ATP: Adenosine triphosphate, ADP: Adenosine diphosphate. Post translational addition of a phosphorylation moiety on Serine, Threonine or Tyrosine residues. The review also includes insights into how such host-directed events have been exploited to lend support to rational design of small molecule therapeutics. In this review, we have focused on phosphorylation events that occur on viral proteins of single stranded RNA viruses as a part of acute viral infections. This learning process that spans multiple generations in the evolutionary scale continues to modify the viral landscape, more extensively so with pathogen-directed therapeutics driving some of the modifications in the quest for evolutionary fitness. In fact, one can envision a co-evolutionary strategy whereby viruses “learnt” to utilize the host enzymatic machinery that has already been activated as a part of the innate immune response. Many viral proteins have been demonstrated to be post translationally modified during various stages of the infectious process and involve enzymatic components that are derived from both the pathogen and the host. These modifications have been subject to intense research because of the unique insights they can offer into host-pathogen interactions that can extend to the development of novel diagnostics and therapeutics. Post translational modifications of pathogen-derived proteins can include phosphorylation, methylation, acetylation, glycosylation, ubiquitylation, Small Ubiquitin-like Modifier (SUMO)ylation and nitrosylation.
Such a flux is the central component of functional regulation of proteins, which will impact protein stability, interaction partners and subcellular localization in a manner that transcends the properties of the nascent translated product. Usually, post-translational modifications are transient in nature with a constant flux of the target protein between the functionally active and functionally inactive states. Post-translational modification may also involve protein cleavage/trimming from a premature to mature form mediated by proteases. The transfer of the chemical moiety occurs as an enzyme catalyzed event involving an electrophilic substrate transfer of the target protein. Such modifications that occur in prokaryotic and eukaryotic cells can take the form of appending of unique chemical moieties to specified side chains on the nascent polypeptide. Post translational modifications are defined as alterations made to a protein at multiple stages after translation and generation of the nascent polypeptide chain. The review additionally explores the possibility of repurposing Food and Drug Administration (FDA) approved inhibitors as antivirals for the treatment of acute RNA viral infections.
This review focuses on phosphorylation modifications that have been documented to occur on viral proteins with emphasis on acutely infectious, single stranded RNA viruses. Phosphorylation of viral proteins for many acute RNA viruses including Flaviviruses and Alphaviruses has been demonstrated to be critical for protein functionality. Preservation of protein phosphorylation moieties in pathogens in a manner that mirrors the host components underscores the co-evolutionary trajectory of pathogens and hosts, and sheds light on how successful pathogens have usurped, either in part or as a whole, the host enzymatic machinery. Protein phosphorylation is also essential for many intracellular pathogens to establish a productive infection cycle. Among the diverse kinds of protein post translational modifications, phosphorylation plays essential roles in protein folding, protein:protein interactions, signal transduction, intracellular localization, transcription regulation, cell cycle progression, survival and apoptosis. Post translational modification of proteins is a critical requirement that regulates function.
0 kommentar(er)
