scholarly journals Molecular interactions of TYLCV capsid protein during assembly of viral particles

2007 ◽  
Author(s):  
Yedidya Gafni ◽  
Vitaly Citovsky
Keyword(s):  
Host Cell ◽  
Capsid Protein ◽  
Molecular Interactions ◽  
Viral Entry ◽  
Molecular Mechanisms ◽  
High Specificity ◽  
Single Amino Acid ◽  
Research Findings ◽  
Specific Proteins ◽  
Nuclear Shuttling

Tomato yellow leaf curl geminivirus (TYLCV) is a major pathogen of cultivated tomato, causing up to 100% crop loss in many parts of the world. The present proposal, a continuation of a BARD-funded project, expanded our understanding of the molecular mechanisms by which CP molecules, as well as its pre-coat partner V2, interact with each other (CP), with the viral genome, and with cellular proteins during assembly and movement of the infectious virions. Specifically, two major objectives were proposed: I. To study in detail the molecular interactions between CP molecules and between CP and ssDNA leading to assembly of infectious TYLCV virions. II. To study the roles of host cell factors in TYLCV assembly. Our research toward these goals has produced the following major achievements: • Characterization of the CP nuclear shuttling interactor, karyopherin alpha 1, its pattern of expression and the putative involvement of auxin in regulation of its expression. (#1 in our list of publication, Mizrachy, Dabush et al. 2004). • Identify a single amino acid in the capsid protein’s sequence that is critical for normal virus life-cycle. (#2 in our list of publications, Yaakov, Levy et al. in preparation). • Development of monoclonal antibodies with high specificity to the capsid protein of TYLCV. (#3 in our list of publications, Solmensky, Zrachya et al. in press). • Generation of Tomato plants resistant to TYLCV by expressing transgene coding for siRNA targeted at the TYLCV CP. (#4 in our list of publications, Zrachya, Kumar et al. in press). •These research findings provided significant insights into (i) the molecular interactions of TYLCV capsid protein with the host cell nuclear shuttling receptor, and (ii) the mechanism by which TYLCV V2 is involved in the silencing of PTGS and contributes to the virus pathogenicity effect. Furthermore, the obtained knowledge helped us to develop specific strategies to attenuate TYLCV infection, for example, by blocking viral entry into and/or exit out of the host cell nucleus via siRNA as we showed in our publication recently (# 4 in our list of publications). Finally, in addition to the study of TYLCV nuclear import and export, our research contributed to our understanding of general mechanisms for nucleocytoplasmic shuttling of proteins and nucleic acids in plant cells. Also integration for stable transformation of ssDNA mediated by our model pathogen Agrobacterium tumefaciens led to identification of plant specific proteins involved. 

scholarly journals Significance of thiol-disulfide balance in SARS-CoV-2 infection

2021 ◽  
Vol 72 (3) ◽  
pp. 30-36
Author(s):  
Tatjana Simić
Keyword(s):  
Cell Surface ◽  
Host Cell ◽  
Protein Interactions ◽  
Viral Entry ◽  
Molecular Mechanisms ◽  
Alkylating Agents ◽  
Protein S ◽  
Protein Protein Interactions ◽  
Virus Surface ◽  
Host Cell Surface

Studies of the molecular mechanisms regarding interaction of different viruses with receptors on the host cell surface have shown that the viral entry depends on the specific relationship between free thiol (SH) groups and disulfides on the virus surface, as well as the thiol disulfide balance on the host cell surface. The presence of oxidizing compounds or alkylating agents, which disturb the thiol-disulfide balance on the surface of the virus, can also affect its infectious potential. Disturbed thiol-disulfide balance may also influence protein-protein interactions between SARS-CoV-2 protein S and ACE2 receptors of the host cell. This review presents the basic mechanisms of maintaining intracellular and extracellular thiol disulfide balance and previous experimental and clinical evidence in favor of impaired balance in SARS-CoV-2 infection. Besides, the results of the clinical application or experimental analysis of compounds that induce changes in the thiol disulfide balance towards reduction of disulfide bridges in proteins of interest in COVID-19 infection are presented.

scholarly journals Lassa Virus Cell Entry Reveals New Aspects of Virus-Host Cell Interaction

2016 ◽  
Vol 91 (4) ◽  
Author(s):  
Giulia Torriani ◽  
Clara Galan-Navarro ◽  
Stefan Kunz
Keyword(s):  
Host Cell ◽  
Viral Entry ◽  
Molecular Mechanisms ◽  
Cell Interaction ◽  
Cell Entry ◽  
Lassa Virus ◽  
Human Pathogen ◽  
Highly Pathogenic ◽  
Receptor Recognition ◽  
Host Cell Interaction

ABSTRACT Viral entry represents the first step of every viral infection and is a determinant for the host range and disease potential of a virus. Here, we review the latest developments on cell entry of the highly pathogenic Old World arenavirus Lassa virus, providing novel insights into the complex virus-host cell interaction of this important human pathogen. We will cover new discoveries on the molecular mechanisms of receptor recognition, endocytosis, and the use of late endosomal entry factors.

scholarly journals Epigenetic Regulation Mechanisms in Viral Infections: A Special Focus on COVID-19

2021 ◽  
Author(s):  
Burcu Biterge Süt
Keyword(s):  
Host Cell ◽  
Epigenetic Regulation ◽  
Viral Entry ◽  
Molecular Mechanisms ◽  
Viral Infections ◽  
Health Concern ◽  
Special Focus ◽  
Comprehensive Overview ◽  
Regulation Mechanisms ◽  
Host Metabolism

The outbreak of Coronavirus Disease-2019 (Covid-19), caused by a novel and highly pathogenic coronavirus (severe acute respiratory syndrome coronavirus-2, SARS-CoV-2), is a persisting global health concern. Research so far has successfully identified the molecular mechanisms of viral entry, alterations within the host cell upon infection, and the stimulation of an immune response to fight it. One of the most important cellular regulatory machineries within the host cell to be affected by the SARS-CoV-2 infection is epigenetic regulation, which modulates transcriptional activity by DNA sequence-independent factors such as DNA-methylation, RNA interference and histone modifications. Several studies in the literature have previously reported epigenetic alterations within the host due to infections of the Coronaviridae family viruses including SARS-CoV and MERS-CoV that antagonized immune system activation. Recent studies have also identified epigenetic dysregulation of host metabolism by SARS-CoV-2 infection, linking epigenetic mechanisms with the pathophysiology and illness severity of Covid-19. Therefore, this book chapter aims to provide a comprehensive overview of the epigenetic regulation mechanisms in viral infections with a special focus on SARS-CoV-2 infection.

E6 and E7 oncoproteins: Potential targets of cervical cancer

2020 ◽  
Vol 27 ◽  
Author(s):  
Ramarao Malla ◽  
Mohammad Amjad Kamal
Keyword(s):  
Cervical Cancer ◽  
Drug Resistance ◽  
Host Cell ◽  
Molecular Mechanisms ◽  
Immune Therapy ◽  
Cervical Lesions ◽  
Diagnostic Strategies ◽  
E6 And E7 Oncoproteins ◽  
E6 And E7

: Cervical cancer (CC) is the fourth leading cancer in women in the age group 15-44 globally. Experimental as well as epidemiological studies identified that type16 and 18 HPV cause 70% of precancerous cervical lesions as well as cervical cancer worldwide by bringing about genetic as well as epigenetic changes in the host genome. The insertion of the HPV genome triggers various defense mechanisms including the silencing of tumor suppressor genes as well as activation of oncogenes associated with cancer metastatic pathway. E6 and E7 are small oncoproteins consisting of 150 and 100 amino acids respectively. These oncoproteins affect the regulation of the host cell cycle by interfering with p53 and pRb. Further these oncoproteins adversely affect the normal functions of the host cell by binding to their signaling proteins. Recent studies demonstrated that E6 and E7 oncoproteins are potential targets for CC. Therefore, this review discusses the role of E6 and E7 oncoproteins in metastasis and drug resistance as well as their regulation, early oncogene mediated signaling pathways. This review also uncovers the recent updates on molecular mechanisms of E6 and E7 mediated phytotherapy, gene therapy, immune therapy, and vaccine strategies as well as diagnosis through precision testing. Therefore, understanding the potential role of E6/E7 in metastasis and drug resistance along with targeted treatment, vaccine, and precision diagnostic strategies could be useful for the prevention and treatment of cervical cancer.

scholarly journals Mutation of the N-Terminal Region of Chikungunya Virus Capsid Protein: Implications for Vaccine Design

mBio ◽  
2017 ◽  
Vol 8 (1) ◽  
Author(s):  
Adam Taylor ◽  
Xiang Liu ◽  
Ali Zaid ◽  
Lucas Y. H. Goh ◽  
Jody Hobson-Peters ◽  
...  
Keyword(s):  
Host Cell ◽  
Capsid Protein ◽  
Chikungunya Virus ◽  
Fluorescent Protein ◽  
Nuclear Translocation ◽  
Vaccine Design ◽  
Terminal Region ◽  
Site Directed Mutagenesis ◽  
Nucleolar Localization ◽  
Localization Sequence

ABSTRACTMosquito-transmitted chikungunya virus (CHIKV) is an arthritogenic alphavirus of theTogaviridaefamily responsible for frequent outbreaks of arthritic disease in humans. Capsid protein, a structural protein encoded by the CHIKV RNA genome, is able to translocate to the host cell nucleolus. In encephalitic alphaviruses, nuclear translocation induces host cell transcriptional shutoff; however, the role of capsid protein nucleolar localization in arthritogenic alphaviruses remains unclear. Using recombinant enhanced green fluorescent protein (EGFP)-tagged expression constructs and CHIKV infectious clones, we describe a nucleolar localization sequence (NoLS) in the N-terminal region of capsid protein, previously uncharacterized in CHIKV. Mutation of the NoLS by site-directed mutagenesis reduced efficiency of nuclear import of CHIKV capsid protein. In the virus, mutation of the capsid protein NoLS (CHIKV-NoLS) attenuated replication in mammalian and mosquito cells, producing a small-plaque phenotype. Attenuation of CHIKV-NoLS is likely due to disruption of the viral replication cycle downstream of viral RNA synthesis. In mice, CHIKV-NoLS infection caused no disease signs compared to wild-type CHIKV (CHIKV-WT)-infected mice; lack of disease signs correlated with significantly reduced viremia and decreased expression of proinflammatory factors. Mice immunized with CHIKV-NoLS, challenged with CHIKV-WT at 30 days postimmunization, develop no disease signs and no detectable viremia. Serum from CHIKV-NoLS-immunized mice is able to efficiently neutralize CHIKV infectionin vitro. Additionally, CHIKV-NoLS-immunized mice challenged with the related alphavirus Ross River virus showed reduced early and peak viremia postchallenge, indicating a cross-protective effect. The high degree of CHIKV-NoLS attenuation may improve CHIKV antiviral and rational vaccine design.IMPORTANCECHIKV is a mosquito-borne pathogen capable of causing explosive epidemics of incapacitating joint pain affecting millions of people. After a series of major outbreaks over the last 10 years, CHIKV and its mosquito vectors have been able to expand their range extensively, now making CHIKV a human pathogen of global importance. With no licensed vaccine or antiviral therapy for the treatment of CHIKV disease, there is a growing need to understand the molecular determinants of viral pathogenesis. These studies identify a previously uncharacterized nucleolar localization sequence (NoLS) in CHIKV capsid protein, begin a functional analysis of site-directed mutants of the capsid protein NoLS, and examine the effect of the NoLS mutation on CHIKV pathogenesisin vivoand its potential to influence CHIKV vaccine design. A better understanding of the pathobiology of CHIKV disease will aid the development of effective therapeutic strategies.

scholarly journals Host Cell Restriction Factors of Bunyaviruses and Viral Countermeasures

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 784
Author(s):  
Solène Lerolle ◽  
Natalia Freitas ◽  
François-Loïc Cosset ◽  
Vincent Legros
Keyword(s):  
Host Cell ◽  
Viral Entry ◽  
Current Knowledge ◽  
Restriction Factors ◽  
Antiviral State ◽  
Cellular Factors ◽  
Pathogenic Viruses ◽  
Genome Transcription ◽  
Infected Cells ◽  
Molecular Patterns

The Bunyavirales order comprises more than 500 viruses (generally defined as bunyaviruses) classified into 12 families. Some of these are highly pathogenic viruses infecting different hosts, including humans, mammals, reptiles, arthropods, birds, and/or plants. Host cell sensing of infection activates the innate immune system that aims at inhibiting viral replication and propagation. Upon recognition of pathogen-associated molecular patterns (PAMPs) by cellular pattern recognition receptors (PRRs), numerous signaling cascades are activated, leading to the production of interferons (IFNs). IFNs act in an autocrine and paracrine manner to establish an antiviral state by inducing the expression of hundreds of IFN-stimulated genes (ISGs). Some of these ISGs are known to restrict bunyavirus infection. Along with other constitutively expressed host cellular factors with antiviral activity, these proteins (hereafter referred to as “restriction factors”) target different steps of the viral cycle, including viral entry, genome transcription and replication, and virion egress. In reaction to this, bunyaviruses have developed strategies to circumvent this antiviral response, by avoiding cellular recognition of PAMPs, inhibiting IFN production or interfering with the IFN-mediated response. Herein, we review the current knowledge on host cellular factors that were shown to restrict infections by bunyaviruses. Moreover, we focus on the strategies developed by bunyaviruses in order to escape the antiviral state developed by the infected cells.

scholarly journals High-resolution view of HIV-1 reverse transcriptase initiation complexes and inhibition by NNRTI drugs

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Betty Ha ◽  
Kevin P. Larsen ◽  
Jingji Zhang ◽  
Ziao Fu ◽  
Elizabeth Montabana ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Viral Entry ◽  
Reverse Transcription ◽  
Molecular Mechanisms ◽  
Dissociation Kinetics ◽  
Structural Mechanism ◽  
Medium Resolution ◽  
Kinetics Of ◽  
Hiv 1

AbstractReverse transcription of the HIV-1 viral RNA genome (vRNA) is an integral step in virus replication. Upon viral entry, HIV-1 reverse transcriptase (RT) initiates from a host tRNALys3 primer bound to the vRNA genome and is the target of key antivirals, such as non-nucleoside reverse transcriptase inhibitors (NNRTIs). Initiation proceeds slowly with discrete pausing events along the vRNA template. Despite prior medium-resolution structural characterization of reverse transcriptase initiation complexes (RTICs), higher-resolution structures of the RTIC are needed to understand the molecular mechanisms that underlie initiation. Here we report cryo-EM structures of the core RTIC, RTIC–nevirapine, and RTIC–efavirenz complexes at 2.8, 3.1, and 2.9 Å, respectively. In combination with biochemical studies, these data suggest a basis for rapid dissociation kinetics of RT from the vRNA–tRNALys3 initiation complex and reveal a specific structural mechanism of nucleic acid conformational stabilization during initiation. Finally, our results show that NNRTIs inhibit the RTIC and exacerbate discrete pausing during early reverse transcription.

Receptor and Molecular Mechanism of AGGF1 Signaling in Endothelial Cell Functions and Angiogenesis

2021 ◽  
Author(s):  
Jingjing Wang ◽  
Huixin Peng ◽  
Ayse Anil Timur ◽  
Vinay Pasupuleti ◽  
Yufeng Yao ◽  
...  
Keyword(s):  
Amino Acids ◽  
Endothelial Cell ◽  
Neutralizing Antibodies ◽  
Molecular Mechanisms ◽  
Capillary Tube ◽  
Therapeutic Angiogenesis ◽  
Angiogenic Factor ◽  
Single Amino Acid ◽  
Binding Motif ◽  
Cell Functions

Objective: Angiogenic factor AGGF1 (angiogenic factor and G-patch and FHA [Forkhead-associated] domain 1) promotes angiogenesis as potently as VEGFA (vascular endothelial growth factor A) and regulates endothelial cell (EC) proliferation, migration, specification of multipotent hemangioblasts and venous ECs, hematopoiesis, and vascular development and causes vascular disease Klippel-Trenaunay syndrome when mutated. However, the receptor for AGGF1 and the underlying molecular mechanisms remain to be defined. Approach and Results: Using functional blocking studies with neutralizing antibodies, we identified α5β1 as the receptor for AGGF1 on ECs. AGGF1 interacts with α5β1 and activates FAK (focal adhesion kinase), Src, and AKT. Functional analysis of 12 serial N-terminal deletions and 13 C-terminal deletions by every 50 amino acids mapped the angiogenic domain of AGGF1 to a domain between amino acids 604-613 (FQRDDAPAS). The angiogenic domain is required for EC adhesion and migration, capillary tube formation, and AKT activation. The deletion of the angiogenic domain eliminated the effects of AGGF1 on therapeutic angiogenesis and increased blood flow in a mouse model for peripheral artery disease. A 40-mer or 15-mer peptide containing the angiogenic domain blocks AGGF1 function, however, a 15-mer peptide containing a single amino acid mutation from −RDD- to −RGD- (a classical RGD integrin-binding motif) failed to block AGGF1 function. Conclusions: We have identified integrin α5β1 as an EC receptor for AGGF1 and a novel AGGF1-mediated signaling pathway of α5β1-FAK-Src-AKT for angiogenesis. Our results identify an FQRDDAPAS angiogenic domain of AGGF1 crucial for its interaction with α5β1 and signaling.

The antiviral lectin cyanovirin-N: probing multivalency and glycan recognition through experimental and computational approaches

2013 ◽  
Vol 41 (5) ◽  
pp. 1170-1176 ◽  
Author(s):  
Brian W. Woodrum ◽  
Jason D. Maxwell ◽  
Ashini Bolia ◽  
S. Banu Ozkan ◽  
Giovanna Ghirlanda
Keyword(s):  
Viral Entry ◽  
High Specificity ◽  
Integrated Approach ◽  
Protein Gp120 ◽  
Computational Work ◽  
Gp120 Glycoprotein ◽  
Anti Hiv Agents ◽  
Anti Hiv ◽  
Envelope Protein Gp120

CVN (cyanovirin-N), a small lectin isolated from cyanobacteria, exemplifies a novel class of anti-HIV agents that act by binding to the highly glycosylated envelope protein gp120 (glycoprotein 120), resulting in inhibition of the crucial viral entry step. In the present review, we summarize recent work in our laboratory and others towards determining the crucial role of multivalency in the antiviral activity, and we discuss features that contribute to the high specificity and affinity for the glycan ligand observed in CVN. An integrated approach that encompasses structural determination, mutagenesis analysis and computational work holds particular promise to clarify aspects of the interactions between CVN and glycans.

Sign in / Sign up

Export Citation Format

Share Document