Characterization of the mechanism of norovirus VPg-dependent RNA priming
Lead Research Organisation:
University of Cambridge
Department Name: Pathology
Abstract
PhD project strategic theme: Understanding the rules of life
Noroviruses have a considerable yearly impact on the global economy of about $60 billion and cause about 200.000 deaths per annum. Despite causing most cases of viral gastroenteritis, they remain poorly characterised compared to many other viruses.
The infectious norovirus genome is positive single stranded RNA molecule that is linked to the viral protein VPg. The process by which VPg is linked to viral RNA is poorly understood, but requires a step known as "nucleotidylylation", whereby a nucleotide is covalently linked to a specific amino acid in VPg. This linkage is critically important during multiple steps of the viral life cycle, as it serves as protein primer for RNA synthesis as well as enabler of viral genome translation and encapsidation. Therefore it represents a key step in the life cycle of this family of viruses and one that is not understood.
Previous work in the lab has discovered an RNA structure on the negative sense of the norovirus genome that functions as a template for the in vitro nucleotidylylation of VPg. This aim of this project is to better understand this process by characterising the RNA structure involved as well as the biochemical interactions that must take place in order for nucleotidylylation to occur. We also wish to generate an assay that would be amenable for screening to allow the identification of inhibitors of this process.
Noroviruses have a considerable yearly impact on the global economy of about $60 billion and cause about 200.000 deaths per annum. Despite causing most cases of viral gastroenteritis, they remain poorly characterised compared to many other viruses.
The infectious norovirus genome is positive single stranded RNA molecule that is linked to the viral protein VPg. The process by which VPg is linked to viral RNA is poorly understood, but requires a step known as "nucleotidylylation", whereby a nucleotide is covalently linked to a specific amino acid in VPg. This linkage is critically important during multiple steps of the viral life cycle, as it serves as protein primer for RNA synthesis as well as enabler of viral genome translation and encapsidation. Therefore it represents a key step in the life cycle of this family of viruses and one that is not understood.
Previous work in the lab has discovered an RNA structure on the negative sense of the norovirus genome that functions as a template for the in vitro nucleotidylylation of VPg. This aim of this project is to better understand this process by characterising the RNA structure involved as well as the biochemical interactions that must take place in order for nucleotidylylation to occur. We also wish to generate an assay that would be amenable for screening to allow the identification of inhibitors of this process.
Organisations
People |
ORCID iD |
| Ian Goodfellow (Primary Supervisor) | |
| Malte Pinckert (Student) |
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| BB/M011194/1 | 01/10/2015 | 31/03/2024 | |||
| 2279469 | Studentship | BB/M011194/1 | 01/10/2019 | 30/09/2023 | Malte Pinckert |