disorder analysis of SARS-CoV-1/2 and pangolin-Cov-2017. The SDM suggests that Omicron is [...] Read more.
Before the SARS-CoV-2 Omicron variant emergence, shell disorder models (SDM) suggested that an attenuated precursor from pangolins may have entered humans in 2017 or earlier. This was based on a shell disorder analysis of SARS-CoV-1/2 and pangolin-Cov-2017. The SDM suggests that Omicron is attenuated with almost identical N (inner shell) disorder as pangolin-CoV-2017 (N-PID (percentage of intrinsic disorder): 44.8% vs. 44.9%—lower than other variants). The outer shell disorder (M-PID) of Omicron is lower than that of other variants and pangolin-CoV-2017 (5.4% vs. 5.9%). COVID-19-related CoVs have the lowest M-PIDs (hardest outer shell) among all CoVs. This is likely to be responsible for the higher contagiousness of SARS-CoV-2 and Omicron, since hard outer shell protects the virion from salivary/mucosal antimicrobial enzymes. Phylogenetic study using M reveals that Omicron branched off from an ancestor of the Wuhan-Hu-1 strain closely related to pangolin-CoVs. M, being evolutionarily conserved in COVID-19, is most ideal for COVID-19 phylogenetic study. Omicron may have been hiding among burrowing animals (e.g., pangolins) that provide optimal evolutionary environments for attenuation and increase shell hardness, which is essential for fecal–oral–respiratory transmission via buried feces. Incoming data support SDM e.g., the presence of fewer infectious particles in the lungs than in the bronchi upon infection. Full article
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Review

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19 pages, 3323 KiB  
Review
Functional Implications of Dynamic Structures of Intrinsically Disordered Proteins Revealed by High-Speed AFM Imaging
by Toshio Ando
Biomolecules 2022, 12(12), 1876; https://doi.org/10.3390/biom12121876 - 14 Dec 2022
Cited by 4 | Viewed by 2120
Abstract
The unique functions of intrinsically disordered proteins (IDPs) depend on their dynamic protean structure that often eludes analysis. High-speed atomic force microscopy (HS-AFM) can conduct this difficult analysis by directly visualizing individual IDP molecules in dynamic motion at sub-molecular resolution. After brief descriptions [...] Read more.
The unique functions of intrinsically disordered proteins (IDPs) depend on their dynamic protean structure that often eludes analysis. High-speed atomic force microscopy (HS-AFM) can conduct this difficult analysis by directly visualizing individual IDP molecules in dynamic motion at sub-molecular resolution. After brief descriptions of the microscopy technique, this review first shows that the intermittent tip–sample contact does not alter the dynamic structure of IDPs and then describes how the number of amino acids contained in a fully disordered region can be estimated from its HS-AFM images. Next, the functional relevance of a dumbbell-like structure that has often been observed on IDPs is discussed. Finally, the dynamic structural information of two measles virus IDPs acquired from their HS-AFM and NMR analyses is described together with its functional implications. Full article
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