scholarly journals Comparative ACE2 variation and primate COVID-19 risk

2020 ◽  
Author(s):  
Amanda D. Melin ◽  
Mareike C. Janiak ◽  
Frank Marrone ◽  
Paramjit S. Arora ◽  
James P. Higham
Keyword(s):  
Amino Acid ◽  
Nonhuman Primates ◽  
Rhesus Macaques ◽  
Cell Receptor ◽  
Primate Species ◽  
Vervet Monkeys ◽  
Amino Acid Residues ◽  
Host Cell Receptor ◽  
Contact Residues ◽  
Novel Coronavirus

AbstractThe emergence of the novel coronavirus SARS-CoV-2, which in humans is highly infectious and leads to the potentially fatal disease COVID-19, has caused hundreds of thousands of deaths and huge global disruption. The viral infection may also represent an existential threat to our closest living relatives, the nonhuman primates, many of which are endangered and often reduced to small populations. The virus engages the host cell receptor, angiotensin-converting enzyme-2 (ACE2), through the receptor binding domain (RBD) on the spike protein. The contact surface of ACE2 displays amino acid residues that are critical for virus recognition, and variations at these critical residues are likely to modulate infection susceptibility across species. While infection studies are emerging and have shown that some primates, such as rhesus macaques and vervet monkeys, develop COVID-19-like symptoms when exposed to the virus, the susceptibility of many other nonhuman primates is unknown. Here, we show that all apes, including chimpanzees, bonobos, gorillas, and orangutans, and all African and Asian monkeys (catarrhines), exhibit the same set of twelve key amino acid residues as human ACE2. Monkeys in the Americas, and some tarsiers, lemurs and lorisoids, differ at significant contact residues, and protein modeling predicts that these differences should greatly reduce the binding affinity of the ACE2 for the virus, hence moderating their susceptibility for infection. Other lemurs are predicted to be closer to catarrhines in their susceptibility. Our study suggests that apes and African and Asian monkeys, as well as some lemurs are all likely to be highly susceptible to SARS-CoV-2, representing a critical threat to their survival. Urgent actions have been undertaken to limit the exposure of Great Apes to humans, and similar efforts may be necessary for many other primate species.

scholarly journals Comparative ACE2 variation and primate COVID-19 risk

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Amanda D. Melin ◽  
Mareike C. Janiak ◽  
Frank Marrone ◽  
Paramjit S. Arora ◽  
James P. Higham
Keyword(s):  
Amino Acid ◽  
Nonhuman Primates ◽  
Cell Receptor ◽  
Primate Species ◽  
Amino Acid Residues ◽  
Host Cell Receptor ◽  
Infection Susceptibility ◽  
Contact Residues ◽  
Critical Residues ◽  
Critical Contact

Abstract The emergence of SARS-CoV-2 has caused over a million human deaths and massive global disruption. The viral infection may also represent a threat to our closest living relatives, nonhuman primates. The contact surface of the host cell receptor, ACE2, displays amino acid residues that are critical for virus recognition, and variations at these critical residues modulate infection susceptibility. Infection studies have shown that some primate species develop COVID-19-like symptoms; however, the susceptibility of most primates is unknown. Here, we show that all apes and African and Asian monkeys (catarrhines), exhibit the same set of twelve key amino acid residues as human ACE2. Monkeys in the Americas, and some tarsiers, lemurs and lorisoids, differ at critical contact residues, and protein modeling predicts that these differences should greatly reduce SARS-CoV-2 binding affinity. Other lemurs are predicted to be closer to catarrhines in their susceptibility. Our study suggests that apes and African and Asian monkeys, and some lemurs, are likely to be highly susceptible to SARS-CoV-2. Urgent actions have been undertaken to limit the exposure of great apes to humans, and similar efforts may be necessary for many other primate species.

Herbal Medicine in Fighting Against COVID-19: New Battle with an Old Weapon

2021 ◽  
Vol 22 ◽  
Author(s):  
Ranjit K. Harwansh ◽  
Shiv Bahadur
Keyword(s):  
Herbal Medicine ◽  
Rna Virus ◽  
Plant Secondary Metabolites ◽  
Cell Receptor ◽  
Inhibitory Effect ◽  
World Population ◽  
Main Process ◽  
Potential Health ◽  
Host Cell Receptor ◽  
Novel Coronavirus

: World population has been suffering due to the outbreak of present pandemic situation of COVID-19. The disease has become life-threatening in a very short time with touching on most of the citizenry and economic systems globally. The novel virus, SARS-CoV-2 has been known as the causative agent of COVID-19. The SARS-CoV-2 is single stranded RNA virus having ~30 kb genomic components which are 70% identical to SARS-CoV. The main process of pathophysiology of COVID-19 has been associated with the interaction of a novel coronavirus with host cell receptor, angiotensin-converting enzyme-2 (ACE 2) by fusion. Therapeutic agents having serine protease inhibitors and ACE-2 blockers may be explored for the treatment by inhibiting the viral target such as Mpro, RdRp, PLpro and helicase. Herbal medicine has a wide array chemical entity with potential health benefits including antiviral activity which may be explored as alternative treatment of COVID-19. The herbal bioactives like catechins, andrographolide, hesperidin, biorobin, scutellarein, silvestrol, shikonin, tryptanthrin, vitexin quercetin, myricetin, caffeic acid, psoralidin, luteolin etc have showed potential inhibitory effect against SARS-CoV-2. Recent research reports indicate that the various plant secondary metabolites have shown the potential antiviral activities. The present review article highlights on the recent information on the mechanism of actions and applications of herbal medicine in the treatment of COVID-19.

scholarly journals Human red blood cell Wright antigens: a genetic and evolutionary perspective on glycophorin A-band 3 interaction

Blood ◽  
1996 ◽  
Vol 87 (9) ◽  
pp. 3942-3947 ◽  
Author(s):  
CH Huang ◽  
ME Reid ◽  
SS Xie ◽  
OO Blumenfeld
Keyword(s):  
Amino Acid ◽  
Nonhuman Primates ◽  
Antigen Expression ◽  
Band 3 ◽  
Structural Basis ◽  
Antigenic Structure ◽  
Glycophorin A ◽  
Amino Acid Residues ◽  
Protein Protein Interaction ◽  
Human Red Blood Cells

The Wright (Wra/Wrb) blood group polymorphism is defined by an allelic change (Lys658Glu) in the band 3 protein; nevertheless, the Wrb antigen apparently requires glycophorin A (GPA) for surface presentation. To gain insight into the structural basis for this protein-protein interaction and delineate its relationship with Wrb antigen expression, we investigated GPA and band 3 sequence polymorphisms occurring in rare humans and nonhuman primates. The lack of GPA or amino acid residues 59 through 71 of GPA results in the absence of Wrb from human red blood cells (RBCs) exhibiting the MkMk, En(a-), or MiV phenotype. However, the SAT homozygous cells carried a Glu658 form of band 3 and a hybrid glycophorin with the entire GPA extramembrane domain from residues 1 through 71, yet expressed no Wrb antigen. This finding suggests that formation of the Wrb antigenic structure is dependent on protein folding and that the transmembrane junction of GPA is important in maintaining the required conformation. Comparative analyses of GPA and band 3 homologues led to the identification in the interacting regions of conserved and dispensable amino acid residues that correlated with the Wrb positive or negative status on nonhuman primates. In particular, the chimpanzee RBCs cells expressed Wrb and the Glu658 form of band 3, which is identical to humans, but their GPA contained the Gly rather than Arg residue at position 61. Taken together, the results suggest that (1) Arg61 of GPA and the proposed Arg61-Glu658 charge pair are not crucial for Wrb antigen exhibition and (2) the role of GPA for interaction with band 3, including Glu658, probably involves a number of amino acid residues located in the alpha-helical region and transmembrane junction.

scholarly journals Recombination and purifying selection preserves covariant movements of mosaic SARS-CoV-2 protein S

2020 ◽  
Author(s):  
Massimiliano S. Tagliamonte ◽  
Nabil Abid ◽  
David A. Ostrov ◽  
Giovanni Chillemi ◽  
Sergei L. Kosakovsky Pond ◽  
...  
Keyword(s):  
Purifying Selection ◽  
Protein S ◽  
Cell Receptor ◽  
The Novel ◽  
Amino Acid Residues ◽  
Dynamic Simulations ◽  
Viral Spread ◽  
Host Cell Receptor ◽  
Pandemic Strains

AbstractIn depth evolutionary and structural analyses of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) isolated from bats, pangolins, and humans are necessary to assess the role of natural selection and recombination in the emergence of the current pandemic strain. The SARS-CoV-2 S glycoprotein unique features have been associated with efficient viral spread in the human population. Phylogeny-based and genetic algorithm methods clearly show that recombination events between viral progenitors infecting animal hosts led to a mosaic structure in the S gene. We identified recombination coldspots in the S glycoprotein and strong purifying selection. Moreover, although there is little evidence of diversifying positive selection during host-switching, structural analysis suggests that some of the residues emerged along the ancestral lineage of current pandemic strains may contribute to enhanced ability to infect human cells. Interestingly, recombination did not affect the long-range covariant movements of SARS-CoV-2 S glycoprotein monomer in pre-fusion conformation but, on the contrary, could contribute to the observed overall viral efficiency. Our dynamic simulations revealed that the movements between the host cell receptor binding domain (RBD) and the novel furin-like cleavage site are correlated. We identified threonine 333 (under purifying selection), at the beginning of the RBD, as the hinge of the opening/closing mechanism of the SARS-CoV-2 S glycoprotein monomer functional to hACE2 binding. Our findings support a scenario where ancestral recombination and fixation of amino acid residues in the RBD of the S glycoprotein generated a virus with unique features, capable of extremely efficient infection of the human host.

scholarly journals Decomposition of the SARS-CoV-2-ACE2 interface reveals a common trend among emerging viral variants

2021 ◽  
Author(s):  
Eileen Socher ◽  
Marcus Conrad ◽  
Lukas Heger ◽  
Friedrich Paulsen ◽  
Heinrich Sticht ◽  
...  
Keyword(s):  
Amino Acid ◽  
Host Cell ◽  
Cell Receptor ◽  
Cell Interaction ◽  
Therapeutic Interventions ◽  
Host Cell Receptor ◽  
Common Trend ◽  
Binding Interface ◽  
Dynamics Simulations ◽  
Viral Surface

New viral variants of the SARS-CoV-2 virus show enhanced infectivity compared to wild type, resulting in an altered pandemic situation in affected areas. These variants are the B.1.1.7 (United Kingdom), B.1.1.7 with the additional E484K mutation, the B.1.351 variant (South Africa) and the P.1 variant (Brazil). Understanding the binding modalities between these viral variants and the host cell receptor ACE2 allows depicting changes, but also common motifs of virus-host cell interaction. The trimeric spike protein expressed at the viral surface contains the receptor-binding domain (RBD) that forms the molecular interface with ACE2. All the above-mentioned variants carry between one and three amino acid exchanges within the interface-forming region of the RBD, thereby altering the binding interface with ACE2. Using molecular dynamics simulations and decomposition of the interaction energies between the RBD and ACE2, we identified phenylalanine 486, glutamine 498, threonine 500 and tyrosine 505 as important interface-forming residues across viral variants. We also suggest a reduced binding energy between RBD and ACE2 in viral variants with higher infectivity, attributed to residue-specific differences in electrostatic interaction energy. Importantly, individual amino acid exchanges not only influence the affected position, but also alter the conformation of surrounding residues and affect their interaction potential as well. We demonstrate how computational methods can help to identify changed as well as common motifs across viral variants. These identified motifs might play a crucial role, in the strategical development of therapeutic interventions against the fast mutating SARS-CoV-2 virus.

scholarly journals Peptide recognition and dephosphorylation by the vaccinia VH1 phosphatase

2020 ◽  
Author(s):  
Bryan M. Zhao ◽  
Megan Hogan ◽  
Michael S Lee ◽  
Beverly K. Dyas ◽  
Robert G. Ulrich
Keyword(s):  
Amino Acid ◽  
Protein Interactions ◽  
Catalytic Site ◽  
Site Directed Mutagenesis ◽  
Amino Acid Residues ◽  
Protein Protein Interactions ◽  
Host Cell Proteins ◽  
Enzyme Substrate ◽  
Dual Specificity ◽  
Contact Residues

ABSTRACTThe VH1 protein encoded by the highly conserved H1 locus of orthopoxviruses is a dual-specificity phosphatase (DUSPs) that hydrolyzes phosphate groups from phosphorylated tyrosine, serine, and threonine residues of viral and host cell proteins. Because the DUSP activities are required for virus replication, VH1 is a prime target for the development of therapeutic inhibitors. However, the presentation of a shallow catalytic site has thwarted all drug development efforts. As an alternative to direct targeting of catalytic pockets, we describe surface contacts between VH1 and substrates that are essential for full activity and provide a new pathway for developing inhibitors of protein-protein interactions. Critical amino acid residues were manipulated by site-directed mutagenesis of VH1, and perturbation of peptide substrate interactions based on these mutations were assessed by high-throughput assays that employed surface plasmon resonance and phosphatase activities. Two positively-charged residues (Lys-20 and Lys-22) and the hydrophobic side chain of Met-60 appear to orient the polarity of the pTyr peptide on the VH1 surface, while additional amino acid residues that flank the catalytic site contribute to substrate recognition and productive dephosphorylation. We propose that the enzyme-substrate contact residues described here may serve as molecular targets for the development of inhibitors that specifically block VH1 catalytic activity and thus poxvirus replication.

scholarly journals Pangolin homology associated with 2019-nCoV

2020 ◽  
Author(s):  
Tao Zhang ◽  
Qunfu Wu ◽  
Zhigang Zhang
Keyword(s):  
Amino Acid ◽  
Intermediate Host ◽  
Common Ancestor ◽  
Whole Genome ◽  
Amino Acid Residues ◽  
Pathogenic Potential ◽  
Lowest Common Ancestor ◽  
Amino Acid Mutations ◽  
Genome Level ◽  
Novel Coronavirus

AbstractTo explore potential intermediate host of a novel coronavirus is vital to rapidly control continuous COVID-19 spread. We found genomic and evolutionary evidences of the occurrence of 2019-nCoV-like coronavirus (named as Pangolin-CoV) from dead Malayan Pangolins. Pangolin-CoV is 91.02% and 90.55% identical at the whole genome level to 2019-nCoV and BatCoV RaTG13, respectively. Pangolin-CoV is the lowest common ancestor of 2019-nCoV and RaTG13. The S1 protein of Pangolin-CoV is much more closely related to 2019-nCoV than RaTG13. Five key amino-acid residues involved in the interaction with human ACE2 are completely consistent between Pangolin-CoV and 2019-nCoV but four amino-acid mutations occur in RaTG13. It indicates Pangolin-CoV has similar pathogenic potential to 2019-nCoV, and would be helpful to trace the origin and probable intermediate host of 2019-nCoV.

scholarly journals In vitro Characterization of Fitness and Convalescent Antibody Neutralization of SARS-CoV-2 Cluster 5 Variant Emerging in Mink at Danish Farms

2021 ◽  
Vol 12 ◽  
Author(s):  
Ria Lassaunière ◽  
Jannik Fonager ◽  
Morten Rasmussen ◽  
Anders Frische ◽  
Charlotta Polacek ◽  
...  
Keyword(s):  
Amino Acid ◽  
Reference Strain ◽  
Rhesus Macaques ◽  
Amino Acid Residues ◽  
Susceptible Animal ◽  
In Vitro Characterization ◽  
Cynomolgus Macaques ◽  
Animal Hosts

In addition to humans, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can transmit to animals that include hamsters, cats, dogs, mink, ferrets, tigers, lions, cynomolgus macaques, rhesus macaques, and treeshrew. Among these, mink are particularly susceptible. Indeed, 10 countries in Europe and North America reported SARS-CoV-2 infection among mink on fur farms. In Denmark, SARS-CoV-2 spread rapidly among mink farms and spilled-over back into humans, acquiring mutations/deletions with unknown consequences for virulence and antigenicity. Here we describe a mink-associated SARS-CoV-2 variant (Cluster 5) characterized by 11 amino acid substitutions and four amino acid deletions relative to Wuhan-Hu-1. Temporal virus titration, together with genomic and subgenomic viral RNA quantitation, demonstrated a modest in vitro fitness attenuation of the Cluster 5 virus in the Vero-E6 cell line. Potential alterations in antigenicity conferred by amino acid changes in the spike protein that include three substitutions (Y453F, I692V, and M1229I) and a loss of two amino acid residues 69 and 70 (ΔH69/V70), were evaluated in a virus microneutralization assay. Compared to a reference strain, the Cluster 5 variant showed reduced neutralization in a proportion of convalescent human COVID-19 samples. The findings underscore the need for active surveillance SARS-CoV-2 infection and virus evolution in susceptible animal hosts.

Inactivation of erythropoietin receptor function by point mutations in a region having homology with other cytokine receptors

1993 ◽  
Vol 13 (3) ◽  
pp. 1788-1795
Author(s):  
O Miura ◽  
J L Cleveland ◽  
J N Ihle
Keyword(s):  
Amino Acid ◽  
Tyrosine Phosphorylation ◽  
Transmembrane Domain ◽  
Point Mutations ◽  
Cell Receptor ◽  
Erythropoietin Receptor ◽  
Immediate Early ◽  
Amino Acid Residues ◽  
Dependent Cell ◽  
Critical Residues

The cytoplasmic domain of the erythropoietin receptor (EpoR) contains a region, proximal to the transmembrane domain, that is essential for function and has homology with other members of the cytokine receptor family. To explore the functional significance of this region and to identify critical residues, we introduced several amino acid substitutions and examined their effects on erythropoietin-induced mitogenesis, tyrosine phosphorylation, and expression of immediate-early (c-fos, c-myc, and egr-1) and early (ornithine decarboxylase and T-cell receptor gamma) genes in interleukin-3-dependent cell lines. Amino acid substitution of W-282, which is strictly conserved at the middle portion of the homology region, completely abolished all the functions of the EpoR. Point mutation at L-306 or E-307, both of which are in a conserved LEVL motif, drastically impaired the function of the receptor in all assays. Other point mutations, introduced into less conserved amino acid residues, did not significantly impair the function of the receptor. These results demonstrate that conserved amino acid residues in this domain of the EpoR are required for mitogenesis, stimulation of tyrosine phosphorylation, and induction of immediate-early and early genes.

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