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Current opinion in neurological manifestations of SARS-CoV-2 infection.

Neurological symptoms occur in approximately one-third of hospitalized patients with coronavirus disease 2019 (COVID-19). Among these sympto … blood-brain barrier. Besides the high angiotensin-converting enzyme-2 (ACE2) binding affinity, and FURIN preactivation, SARS-CoV-2 maintains efficient neuronal entry while evading immune surveillance by using basigin and neuropilin-1 receptors. However, the neurological manifestations and their pathogenic mechanisms are still debated in COVID-19 patien …

The R203W substitution drives PACS-1 syndrome by disrupting intramolecular regulation.

The c607C>T mutation in the PACS1 gene results in an Arg203Trp substitution in the multifunctional protein PACS-1, and drives a syndrome characterized by intellectual disability, seizures, craniofacial dysmorphisms, and various characteristics of the autism spectrum. On the molecular level, this syndrome, in part, results from enhanced association of PACS-1 with the protein deacetylase HDAC6. PACS-1 uses its Furin binding region (FBR: amino acids 101-273) to directly interact with the catalytic domains of HDAC6. We present the solution structure of a chimeric PACS-1 FBR and use NMR to demonstr…

Emerging mutation patterns in SARS-CoV-2 variants.

There is an urgent need to understand the functional effects of mutations in emerging variants of SARS-CoV-2. Variants of concern (alpha, beta, gamma and delta) acquired four patterns of spike glycoprotein mutations that enhance transmissibility and immune evasion: 1) mutations in the N-terminal domain (NTD), 2) mutations in the Receptor Binding Domain (RBD), 3) mutations at interchain contacts of the spike trimer, and 4) furin cleavage site mutations. Most distinguishing mutations among variants of concern are exhibited in the NTD, localized to sites of high structural flexibility. Emerging v…

Epitope-cavities generated by molecularly imprinted films measure the coincident response to anthrax protective antigen and its segments.

A molecularly imprinted film was fabricated, in the presence of epitope-peptides, onto a quartz crystal microbalance (QCM) chip. These five … s differentiated their epitope region on the protective antigen PA(83) as well as the corresponding furin cleavage fragments PA(63) and PA(20). The QCM chip differential response to the protective antigen fragment was observed in the picomolar range, thus demonstrating a method to manipulate protein on the surface with defined orientation.

Natural selection differences detected in key protein domains between non-pathogenic and pathogenic feline coronavirus phenotypes.

Feline coronaviruses (FCoVs) commonly cause mild enteric infections in felines worldwide (termed feline enteric coronavirus [FECV]), with ar … es exhibiting differences in natural selection pressure between FECV and FIPV: one within the S1/S2 furin cleavage site (FCS) and the other within the fusion domain of Spike. We also found fifteen sites subject to positive selection associated with FIPV within Spike, eleven of which have not previously been suggested as possibly relevant to FIP developm …

Polymerase trapping as the mechanism of H5 highly pathogenic avian influenza virus genesis.

Highly pathogenic avian influenza viruses (HPAIVs) derive from H5 and H7 low pathogenic avian influenza viruses (LPAIVs). Although insertion of a furin-cleavable multibasic cleavage site (MBCS) in the hemagglutinin gene was identified decades ago as the genetic basis for the LPAIV-to-HPAIV transition, the mechanisms underlying the occurrence of insertion are unknown. Here, we show that transient H5 RNA structures, predicted to trap the influenza virus polymerase on purine-rich sequences, drive nucleotide insertions, providing empirical evidence of RNA structure involvement in MBCS acquisition.…

Inhibition of placental trophoblast fusion by guanylate-binding protein 5.

Syncytin-1 and Syncytin-2 are envelope glycoproteins encoded by human endogenous retroviruses that have been exapted for the fusion of cytot … odestly reduced. Mechanistic analyses revealed that Syncytin-1 is mainly cleaved by the GBP5 target furin, whereas Syncytin-2 is also efficiently processed by the proprotein convertase subtilisin/kexin type 7 (PCSK7) and thus resistant to GBP5-mediated restriction. Mutational analyses mapped PCSK7 processing of Syncytin-2 to a leucine residue upstream o …

Advances in Targeting HPV Infection as Potential Alternative Prophylactic Means.

Infection by oncogenic human papillomavirus (HPV) is the primary cause of cervical cancer and other anogenital cancers. The majority of cervical cancer cases occur in low- and middle- income countries (LMIC). Concurrent infection with Human Immunodeficiency Virus (HIV) further increases the risk of HPV infection and exacerbates disease onset and progression. Highly effective prophylactic vaccines do exist to combat HPV infection with the most common oncogenic types, but the accessibility to these in LMIC is severely limited due to cost, difficulties in accessing the target population, cultural

[Efficient expression of anthrax edema factor in Escherichia coli and its single-step purification].

OBJECTIVE: To develop a new method for efficient expression and rapid preparation of biologically active anthrax edema factor (EF). METHODS … in soluble form and then purified to 96% purity by single-step. The recombinant EF was able to bind furin-nicked protective antigen (PA) to form edema toxin, which could elevate the intracellular cAMP level of CHO-K1 cells dramatically. CONCLUSION: This work provides a timesaving method for purification of EF with high purity and good biological activi …

Antibody to the E3 glycoprotein protects mice against lethal venezuelan equine encephalitis virus infection.

Six monoclonal antibodies were isolated that exhibited specificity for a furin cleavage site deletion mutant (V3526) of Venezuelan equine encephalitis virus (VEEV). These antibodies comprise a single competition group and bound the E3 glycoprotein of VEEV subtype I viruses but failed to bind the E3 glycoprotein of other alphaviruses. These antibodies neutralized V3526 virus infectivity but did not neutralize the parental strain of Trinidad donkey (TrD) VEEV. However, the E3-specific antibodies did inhibit the production of virus from VEEV TrD-infected cells. In addition, passive immunization o…

Post-translational modification of Fibroblast Growth Factor 23.

Fibroblast Growth Factor (FGF) 23 has been shown to play important roles in the development of hypophosphatemic rickets/osteomalacia. Comple … its effect to cause hypophosphatemia. This processing was shown to be prevented by an inhibitor of furin indicating that the cleavage is mediated by subtilisin-like proprotein convertase. In addition to this processing, FGF23 protein seems to have O-linked glycosylation. Further studies are necessary to clarify the importance of O-glycosylation for FGF …

Gain-of-function and origin of Covid19.

In nature, wild viruses adapted for transmission circulate in many animal species (bats, birds, primates…). Contamination of other animals, … ut evidence for adaptive mutations. In addition, the Spike protein, a major virulence factor, has a furin site, not found in any other known sarbecovirus. Unlike the SARS and MERS epidemics, no intermediate host has been detected so far. Finally, no other outbreaks were reported at the beginning of the pandemic outside of Wuhan, contrary to what happene …

Neuropilin-1 is a host factor for SARS-CoV-2 infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), uses the viral spike (S) protein for host cell attachment and entry. The host protease furin cleaves the full-length precursor S glycoprotein into two associated polypeptides: S1 and S2. Cleavage of S generates a polybasic Arg-Arg-Ala-Arg carboxyl-terminal sequence on S1, which conforms to a C-end rule (CendR) motif that binds to cell surface neuropilin-1 (NRP1) and NRP2 receptors. We used x-ray crystallography and biochemical approaches to show that the S1 CendR motif dire…

Airway protease availability governs a reversible shift between syncytial and cell-free spread.

UNLABELLED: Paramyxoviruses such as respiratory syncytial virus (RSV) and human parainfluenza virus 3 (HPIV3) spread in the airway by releasing virions and by forming syncytia. Spread phenotypes are typically attributed to the fusion protein cleavage site, yet it remains unclear whether, and if so, how, host protease context biases syncytial versus cell-free spread. We compared RSV and HPIV3-two closely related viruses with overlapping epithelial tropism but distinct F cleavage-site composition (polybasic, furin-type for RSV versus a distinct, less polybasic cleavage-site motif for HPIV3)-in r…

[Preliminary study of LFn-MAGE3 fusion protein expression and its biological function].

AIM: To explore the possibility of using the nontoxic form of anthrax toxin in cancer immunotherapy by LFn-MAGE3 fusion protein expression. METHODS: A fusion expression vector named PET21a-LFn was constructed by inserting LFn coding senquence into PET21a. PET21a-LFn-MAGE3 fusion protein expression vector was constructed by cloning the whole MAGE-3 gene into plasmid PET21a-LFn. Q sepharose FF and Phe HP columns were employed to purify the fusion protein. The biological activity of LFn-MAGE3 was determined by cell test of repressing the cytotoxity of LF and the tests of immunofluscence of mouse

Dyggve-Melchior-Clausen syndrome: chondrodysplasia resulting from defects in intracellular vesicle traffic.

Dyggve-Melchior-Clausen syndrome and Smith-McCort dysplasia are recessive spondyloepimetaphyseal dysplasias caused by loss-of-function mutat … delayed retrograde traffic of an endoplasmic reticulum-targeted Shiga toxin B subunit, and altered furin trafficking; and the Dym protein associates with multiple cellular proteins involved in vesicular traffic. These results establish dymeclin as a novel protein involved in Golgi organization and intracellular vesicle traffic and clarify the molecular …

From mechanisms to therapies: the multifaceted roles of guanylate-binding protein 2 in immunity, cancer, and beyond.

Guanylate-binding protein 2 (GBP2) is an interferon-inducible GTPase that plays a critical role in innate immunity by defending against viral, bacterial, and parasitic infections through mechanisms such as furin inhibition and inflammasome activation. Beyond infectious disease, GBP2 demonstrates a context-dependent dual role in cancer-acting as either a tumor suppressor or an oncogene by modulating key signaling pathways including JAK-STAT, Wnt/β-catenin, and PI3K/AKT/mTOR. Its dysregulation is also increasingly implicated in autoimmune, neurological, and metabolic disorders, underscoring its …

Структура незрелого вируса энцефалита, переносимого клещами, поддерживает рухнувшую модель созревания флавивируса.

Мы представляем структуру трех незрелых вирусов энцефалита (ТБЭВ), передающихся через тикали. Наши атомные модели основных вирусных компонентов, белков E и prM, показывают, что области prM играют важнейшую роль в удерживании гетерогексамерических пиков prM3E3 в метастабной конформации. Дестабилизация петли, чувствительной к фурину, при кислотном pH облегчает ее обработку. prM топология и домена домена в ТБЭВ аналогичны вирусу, переносимому комарами, но контрастируют с другими незрелыми флавивирусными моделями. Эти результаты подтверждают, что prM решетка, обвал белковых эктодоменов Е на поверх

Совпадение в аннотации оригинала
We present structures of three immature tick-borne encephalitis virus (TBEV) isolates. Our atomic models of the major viral components, the E and prM proteins, indicate that the pr domains of prM have a critical role in holding the heterohexameric prM3E3 spikes in a metastable conformation. Destabilization of the prM furin-sensitive loop at acidic pH facilit…

Interfering with Host Proteases in SARS-CoV-2 Entry as a Promising Therapeutic Strategy.

Due to its fast international spread and substantial mortality, the coronavirus disease COVID-19 evolved to a global threat. Since there is … eview, we discuss the current state of the art of developing inhibitors against the entry proteases furin, the transmembrane serine protease type-II (TMPRSS2), trypsin, and cathepsin L.

There is still no evidence of SARS-CoV-2 laboratory origin: Response to Segreto and Deigin (10.1002/bies.202100137).

The causative agent of COVID-19 SARS-CoV-2 has led to over 4 million deaths worldwide. Understanding the origin of this coronavirus is impor … e discussion of the proposed arguments for this hypothesis. We show that neither the existence of a furin cleavage site in SARS-CoV-2, nor the presence of specific sequences within the nucleotide insertion encoding that site are evidence for intelligent design. We also explain why existing genetic data, viral diversity and past human history suggest tha …