Brezellec, P. | bioRxiv Science

bioRxiv2025

Evidence suggests that the SARS-CoV-2 Spike (S) protein may target coiled-coil regions of numerous cytoskeletal and cytoskeleton-associated proteins

AO_SCPLOWBSTRACTC_SCPLOWUnderstanding the interactions between host and viral envelope proteins is essential to get insights into the dynamics of viral infection. To investigate more closely the mechanisms governing SARS-CoV-2 entry and intracellular trafficking, I reanalyzed the most extensive SARS-CoV-2-human protein-protein interactome dataset currently available. My investigation centered on the Spike S protein, a key player in initiating viral infection by binding to the host cell membrane receptor Angiotensin-Converting Enzyme 2 (ACE2). I first present evidence demonstrating the statistical overrepresentation of actin-binding proteins among the Spike S partners/interactors. Next, I show that a majority of these partners contains a structural domain sharing high similarity with the C-terminal region of the Myosin II heavy chain, Myosin II being known for its roles in muscle contraction and various cellular motility processes. I subsequently demonstrate that this domain is particularly prevalent in actin-binding proteins, intermediate filaments proteins and kinesins, which all are related to the cytoskeleton known to be involved in diverse cellular functions, including endocytosis and intracellular transport -- processes crucial for viral infections. Finally, I highlight that the structural domain mentioned above is a bonafide coiled-coil region. I therefore conclude that Spike S might target proteins possessing such regions. Collectively, my findings suggest that the interactions between SARS-CoV-2 Spike S and human proteins, potentially mediated by coiled-coil regions, may have been underestimated. As this work relies on in silico evidence, direct biological extrapolations require caution.

genomics↗

bioRxiv2023

Re-annotation of SARS-CoV-2 proteins using an HHpred-based approach opens new opportunities for a better understanding of this virus

AO_SCPLOWBSTRACTC_SCPLOWSince the publication of the genome of SARS-CoV-2 - the causative agent of COVID-19 - in January 2020, many bioinformatic tools have been applied to annotate its proteins. Although effcient methods have been used, such as the identification of protein domains stored in Pfam, most of the proteins of this virus have no detectable homologous protein domains outside the viral taxa. As it is now well established that some viral proteins share similarities with proteins of their hosts, we decided to explore the hypothesis that this lack of homologies could be, at least in part, the result of the documented loss of sensitivity of Pfam Hidden Markov Models (HMMs) when searching for domains in "divergent organisms". In order to improve the annotation of SARS-CoV-2 proteins, we used the HHpred protein annotation tool. To avoid "false positive predictions" as much as possible, we designed a robustness procedure to evaluate the HHpred results. In total, 6 robust similarities involving 6 distinct SARS-CoV-2 proteins were detected. Of these 6 similarities, 3 are already known and well documented, and one is in agreement with recent crystallographic results. We then examined carefully the two similarities that have not yet been reported in the literature. We first show that the C-terminal part of Spike S (the protein that binds the virion to the cell membrane by interacting with the host receptor, triggering infection) has similarities with the human prominin-1/CD133; after reviewing what is known about prominin-1/CD133, we suggest that the C-terminal part of Spike S could both improve the docking of Spike S to ACE2 (the main cell entry receptor for SARS-CoV-2) and be involved in the delivery of virions to regions where ACE2 is located in cells. Secondly, we show that the SARS-CoV-2 ORF3a protein shares similarities with human G protein-coupled receptors (GPCRs), such as Lutropin-choriogonadotropic hormone receptor, primarily belonging to the "Rhodopsin family". To further investigate these similarities, we compared Prominin 1 and Lutropin-choriogonadotropic hormone receptor to a set of viral proteins using HHPRED. Interestingly, Prominin 1 showed similarities with 6 viral Spike glycoproteins, primarily from coronaviruses. Equally interestingly, Lutropin-choriogonadotropic hormone receptor showed similarities with 23 viral G-protein coupled receptors, particularly from Herpesvirales. We conclude that the approach described here (or similar approaches) opens up new avenues of research to better understand SARS-CoV-2 and could be used to complement virus annotations, particularly for less-studied viruses.

genomics↗