Publications by authors named "Gonzalo de Prat Gay"
Article Synopsis
- * Researchers discovered that the C-terminal domain (CTD) of the JUNV NP can be purified and has a stable structure similar to NP from other viruses, and it interacts with the viral matrix protein Z.
- * The JUNV NP CTD shows metal-ion-dependent nuclease activity on DNA and RNA, suggesting a new function that could influence the immune response to this virus, especially if mutations occur in key residues.
Article Synopsis
- A variety of viruses, especially non-segmented negative stranded RNA viruses, replicate in specialized liquid-like structures called viral factories, driven by specific proteins like nucleoprotein (N) and phosphoprotein (P).
- The respiratory syncytial virus (RSV) has a unique transcription antiterminator protein, M, which helps bind RNA and increases the efficiency of RNA production, while also promoting the formation of protein-RNA clusters (coacervates).
- The study reveals how these protein interactions, particularly the roles of M, N, and P, influence the size and organization of these condensates, shedding light on the complex processes behind viral replication and potential infection mechanisms.
Article Synopsis
- Viral factories, which have a liquid-like nature, are essential for the transcription and replication processes in most viruses, including the respiratory syncytial virus (RSV).
- The interaction between the phosphoprotein (P) and nucleoprotein (N) is crucial, as it regulates the formation and dissolution of these viral factories through a phase separation process.
- This phase separation of P is typically kept in check by its structure but is activated when partnered with N or when certain sequences are removed, highlighting P's role as a "solvent-protein" in the organization of viral components.
p53 exerts its tumour suppressor activity by modulating hundreds of genes and it can also repress viral replication. Such is the case of human papillomavirus (HPV) through targeting the E2 master regulator, but the biochemical mechanism is not known. We show that the C-terminal DNA binding domain of HPV16 E2 protein (E2C) triggers heterotypic condensation with p53 at a precise 2/1 E2C/p53 stoichiometry at the onset for demixing, yielding large regular spherical droplets that increase in size with E2C concentration.
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- - The study investigates how disordered proteins, like the adenovirus E1A protein, maintain their essential functions despite having diverse sequences, focusing on the mechanism of functional selection.
- - E1A competes with host factors to bind the retinoblastoma (Rb) protein, affecting cell cycle regulation, and this interaction is driven by specific binding motifs linked by a disordered region that ensures strong binding affinity.
- - The authors introduce the concept of "conformational buffering," which describes how changes in amino acid composition and sequence length help maintain effective binding across various E1A linkers, indicating a broader principle applicable to many disordered proteins.
Article Synopsis
- Viruses have developed specialized methods to exploit host cell processes for their replication, utilizing structures called viral factories (VFs) that act as sites for viral gene function.
- Recent research indicates that these VFs exhibit liquid-like qualities due to a phenomenon called liquid-liquid phase separation (LLPS), particularly in negative stranded RNA viruses towards the end of their infectious cycle.
- Understanding the mechanisms behind viral biomolecular condensation opens avenues for new treatments and enhances our knowledge of cellular gene regulation through similar phase separation processes.
Article Synopsis
- Researchers studied bovine papillomavirus proteins to gain insights into human papillomavirus.
- The crystal structure of the E2 DNA-binding domain from bovine papillomavirus was analyzed, revealing a specific arrangement of protein dimers.
- This new configuration reduced the movement of a loop essential for protein-DNA interaction, allowing for its modeling for the first time.
Conformational Isomerization Involving Conserved Proline Residues Modulates Oligomerization of the NS1 Interferon Response Inhibitor from the Syncytial Respiratory Virus.
Julieta Conci Damian Alvarez-Paggi Guilherme A P de Oliveira Talita D Pagani Sebastian A Esperante Gonzalo de Prat-Gay
Biochemistry
July 2019
Article Synopsis
- Interferon response suppression in respiratory syncytial virus (RSV) is facilitated by nonstructural proteins NS1 and NS2, which form high-order complexes with cellular partners.
- Proline residues P81 and P67 are crucial for the conformational changes that enable NS1 oligomerization, with P81 involved in stabilizing the structure and P67 influencing aggregation tendencies.
- Despite their spatial distance from the C-terminal helix, both proline mutations affect the stability of oligomerization and aggregation processes, highlighting a significant connection between structural dynamics and the functionality of NS1 in multiprotein complexes.
Article Synopsis
- - Redox regulation in biology heavily involves cysteine chemistry, which can be both beneficial for protein function and harmful due to potential oxidation, affecting how proteins operate under different cellular conditions.
- - Papillomaviruses provide a unique opportunity to study protein evolution, particularly through the oncoprotein E7, which is rich in cysteine and showcases both conserved and variable properties that help understand redox-sensitive mechanisms.
- - Analysis of E7 sequences reveals that while noncanonical cysteines don't follow a clear sequence pattern, their positioning is influenced by topological constraints, suggesting a method to identify unrecognized regulatory cysteines that aren't detected through typical sequence-based approaches.
Article Synopsis
- The Pneumovirus family, part of Mononegavirales, relies on the M2-1 protein for RNA polymerase processivity and viral particle assembly, which is influenced by a zinc-binding motif.
- Respiratory syncytial virus M2-1 exhibits higher stability, while the human metapneumovirus (HMPV) M2-1 shows greater intersubunit affinity; removing zinc leads to slow oligomerization with altered structures.
- Structural modeling indicates that the CCCH motif significantly impacts the strength of protein interactions, with HMPV-M2-1 having unique intersubunit contacts that explain differences in stability and dissociation kinetics.
Article Synopsis
- E1A is a key protein in mastadenoviruses, and this study uses bioinformatics to analyze its structure and function across different adenovirus serotypes based on what is known about serotypes 5 and 12.
- The E1A protein has a unique domain structure characterized by high intrinsic disorder, which allows it to interact with over fifty host proteins through various linear motifs, though these motifs can vary significantly between different serotypes.
- The findings suggest that while E1A maintains some sequence conservation due to evolutionary pressures, it is primarily disordered and shaped in a way that enhances its ability to hijack host cell machinery through multiple binding interactions.
Article Synopsis
- - RNA transcription in mononegavirales decreases from the 3' to the 5' end due to reduced polymerase efficiency, with M protein playing a key role in transcription anti-termination for viruses like respiratory syncytial virus (RSV) and metapneumovirus.
- - RSV M protein can bind two RNA molecules of at least 13 nucleotides each, and its interaction leads to changes in RNA structure, demonstrating a cooperative binding mechanism that enhances RNA affinity through conformational changes.
- - This research reveals how the M protein's binding affects gene transcription, providing insight into transcription regulation in pneumoviruses and related mechanisms in other viruses like Ebola.
Structure and stability of the Human respiratory syncytial virus M RNA-binding core domain reveals a compact and cooperative folding unit.
Ivana G Molina Inokentijs Josts Yasser Almeida Hernandez Sebastian Esperante Mariano Salgueiro Gonzalo de Prat-Gay
Acta Crystallogr F Struct Biol Commun
January 2018
Article Synopsis
- Human syncytial respiratory virus (HRSV) is a negative-strand RNA virus that primarily affects infants and has been reclassified into the Pneumoviridae family due to its unique features.
- The virus has a transcriptional antiterminator named M, which plays a crucial role in RNA synthesis and is unusual among viruses, making its mechanism of action intriguing to researchers.
- Recent studies provide a detailed crystal structure of the M protein, revealing important insights into its RNA-binding domain and stability, which could have implications for understanding transcription regulation and developing antiviral therapies.
Intrinsic disorder is a major structural category in biology, accounting for more than 30% of coding regions across the domains of life, yet consists of conformational ensembles in equilibrium, a major challenge in protein chemistry. Anciently evolved papillomavirus genomes constitute an unparalleled case for sequence to structure-function correlation in cases in which there are no folded structures. E7, the major transforming oncoprotein of human papillomaviruses, is a paradigmatic example among the intrinsically disordered proteins.
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- Mammarenaviruses are a type of enveloped virus with a unique RNA genome that encodes important viral proteins, including the nucleocapsid and envelope glycoproteins.
- The study focused on Tacaribe virus (TCRV) and examined how its mRNA translation is influenced by the structure of the untranslated regions (UTR) at the 5' and 3' ends, discovering that a proper cap structure at the 5' end and specific sequences in the UTRs significantly affect translation rates.
- Findings suggest that TCRV uses a cap-dependent translation mechanism that is less reliant on traditional cellular factors, hinting at possible interactions with unknown factors during mRNA translation.
Infection with oncogenic human papillomavirus induces deregulation of cellular redox homeostasis. Virus replication and papillomavirus-induced cell transformation require persistent expression of viral oncoproteins E7 and E6 that must retain their functionality in a persistent oxidative environment. Here, we dissected the molecular mechanisms by which E7 oncoprotein can sense and manage the potentially harmful oxidative environment of the papillomavirus-infected cell.
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- * The study investigated the disorder-order transitions of P using a domain fragmentation technique, revealing that P remains a tetramer at high temperatures but undergoes significant structural changes between 10 and 60 °C, showcasing different behaviors in its N-terminal and C-terminal modules.
- * These findings indicate that the C-terminal module, when linked to the tetramerization component, exhibits increased structural stability and temperature sensitivity, which may serve to fine-tune protein interactions necessary for the
Article Synopsis
- The NS1 protein of the human respiratory syncytial virus plays a crucial role in evading the host's immune response, lacking structural or functional equivalents in other viruses.
- Its folding and assembly mechanisms are complex, involving both slow and ultrafast processes, leading to stable oligomeric forms that form at specific conditions.
- The protein's ability to undergo significant structural changes and its multiple binding activities, despite its small size, highlight its unique role in viral virulence and immune evasion.
Article Synopsis
- - Pathogen linear motif mimics are adaptable elements that help pathogens change how they interact with host proteins, leading to differences in the structure and function of these interactions.
- - The effectiveness of these mimics relies on both the specific linear motifs and the domains present in the pathogen proteins, influencing their evolutionary changes and roles in the host.
- - The study of these motifs, including their evolutionary rates and selection pressures, reveals that similar mimicry strategies arise independently across various pathogens, impacting traits like infection ability and disease severity.
Article Synopsis
- The E7 protein from high-risk HPV is crucial for causing cancer by inactivating the Rb tumor suppressor, with a unique structure that includes seven cysteine residues.
- Under oxidative stress, a disulfide bond forms between cysteines 59 and 68, which alters E7's structure and its interaction with the Rb protein.
- The findings suggest a new role for E7 in redox activity, complementing its known functions, and highlight the protein's ability to change its conformation in response to cellular environments, hinting at its complex role in HPV-related cancers.
Article Synopsis
- * The study identifies two transient α-helix segments within the E7 protein, with one being linked to a binding motif for the retinoblastoma tumor suppressor, and the other displaying pH sensitivity.
- * The findings highlight how the E7N domain can alternate between various structural forms, potentially impacting its ability to engage in multiple cellular interactions and contribute to cancer development.
Article Synopsis
- Human respiratory syncytial virus (hRSV) is a significant cause of respiratory disease in children, and its NS1 protein plays a key role in evading the immune response by suppressing type I interferon signaling.
- The study reveals that NS1 undergoes conformational changes at elevated temperatures, transitioning into soluble spherical oligomers with amyloid-like structures, which form around 45°C and become more prevalent at warmer temperatures.
- Experiments show that NS1 can reversibly transition between a stable monomer and these oligomers, indicating a complex behavior influenced by environmental conditions, which might affect how the virus interacts within host cells.
Article Synopsis
- Human respiratory syncytial virus (hRSV) predominantly affects infants and the elderly, with the M2-1 protein playing a key role in viral processes like transcription and particle budding, making it a target for antiviral drugs.
- The M2-1 protein contains a zinc-binding motif crucial for its function; removing zinc turns it into a monomeric form while maintaining similar structural stability to its tetrameric state.
- This zinc removal process is potentially reversible and can be influenced by natural chelators, indicating that it may modulate M2-1's role in viral assembly and release.
Article Synopsis
- The retinoblastoma tumor suppressor (Rb) is crucial for regulating cell growth and development, and its malfunction can lead to cancer.
- Research shows that the RbAB pocket domain undergoes a complex unfolding process involving multiple structural changes, which is influenced by specific ligand interactions.
- The marginal stability and tendency to form oligomers may help Rb function as a "hub" protein, similar to the p53 tumor suppressor, showing a potential link between protein folding and cancer regulation.
Article Synopsis
- The study examines how a monoclonal antibody, M1, interacts with the E7 protein from human papillomavirus, focusing on a crucial 12-amino acid epitope located in a hinge region.
- It reveals that this epitope exists in at least two forms, with a high energy barrier between them, and that the less common cis isomer is actually necessary for binding, meaning the majority of molecules must undergo a transformation to bind properly.
- The findings imply that for effective targeting by antibodies, the viral epitope should be presented in a specific cis conformation by antigen-presenting cells, rather than the more prevalent trans isomer.