scholarly journals COVID-19 Pandemic: Insights into Structure, Function, and hACE2 Receptor Recognition by SARS-CoV-2

2020 ◽  
Author(s):  
Anshumali Mittal ◽  
Kavyashree Manjunath ◽  
Rajesh Kumar Ranjan ◽  
Sandeep Kaushik ◽  
Sujeet Kumar ◽  
...  
Keyword(s):  
Host Cell ◽  
Receptor Binding ◽  
Conformational Changes ◽  
Large Scale ◽  
Current Knowledge ◽  
Structural Characteristics ◽  
Global Public Health ◽  
Host Cell Membrane ◽  
Origin And Evolution ◽  
Receptor Recognition

SARS-CoV-2 is a newly emerging, highly transmissible, and pathogenic coronavirus in humans, which has caused global public health emergency and economic crisis. To date, millions of infections and thousands of deaths have been reported worldwide, and the numbers continue to rise. Currently, there is no specific drug or vaccine against this deadly virus; therefore, there is a pressing need to understand the mechanism through which this virus enters the host cell. Viral entry into the host cell is a multistep process in which SARS-CoV-2 utilizes the receptor binding domain of the spike glycoprotein (S) to recognize ACE2 receptors on the human cells; this initiates host cell entry by promoting viral-host cell membrane fusion through large scale conformational changes in the S protein. Receptor recognition and fusion are critical and essential steps of viral infections and are key determinants of the viral host range and cross-species transmission. In this review, we summarize the current knowledge on the origin and evolution of SARS-CoV-2 and the roles of key viral factors. We discuss the RNA dependent RNA polymerase structure of SARS-CoV-2, its significance in drug discovery, and explain the receptor recognition mechanisms of coronaviruses. We provide a comparative analysis of the SARS-CoV and SARS-CoV-2 S proteins, receptor-binding specificity, and discuss the differences in their antigenicity based on biophysical and structural characteristics.

scholarly journals COVID-19 Pandemic: Insights into Structure, Function, and hACE2 Receptor Recognition by the SARS-CoV-2

2020 ◽  
Author(s):  
Anshumali Mittal ◽  
Kavyashree Manjunath ◽  
Rajesh Kumar Ranjan ◽  
Sandeep Kaushik ◽  
Sujeet Kumar ◽  
...  
Keyword(s):  
Host Cell ◽  
Receptor Binding ◽  
Conformational Changes ◽  
Large Scale ◽  
Current Knowledge ◽  
Structural Characteristics ◽  
Global Public Health ◽  
Host Cell Membrane ◽  
Origin And Evolution ◽  
Receptor Recognition

SARS-CoV-2 is a newly emerging, highly transmissible, and pathogenic coronavirus in humans, which has caused global public health emergency and economic crisis. To date, millions of infections and thousands of deaths have been reported worldwide, and the numbers continue to rise. Currently, there is no specific drug or vaccine against this deadly virus; therefore, there is a pressing need to understand the mechanism through which this deadly virus enters the host cell. Viral entry into the host cell is a multistep process in which SARS-CoV-2 utilizes the receptor binding domain of the spike glycoprotein (S) to recognize ACE2 receptors on the human cells; this initiates the host cell entry by promoting the viral-host cell membrane fusion through large scale conformational changes in the S protein. Receptor recognition and fusion are critical and essential steps of viral infections and are key determinants of the viral host range and cross-species transmission. In this review, we summarize the current knowledge on the origin and evolution of SARS-CoV-2, roles of key viral factors and discuss the receptor recognition mechanisms of coronaviruses. We provide a comparative analysis of the SARS-CoV and SARS-CoV-2 S proteins, receptor-binding specificity, and discuss the differences in their antigenicity based on biophysical and structural characteristics. Finally, we dive into available medications, and the current COVID-19 treatment options, which will be beneficial for the scientific community as well as for the general public.

scholarly journals Hemagglutinin-Mediated Membrane Fusion: A Biophysical Perspective

2018 ◽  
Vol 47 (1) ◽  
pp. 153-173 ◽  
Author(s):  
Sander Boonstra ◽  
Jelle S. Blijleven ◽  
Wouter H. Roos ◽  
Patrick R. Onck ◽  
Erik van der Giessen ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Host Cell ◽  
Conformational Changes ◽  
Fusion Process ◽  
Host Cell Membrane ◽  
Activation Barriers ◽  
Viral Membrane ◽  
Influenza Hemagglutinin ◽  
Working Together

Influenza hemagglutinin (HA) is a viral membrane protein responsible for the initial steps of the entry of influenza virus into the host cell. It mediates binding of the virus particle to the host-cell membrane and catalyzes fusion of the viral membrane with that of the host. HA is therefore a major target in the development of antiviral strategies. The fusion of two membranes involves high activation barriers and proceeds through several intermediate states. Here, we provide a biophysical description of the membrane fusion process, relating its kinetic and thermodynamic properties to the large conformational changes taking place in HA and placing these in the context of multiple HA proteins working together to mediate fusion. Furthermore, we highlight the role of novel single-particle experiments and computational approaches in understanding the fusion process and their complementarity with other biophysical approaches.

scholarly journals Reovirus Infection Activates JNK and the JNK-Dependent Transcription Factor c-Jun

2001 ◽  
Vol 75 (23) ◽  
pp. 11275-11283 ◽  
Author(s):  
Penny Clarke ◽  
Suzanne M. Meintzer ◽  
Christian Widmann ◽  
Gary L. Johnson ◽  
Kenneth L. Tyler
Keyword(s):  
Transcription Factor ◽  
Host Cell ◽  
Receptor Binding ◽  
Cell Interaction ◽  
Host Cell Membrane ◽  
Erk Activation ◽  
Reovirus Infection ◽  
Induced Apoptosis ◽  
Factor C ◽  
Jnk Activation

ABSTRACT Viral infection often perturbs host cell signaling pathways including those involving mitogen-activated protein kinases (MAPKs). We now show that reovirus infection results in the selective activation of c-Jun N-terminal kinase (JNK). Reovirus-induced JNK activation is associated with an increase in the phosphorylation of the JNK-dependent transcription factor c-Jun. Reovirus serotype 3 prototype strains Abney (T3A) and Dearing (T3D) induce significantly more JNK activation and c-Jun phosphorylation than does the serotype 1 prototypic strain Lang (T1L). T3D and T3A also induce more apoptosis in infected cells than T1L, and there was a significant correlation between the ability of these viruses to phosphorylate c-Jun and induce apoptosis. However, reovirus-induced apoptosis, but not reovirus-induced c-Jun phosphorylation, is inhibited by blocking TRAIL/receptor binding, suggesting that apoptosis and c-Jun phosphorylation involve parallel rather than identical pathways. Strain-specific differences in JNK activation are determined by the reovirus S1 and M2 gene segments, which encode viral outer capsid proteins (ς1 and μ1c) involved in receptor binding and host cell membrane penetration. These same gene segments also determine differences in the capacity of reovirus strains to induce apoptosis, and again a significant correlation between the capacity of T1L × T3D reassortant reoviruses to both activate JNK and phosphorylate c-Jun and to induce apoptosis was shown. The extracellular signal-related kinase (ERK) is also activated in a strain-specific manner following reovirus infection. Unlike JNK activation, ERK activation could not be mapped to specific reovirus gene segments, suggesting that ERK activation and JNK activation are triggered by different events during virus-host cell interaction.

scholarly journals A modular molecular framework for quickly estimating the binding affinity of the spike protein of SARS-CoV-2 variants for ACE2, in presence of mutations at the spike receptor binding domain.

2021 ◽  
Author(s):  
Vincenzo Tragni ◽  
Francesca Preziusi ◽  
Luna Laera ◽  
Angelo Onofrio ◽  
Simona Todisco ◽  
...  
Keyword(s):  
Host Cell ◽  
Receptor Binding ◽  
Conformational Changes ◽  
Binding Domain ◽  
Host Cells ◽  
Spike Protein ◽  
Binding Affinities ◽  
Receptor Binding Domain ◽  
Rapid Spread ◽  
Related Proteins

The rapid spread of new SARS-CoV-2 variants needs the development of rapid tools for predicting the affinity of the mutated proteins responsible for the infection, i.e., the SARS-CoV-2 spike protein, for the human ACE2 receptor, aiming to understand if a variant can be more efficient in invading host cells. Here we show how our computational pipeline, previously used for studying SARS-CoV-2 spike receptor-binding domain (RBD)/ACE2 interactions and pre-/post-fusion conformational changes, can be used for predicting binding affinities of the human ACE2 receptor for the spike protein RBD of the characterized infectious variants of concern/interest B.1.1.7-UK (carrying the mutations N501Y, S494P, E484K at the RBD), P.1-Japan/Brazil (RBD mutations: K417N/T, E484K, N501Y), B.1.351-South Africa (RBD mutations: K417N, E484K, N501Y), B.1.427/B.1.429-California (RBD mutations: L452R), the B.1.141 variant (RBD mutations: N439K), and the recent B.1.617.1-India (RBD mutations: L452R; E484Q) and the B.1.620 (RBD mutations: S477N; E484K). Furthermore, we searched for ACE2 structurally related proteins that might be involved in interactions with the SARS-CoV-2 spike protein, in those tissues showing low ACE2 expression, revealing two new proteins, THOP1 and NLN, deserving to be investigated for their possible inclusion in the group of host-cell entry factors responsible for host-cell SARS-CoV-2 invasion and immunity response.

scholarly journals Fusion Promotion by a Paramyxovirus Hemagglutinin-Neuraminidase Protein: pH Modulation of Receptor Avidity of Binding Sites I and II

2007 ◽  
Vol 81 (17) ◽  
pp. 9152-9161 ◽  
Author(s):  
Laura M. Palermo ◽  
Matteo Porotto ◽  
Olga Greengard ◽  
Anne Moscona
Keyword(s):  
Host Cell ◽  
Receptor Binding ◽  
Viral Entry ◽  
Ph Dependence ◽  
Initial Step ◽  
Viral Envelope ◽  
Respiratory Pathogen ◽  
Receptor Binding Site ◽  
Host Cell Membrane ◽  
Neutral Ph

ABSTRACT Paramyxoviruses, including the childhood respiratory pathogen human parainfluenza virus type 3 (HPIV3), possess an envelope protein hemagglutinin-neuraminidase (HN) that has receptor-cleaving (neuraminidase), as well as receptor-binding, activity. HN is a type II transmembrane glycoprotein, present on the surface of the virus as a tetramer composed of two dimers. HN is also essential for activating the fusion protein (F) to mediate merger of the viral envelope with the host cell membrane. This initial step of viral entry occurs at the host cell surface at neutral pH. The HN molecule carries out these three different critical activities at specific points in the process of viral entry, and understanding the regulation of these activities is key for the design of strategies that block infection. One bifunctional site (site I) on the HN of HPIV3 possesses both receptor binding and neuraminidase activities, and we recently obtained experimental evidence for a second receptor binding site (site II) on HPIV3 HN. Mutation of HN at specific residues at this site, which is next to the HN dimer interface, confers enhanced fusion properties, without affecting neuraminidase activity or receptor binding at neutral pH. We now demonstrate that mutations at this site II, as well as at site I, confer pH dependence on HN′s receptor avidity. These mutations permit pH to modulate the binding and fusion processes of the virus, potentially providing regulation at specific stages of the viral life cycle.

scholarly journals Mechanisms of phosphatidylserine influence on viral production: a computational model of Ebola virus matrix protein assembly

2021 ◽  
Author(s):  
Xiao Liu ◽  
Ethan J Pappas ◽  
Monica L Husby ◽  
Robert V Stahelin ◽  
Elsje Pienaar
Keyword(s):  
Cell Membrane ◽  
Computational Model ◽  
Host Cell ◽  
Matrix Protein ◽  
Ebola Virus ◽  
Global Public Health ◽  
Matrix Assembly ◽  
Host Cell Membrane ◽  
Western Africa

Ebola virus (EBOV) infections continue to pose a global public health threat, with high mortality rates and sporadic outbreaks in Central and Western Africa. A quantitative understanding of the key processes driving EBOV assembly and budding could provide valuable insights to inform drug development. Here we used a computational model to evaluate EBOV matrix assembly. Our model focused on the assembly kinetics of VP40, the matrix protein in EBOV, and its interaction with phosphatidylserine (PS) in the host cell membrane. Human cells transfected with VP40-expressing plasmids are capable of producing virus-like particles (VLPs) that closely resemble EBOV virions. We used data from this in vitro VP40 system to calibrate our computational model. PS levels in the host cell membrane had been shown to affect VP40 dynamics as well as VLP production through recruiting VP40 dimers to plasma membrane inner leaflet. Our computational results indicated that PS may have direct influence on VP40 filament growth and affect multiple steps in the assembly and budding of VP40 VLPs. We also proposed that the assembly of VP40 filaments may follow the nucleation-elongation theory where initialization and oligomerization of VP40 are two separate and distinct steps in the assembly process. This work illustrated how computational and experimental approaches can be combined to allow for additional analysis and hypothesis generation. Our findings advanced understanding of the molecular process of EBOV assembly and budding processes and may help the development of new EBOV treatments targeting VP40 matrix assembly.

Double Lock of a Potent Human Monoclonal Antibody against SARS-CoV-2

2020 ◽  
Author(s):  
Ling Zhu ◽  
Yong-Qiang Deng ◽  
Rong-Rong Zhang ◽  
Zhen Cui ◽  
Chun-Yun Sun ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Membrane Fusion ◽  
Receptor Binding ◽  
Conformational Changes ◽  
Rhesus Macaques ◽  
Human Monoclonal Antibody ◽  
List Type ◽  
Viral Receptor ◽  
Successful Infection ◽  
Receptor Recognition

SummaryReceptor recognition and subsequent membrane fusion are essential for the establishment of successful infection by SARS-CoV-2. Halting these steps can cure COVID-19. Here we have identified and characterized a potent human monoclonal antibody, HB27, that blocks SARS-CoV-2 attachment to its cellular receptor at sub-nM concentrations. Remarkably, HB27 can also prevent SARS-CoV-2 membrane fusion. Consequently, a single dose of HB27 conferred effective protection against SARS-CoV-2 in two established mouse models. Rhesus macaques showed no obvious adverse events when administrated with 10-fold of effective dose of HB27. Cryo-EM studies on complex of SARS-CoV-2 trimeric S with HB27 Fab reveal that three Fab fragments work synergistically to occlude SARS-CoV-2 from binding to ACE2 receptor. Binding of the antibody also restrains any further conformational changes of the RBD, possibly interfering with progression from the prefusion to the postfusion stage. These results suggest that HB27 is a promising candidate for immuno-therapies against COVID-19.HighlightsSARS-CoV-2 specific antibody, HB27, blocks viral receptor binding and membrane fusionHB27 confers prophylactic and therapeutic protection against SARS-CoV-2 in mice modelsRhesus macaques showed no adverse side effects when administered with HB27Cryo-EM studies suggest that HB27 sterically occludes SARS-CoV-2 from its receptor

scholarly journals Structural intermediates in the low pH-induced transition of influenza hemagglutinin

2020 ◽  
Vol 16 (11) ◽  
pp. e1009062
Author(s):  
Jingjing Gao ◽  
Miao Gui ◽  
Ye Xiang
Keyword(s):  
Host Cell ◽  
Conformational Change ◽  
Conformational Changes ◽  
Virus Entry ◽  
Low Ph ◽  
Influenza Viruses ◽  
Fusion Peptides ◽  
Host Cell Membrane ◽  
Influenza Hemagglutinin ◽  
Binding Pockets

The hemagglutinin (HA) glycoproteins of influenza viruses play a key role in binding host cell receptors and in mediating virus-host cell membrane fusion during virus infection. Upon virus entry, HA is triggered by low pH and undergoes large structural rearrangements from a prefusion state to a postfusion state. While structures of prefusion state and postfusion state of HA have been reported, the intermediate structures remain elusive. Here, we report two distinct low pH intermediate conformations of the influenza virus HA using cryo-electron microscopy (cryo-EM). Our results show that a decrease in pH from 7.8 to 5.2 triggers the release of fusion peptides from the binding pockets and then causes a dramatic conformational change in the central helices, in which the membrane-proximal ends of the central helices unwind to an extended form. Accompanying the conformational changes of the central helices, the stem region of the HA undergoes an anticlockwise rotation of 9.5 degrees and a shift of 15 Å. The HA head, after being stabilized by an antibody, remains unchanged compared to the neutral pH state. Thus, the conformational change of the HA stem region observed in our research is likely to be independent of the HA head. These results provide new insights into the structural transition of HA during virus entry.

scholarly journals SARS-CoV-2, Early Entry Events

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
James P. Chambers ◽  
Jieh Yu ◽  
James J. Valdes ◽  
Bernard P. Arulanandam
Keyword(s):  
Host Cell ◽  
Receptor Binding ◽  
Conformational Changes ◽  
Cell Types ◽  
Proteolytic Processing ◽  
Binding Motif ◽  
Susceptible Host ◽  
S Protein ◽  
Protein Receptor ◽  
Specific Protease

Viruses are obligate intracellular parasites, and host cell entry is the first step in the viral life cycle. The SARS-CoV-2 (COVID-19) entry process into susceptible host tissue cells is complex requiring (1) attachment of the virus via the conserved spike (S) protein receptor-binding motif (RBM) to the host cell angiotensin-converting-enzyme 2 (ACE2) receptor, (2) S protein proteolytic processing, and (3) membrane fusion. Spike protein processing occurs at two cleavage sites, i.e., S1/S2 and S 2 ′ . Cleavage at the S1/S2 and S 2 ′ sites ultimately gives rise to generation of competent fusion elements important in the merging of the host cell and viral membranes. Following cleavage, shedding of the S1 crown results in significant conformational changes and fusion peptide repositioning for target membrane insertion and fusion. Identification of specific protease involvement has been difficult due to the many cell types used and studied. However, it appears that S protein proteolytic cleavage is dependent on (1) furin and (2) serine protease transmembrane protease serine 2 proteases acting in tandem. Although at present not clear, increased SARS-CoV-2 S receptor-binding motif binding affinity and replication efficiency may in part account for observed differences in infectivity. Cleavage of the ACE2 receptor appears to be yet another layer of complexity in addition to forfeiture and/or alteration of ACE2 function which plays an important role in cardiovascular and immune function.

scholarly journals Origin and evolution of nonulosonic acid synthases and their relationship with bacterial pathogenicity revealed by a large-scale phylogenetic analysis

2021 ◽  
Vol 7 (4) ◽  
Author(s):  
Alexandre Zanatta Vieira ◽  
Roberto Tadeu Raittz ◽  
Helisson Faoro
Keyword(s):  
Phylogenetic Analysis ◽  
Pathogenic Bacteria ◽  
Large Scale ◽  
Membrane Surface ◽  
Reference Sequence ◽  
Host Cell Membrane ◽  
Specific Domain ◽  
Content Type ◽  
Origin And Evolution ◽  
Environmental Bacteria

Nonulosonic acids (NulOs) are a group of nine-carbon monosaccharides with different functions in nature. N-acetylneuraminic acid (Neu5Ac) is the most common NulO. It covers the membrane surface of all human cells and is a central molecule in the process of self-recognition via SIGLECS receptors. Some pathogenic bacteria escape the immune system by copying the sialylation of the host cell membrane. Neu5Ac production in these bacteria is catalysed by the enzyme NeuB. Some bacteria can also produce other NulOs named pseudaminic and legionaminic acids, through the NeuB homologues PseI and LegI, respectively. In Opisthokonta eukaryotes, the biosynthesis of Neu5Ac is catalysed by the enzyme NanS. In this study, we used publicly available data of sequences of NulOs synthases to investigate its distribution within the three domains of life and its relationship with pathogenic bacteria. We mined the KEGG database and found 425 NeuB sequences. Most NeuB sequences (58.74 %) from the KEGG orthology database were classified as from environmental bacteria; however, sequences from pathogenic bacteria showed higher conservation and prevalence of a specific domain named SAF. Using the HMM profile we identified 13 941 NulO synthase sequences in UniProt. Phylogenetic analysis of these sequences showed that the synthases were divided into three main groups that can be related to the lifestyle of these bacteria: (I) predominantly environmental, (II) intermediate and (III) predominantly pathogenic. NeuB was widely distributed in the groups. However, LegI and PseI were more concentrated in groups II and III, respectively. We also found that PseI appeared later in the evolutionary process, derived from NeuB. We use this same methodology to retrieve sialic acid synthase sequences from Archaea and Eukarya. A large-scale phylogenetic analysis showed that while the Archaea sequences are spread across the tree, the eukaryotic NanS sequences were grouped in a specific branch in group II. None of the bacterial NanS sequences grouped with the eukaryotic branch. The analysis of conserved residues showed that the synthases of Archaea and Eukarya present a mutation in one of the three catalytic residues, an E134D change, related to a Neisseria meningitidis reference sequence. We also found that the conservation profile is higher between NeuB of pathogenic bacteria and NanS of eukaryotes than between NeuB of environmental bacteria and NanS of eukaryotes. Our large-scale analysis brings new perspectives on the evolution of NulOs synthases, suggesting their presence in the last common universal ancestor.

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