Their interactions with other proteins are weak and generally short-term, however SLiMs are however significant contributors to protein function and regulatory systems in the cell.Structured protein domainsSLiMsApproximately 50– 200 amino acids, with numerous points of contactJust ~ 2– 10 amino acids, with just 2– 3 that act as core binding determinantsDistinct three-dimensional structureLack a three-dimensional structureStrong and often lasting interactions, such as in protein complex formationWeak, short-term interactionsBind domains of other protein partners, interactions that typically look like alock-and-key mechanismTypically bind to a conserved pocket on a globular protein domain © Scott Leighton © Scott LeightonSLiMS IN SARS-COV-2 INFECTIONSARS-CoV-2 appears to take benefit of the host stress granule equipment deployed in reaction to viral infection to favor its expansion. Specifically, our work reveals that its nucleocapsid (N) protein, responsible for encapsulating viral RNA and collaborating replication and other functions, contains a SLiM that contends with cellular proteins in binding with stress granule– forming proteins, namely G3BP1 and G3BP2 (G3BPs). © Scott LeightonSARS-CoV-2 infection In the case of SARS-CoV-2, we found in human cells that the N protein is able to bind G3BP proteins through an ΦxFG SLiM, possibly to localize viral duplication to stress granules in early infection.
In the early days of studying protein behavior, researchers recognized that big, structured protein domains often communicated with each other in a lock-and-key style, fitting together almost like puzzle pieces. Towards completion of the 20th century, however, the growing discovery of formerly overlooked unstructured areas recommended that there was more to the story. One kind of protein interaction moderated by the unstructured proteome involves short direct concepts (SLiMs), abundant stretches of as much as 10 amino acids. Their interactions with other proteins are weak and normally transient, but SLiMs are nonetheless significant contributors to protein function and regulative mechanisms in the cell.Structured protein domainsSLiMsApproximately 50– 200 amino acids, with several points of contactJust ~ 2– 10 amino acids, with just 2– 3 that serve as core binding determinantsDistinct three-dimensional structureLack a three-dimensional structureStrong and typically long-lasting interactions, such as in protein complex formationWeak, transient interactionsBind domains of other protein partners, interactions that frequently look like alock-and-key mechanismTypically bind to a conserved pocket on a globular protein domain © Scott Leighton © Scott LeightonSLiMS IN SARS-COV-2 INFECTIONSARS-CoV-2 appears to take benefit of the host stress granule machinery deployed in action to viral infection to favor its expansion. Specifically, our work reveals that its nucleocapsid (N) protein, responsible for encapsulating viral RNA and collaborating duplication and other functions, includes a SLiM that competes with cellular proteins in binding with tension granule– forming proteins, particularly G3BP1 and G3BP2 (G3BPs). In doing so, the virus efficiently promotes its expansion while dampening the cells antiviral defenses. Targeting these SLiM-mediated protein interactions might one day show to be a practical antiviral therapy approach.Normal stress reaction In response to viral infection or other stress factors, cells form tension granules, membraneless organelles which contain host mRNA, viral RNA, translation aspects, and RNA-binding proteins. These consist of G3BPs, which bind to other tension granule proteins through an ΦxFG SLiM, where Φ represents a hydrophobic amino acid, x represents any residue, and F and G represent phenylalanine and glycine, respectively. This action triggers cells to limit their energy use and restrict protein production. Due to the fact that viruses require the cellular machinery to produce their viral proteins and multiply, the stress action can obstruct this, with stress granules frequently related to an antiviral function. © Scott LeightonSARS-CoV-2 infection In the case of SARS-CoV-2, we found in human cells that the N protein is able to bind G3BP proteins by means of an ΦxFG SLiM, potentially to localize viral duplication to tension granules in early infection. As levels of the SARS-CoV-2 N protein boost in later infection phases, N efficiently displaces all cellular proteins from G3BPs and interferes with cytoplasmic stress granules. This eventually promotes viral proliferation and the dampening of antiviral defense reaction. © Scott LeightonTargeting stress granule formationBased on these findings, we created a peptide inhibitor containing ΦxFG-like SLiMs that bound strongly to G3BPs, avoiding the binding of SARS-CoV-2 N protein in human cells. This peptide (G3BPi) prevented viral proliferation in a monkey cell line frequently utilized in SARS-CoV-2 studies, though the particular downstream mechanisms remain to be elucidated. © Scott LeightonRead the complete story.