Authors: Isabel A Lüthy, Isabel N Kantor

In April 2019, UNICEF denounced that more than 20 million children worldwide had not been vaccinated and alerted on possible outbreaks of measles which, due to the high transmissibility of this virus, is the first disease preventable by vaccination to emerge. If the decline in vaccinations continues, pertussis, tetanus and other diseases, which require less coverage to achieve population protection, may also reappear. In Argentina, the current outbreak began in late August 2019. Measles virus is transmitted by air, infects multiple organs, and is associated with immunosuppression. Its genome consists of single stranded RNA. Genotyping is carried out by sequencing a 450-nucleotide fragment of the N protein, which contains the highest density of nucleotide variation. In South America, D8 is the circulating genotype and in North America, B3 accounts for 8% of the cases. Each person with measles infects, on average, another 12-18 people in a susceptible population. Vaccination confers direct and indirect protection, and induces both antibodies and cellular immunity. Newborns are protected by maternal antibodies transmitted via the placenta, up to 6 months. In Argentina, the Vaccination Calendar includes two doses of triple viral vaccine, at 12 months and 5 years, and a zero dose (6-11 months of age) in districts with disease cases. The protection conferred by the vaccine is 93% at 12 months with a dose, and with 2 doses 97% for life.

Topics: Argentina; Child, Preschool; Disease Outbreaks; Genotype; History, 19th Century; Humans; Infant; Measles; Nucleocapsid Proteins; Nucleoproteins; Vaccination; Viral Proteins

PubMed: 32282323
DOI: No ID Found

Authors: Reika Watanabe, Dawid Zyla, Diptiben Parekh...

Filoviruses, including the Ebola and Marburg viruses, cause hemorrhagic fevers with up to 90% lethality. The viral nucleocapsid is assembled by polymerization of the nucleoprotein (NP) along the viral genome, together with the viral proteins VP24 and VP35. We employed cryo-electron tomography of cells transfected with viral proteins and infected with model Ebola virus to illuminate assembly intermediates, as well as a 9 Å map of the complete intracellular assembly. This structure reveals a previously unresolved third and outer layer of NP complexed with VP35. The intrinsically disordered region, together with the C-terminal domain of this outer layer of NP, provides the constant width between intracellular nucleocapsid bundles and likely functions as a flexible tether to the viral matrix protein in the virion. A comparison of intracellular nucleocapsids with prior in-virion nucleocapsid structures reveals that the nucleocapsid further condenses vertically in the virion. The interfaces responsible for nucleocapsid assembly are highly conserved and offer targets for broadly effective antivirals.

Topics: Ebolavirus; Nucleocapsid; Humans; Electron Microscope Tomography; Virus Assembly; Cryoelectron Microscopy; Nucleocapsid Proteins; Nucleoproteins; Animals; Viral Proteins; Models, Molecular; Virion; Hemorrhagic Fever, Ebola; Chlorocebus aethiops

PubMed: 39293445
DOI: 10.1016/j.cell.2024.08.044

Authors: James M Dunce, Owen R Davies

BRCA2 is essential for DNA repair by homologous recombination in mitosis and meiosis. It interacts with recombinases RAD51 and DMC1 to facilitate the formation of nucleoprotein filaments on resected DNA ends that catalyse recombination-mediated repair. BRCA2's BRC repeats bind and disrupt RAD51 and DMC1 filaments, whereas its PhePP motifs bind recombinases and stabilise their nucleoprotein filaments. However, the mechanism of filament stabilisation has hitherto remained unknown. Here, we report the crystal structure of a BRCA2-DMC1 complex, revealing how core interaction sites of PhePP motifs bind to recombinases. The interaction mode is conserved for RAD51 and DMC1, which selectively bind to BRCA2's two distinct PhePP motifs via subtly divergent binding pockets. PhePP motif sequences surrounding their core interaction sites protect nucleoprotein filaments from BRC-mediated disruption. Hence, we report the structural basis of how BRCA2's PhePP motifs stabilise RAD51 and DMC1 nucleoprotein filaments for their essential roles in mitotic and meiotic recombination.

Topics: Rad51 Recombinase; BRCA2 Protein; Cell Cycle Proteins; Humans; DNA-Binding Proteins; Protein Binding; Nucleoproteins; Crystallography, X-Ray; Meiosis; Binding Sites; Amino Acid Motifs; Models, Molecular; Mitosis

PubMed: 39333100
DOI: 10.1038/s41467-024-52699-3

Authors: Sheli R Radoshitzky, Michael J Buchmeier, Rémi N Charrel...

is a family for ambisense RNA viruses with genomes of about 10.5 kb that infect mammals, snakes, and fish. The arenavirid genome consists of two or three single-stranded RNA segments and encodes a nucleoprotein (NP), a glycoprotein (GP) and a large (L) protein containing RNA-directed RNA polymerase (RdRP) domains; some arenavirids encode a zinc-binding protein (Z). This is a summary of the International Committee on Taxonomy of Viruses (ICTV) report on the family , which is available at www.ictv.global/report/arenaviridae.

Topics: Animals; Arenaviridae; Nucleoproteins; RNA; RNA-Dependent RNA Polymerase; Mammals

PubMed: 37698490
DOI: 10.1099/jgv.0.001891

Review

Authors: Robert Craigie

Integration of a DNA copy of the viral genome into host DNA is an essential step in the replication cycle of HIV-1 and other retroviruses and is an important therapeutic target for drugs. DNA integration is catalyzed by the viral integrase protein and proceeds through a series of stable nucleoprotein complexes of integrase, viral DNA ends and target DNA. These nucleoprotein complexes are collectively called intasomes. Retroviral intasomes undergo a series of transitions between initial formation and catalysis of the DNA cutting and joining steps of DNA integration. Intasomes, rather than free integrase protein, are the target of currently approved drugs that target HIV-1 DNA integration. High-resolution structures of HIV-1 intasomes are needed to understand their detailed mechanism of action and how HIV-1 may escape by developing resistance. Here, we focus on our current knowledge of the structure and function of HIV-1 intasomes, with reference to related systems as required to put this knowledge in context.

Topics: Animals; DNA, Viral; HIV-1; Humans; Nucleoproteins; Structure-Activity Relationship; Virus Integration

PubMed: 29900498
DOI: 10.1007/978-981-10-8456-0_9

Authors: Wenjun Shi, Zhibo Shan, Li Jiang...

Influenza A viruses (IAVs) continue to cause tremendous economic losses to the global animal industry and respiratory diseases and deaths among humans. The nuclear import of the vRNP complex, composed of polymerase basic protein 1 (PB1), polymerase basic protein 2 (PB2), polymerase acidic protein (PA), nucleoprotein (NP), and viral RNA, is essential for the efficient replication of IAV. Host factors involved in this process can be targeted for the development of countermeasures against IAV infection. Here, we found that Ankyrin Repeat and BTB Domain Containing 1 (ABTB1) promotes the replication of IAV, and positively regulates the nuclear import of the vRNP complex. ABTB1 did not interact directly with NP, indicating that ABTB1 plays an indirect role in facilitating the nuclear import of the vRNP complex. Immunoprecipitation and mass spectrometry revealed that Tripartite Motif Containing 4 (TRIM4) interacts with ABTB1. We found that TRIM4 relies on its E3 ubiquitin ligase activity to inhibit the replication of IAV by targeting and degrading NP within the incoming vRNP complex as well as the newly synthesized NP. ABTB1 interacted with TRIM4, leading to TRIM4 degradation through the proteasome system. Notably, ABTB1-mediated degradation of TRIM4 blocked the effect of TRIM4 on NP stability, and largely counteracted the inhibitory effect of TRIM4 on IAV replication. Our findings define a novel role for ABTB1 in aiding the nuclear import of the vRNP complex of IAV by counteracting the destabilizing effect of TRIM4 on the viral NP protein.

Topics: Animals; Humans; Nucleoproteins; Viral Proteins; Influenza A virus; Viral Core Proteins; Protein Binding; Virus Replication; Repressor Proteins

PubMed: 37823597
DOI: 10.1080/22221751.2023.2270073

Authors: Nicolas Papageorgiou, Afroditi Vaitsopoulou, Awa Diop...

Arenaviruses are enveloped viruses containing a segmented, negative, and ambisense single-stranded RNA genome wrapped with a nucleoprotein (NP). The NP is the most abundant viral protein in infected cells and plays a critical role in both replication/transcription and virion assembly. The NP associates with RNA to form a ribonucleoprotein (RNP) complex, and this implies self-assembly while the exact structure of this polymer is not yet known. Here, we report a measurement of the full-length Mopeia virus NP by negative stain transmission electron microscopy. We observed RNP complex particles with diameter 15 ± 1 nm as well as symmetric circular heptamers of the same diameter, consistent with previous observations.

Topics: Amino Acid Sequence; Arenavirus; Models, Molecular; Nucleoproteins; Protein Conformation; Protein Interaction Domains and Motifs; Protein Multimerization; RNA-Binding Proteins; Recombinant Proteins; Viral Proteins

PubMed: 33534950
DOI: 10.1002/2211-5463.13106

Review

Authors: Anatoly D Altstein

In this article, I review the results of studies on the origin of life distinct from the popular RNA world hypothesis. The alternate scenario postulates the origin of the first bimolecular genetic system (a polynucleotide gene and a polypeptide processive polymerase) with simultaneous replication and translation and includes the following key features: 1. The bimolecular genetic system emerges not from mononucleotides and monoamino acids, but from progenes, namely, trinucleotides aminoacylated on 3'-end by a non-random amino acid (NpNpNp ~ pX ~ Aa, where N--deoxyribo- or ribonucleoside, p--phosphate, X--a bifunctional agent, for example ribose, Aa--amino acid, ~ macroerge bond). Progenes are used as substrates for simultaneous synthesis of a polynucleotide and a polypeptide. Growth of the system is controlled by the growing polypeptide, and the bimolecular genetic system emerges as an extremely rare event. The first living being (virus-like organism protoviroid, Protoviroidum primum) arises and reproduces in prebiotic liposome-like structures using progenes. A population of protoviroids possessing the genetic system evolves in accordance with the Darwinian principle. Early evolution from protoviroid world to protocell world is shortly described. 2. The progene forming mechanism (NpNp + Np ~ pX ~ Aa) makes it possible to explain the emergence of the prebiotic physicochemical group genetic code, as well as the selection of organic compounds for the future genetic system from the racemic environment. 3. The protoviroid is reproduced on a progene basis via replicative transcription-translation (RTT, the first molecular genetic process) that is similar to its modern counterparts. Nothing is required for the emergence and reproduction of the protoviroid except for progenes and conditions for their formation. 4. The general scheme of early evolution is as follows: prebiotic world → protoviroid (nucleoprotein) world → protocell (DNA-RNA-protein) world → LUCA (Last Universal Common Ancestor) → modern cell world. This scheme exclude the existence of an independent RNA world as predecessor of the cellular world.

Topics: Genetic Code; Models, Genetic; Nucleoproteins; Origin of Life

PubMed: 26612610
DOI: 10.1186/s13062-015-0096-z

Authors: Scott Adkins, Katherine Brown, Juan Carlos de la Torre...

is a family of negative-sense RNA viruses with genomes of about 8.0 kb that have been found in protists. The leishbuvirid genome consists of three monocistronic RNA segments with open reading frames (ORFs) that encode a nucleoprotein (NP), a glycoprotein (GP), and a large (L) protein containing an RNA-directed RNA polymerase (RdRP) domain. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the family , which is available at ictv.global/report/leishbuviridae.

Topics: Genome, Viral; RNA Viruses; Negative-Sense RNA Viruses; Nucleoproteins; Virus Replication; Virion

PubMed: 38064269
DOI: 10.1099/jgv.0.001934

Authors: Antoine Gruet, Marion Dosnon, David Blocquel...

Despite the partial disorder-to-order transition that intrinsically disordered proteins often undergo upon binding to their partners, a considerable amount of residual disorder may be retained in the bound form, resulting in a fuzzy complex. Fuzzy regions flanking molecular recognition elements may enable partner fishing through non-specific, transient contacts, thereby facilitating binding, but may also disfavor binding through various mechanisms. So far, few computational or experimental studies have addressed the effect of fuzzy appendages on partner recognition by intrinsically disordered proteins. In order to shed light onto this issue, we used the interaction between the intrinsically disordered C-terminal domain of the measles virus (MeV) nucleoprotein (NTAIL ) and the X domain (XD) of the viral phosphoprotein as model system. After binding to XD, the N-terminal region of NTAIL remains conspicuously disordered, with α-helical folding taking place only within a short molecular recognition element. To study the effect of the N-terminal fuzzy region on NTAIL /XD binding, we generated N-terminal truncation variants of NTAIL , and assessed their binding abilities towards XD. The results revealed that binding increases with shortening of the N-terminal fuzzy region, with this also being observed with hsp70 (another MeV NTAIL binding partner), and for the homologous NTAIL /XD pairs from the Nipah and Hendra viruses. Finally, similar results were obtained when the MeV NTAIL fuzzy region was replaced with a highly dissimilar artificial disordered sequence, supporting a sequence-independent inhibitory effect of the fuzzy region.

Topics: Intrinsically Disordered Proteins; Measles virus; Nucleoproteins; Phosphoproteins; Protein Binding

PubMed: 26684000
DOI: 10.1111/febs.13631