4 research outputs found
The SARS-CoV-2 SSHHPS Recognized by the Papain-like Protease
Viral proteases are highly specific and recognize conserved cleavage site sequences of
âŒ6â8 amino acids. Short stretches of homologous hostâpathogen
sequences (SSHHPS) can be found spanning the viral protease cleavage sites. We
hypothesized that these sequences corresponded to specific host protein targets since
>40 host proteins have been shown to be cleaved by Group IV viral proteases and one
Group VI viral protease. Using PHI-BLAST and the viral protease cleavage site sequences,
we searched the human proteome for host targets and analyzed the hit results. Although
the polyprotein and host proteins related to the suppression of the innate immune
responses may be the primary targets of these viral proteases, we identified other
cleavable host proteins. These proteins appear to be related to the virus-induced
phenotype associated with Group IV viruses, suggesting that information about viral
pathogenesis may be extractable directly from the viral genome sequence. Here we
identify sequences cleaved by the SARS-CoV-2 papain-like protease (PLpro) in
vitro within human MYH7 and MYH6 (two cardiac myosins linked to several
cardiomyopathies), FOXP3 (an X-linked Treg cell transcription factor), ErbB4
(HER4), and vitamin-K-dependent plasma protein S (PROS1), an anticoagulation protein
that prevents blood clots. Zinc inhibited the cleavage of these host sequences
in vitro. Other patterns emerged from multispecies sequence
alignments of the cleavage sites, which may have implications for the selection of
animal models and zoonosis. SSHHPS/nsP is an example of a sequence-specific
post-translational silencing mechanism
Automated SSHHPS Analysis Predicts a Potential Host Protein Target Common to Several Neuroinvasive (+)ssRNA Viruses
Within the viral genome, short stretches of homologous host pathogen sequences (SSHHPS) span the protease cleavage sites. To identify host proteins that may be cleaved during infection, we searched the human proteome for viral protease cleavage sites (~20 amino acids). We developed a sequence-to-symptom tool, automating the search and pairing process. We used the viral protein sequence, PHI-BLAST, and UniProt database for gene ontologies and disease relationships. We applied the tool to nine neuroinvasive viruses: Venezuelan and Eastern Equine encephalitis virus (VEEV, EEEV); severe acute respiratory syndrome (SARS, SARS-CoV-2); Middle East respiratory syndrome (MERS); EV-71; Japanese encephalitis virus (JEV); West Nile (WNV); and Zika (ZIKV). A comparison of the hits identified a protein common to all nine viruses called ADGRA2 (GPR124). ADGRA2 was a predicted hit of the 3CL main protease and papain-like protease (PLpro) of SARS-CoV-2. ADGRA2 is an adhesion G protein-coupled receptor and a key endothelial regulator of brain-specific angiogenesis. It is a Wnt7A/Wnt7B specific coactivator of beta-catenin signaling and is essential for bloodâbrain barrier (BBB) integrity in central nervous system (CNS) diseases. We show the cleavage of the predicted sequences in MYOM1, VWF by the SARS-CoV-2 PLpro; DNAH8 (dynein) by the MERS PLpro; ADGRA2 by the alphaviral VEEV nsP2 protease; and POT1 by the SARS-CoV-2 and MERS PLpro
Search for intermediate-mass black hole binaries in the third observing run of Advanced LIGO and Advanced Virgo
International audienceIntermediate-mass black holes (IMBHs) span the approximate mass range 100â105âMâ, between black holes (BHs) that formed by stellar collapse and the supermassive BHs at the centers of galaxies. Mergers of IMBH binaries are the most energetic gravitational-wave sources accessible by the terrestrial detector network. Searches of the first two observing runs of Advanced LIGO and Advanced Virgo did not yield any significant IMBH binary signals. In the third observing run (O3), the increased network sensitivity enabled the detection of GW190521, a signal consistent with a binary merger of mass âŒ150âMâ providing direct evidence of IMBH formation. Here, we report on a dedicated search of O3 data for further IMBH binary mergers, combining both modeled (matched filter) and model-independent search methods. We find some marginal candidates, but none are sufficiently significant to indicate detection of further IMBH mergers. We quantify the sensitivity of the individual search methods and of the combined search using a suite of IMBH binary signals obtained via numerical relativity, including the effects of spins misaligned with the binary orbital axis, and present the resulting upper limits on astrophysical merger rates. Our most stringent limit is for equal mass and aligned spin BH binary of total mass 200âMâ and effective aligned spin 0.8 at 0.056 Gpcâ3 yrâ1 (90% confidence), a factor of 3.5 more constraining than previous LIGO-Virgo limits. We also update the estimated rate of mergers similar to GW190521 to 0.08 Gpcâ3 yrâ1.Key words: gravitational waves / stars: black holes / black hole physicsCorresponding author: W. Del Pozzo, e-mail: [email protected]â Deceased, August 2020