Structure/function studies of a cyclomodulin

Lead Research Organisation: John Innes Centre
Department Name: Contracts Office

Abstract

During infection, one route of communication used by certain gram-negative pathogens to interact with their host involves direct injection of proteins known as 'effectors' from the bacterial to host cell cytoplasm using a virulence-associated type III secretion system (T3SS). The host cell cycle is one pathway being increasingly recognised as a target for bacterial virulence mechanisms, including via this route. One T3SS effector protein, cycle inhibiting factor (Cif), has been identified in a variety of pathogens that target different hosts and harbour at least one T3SS, including enteropathogenic E. coli , enterohemorrhagic E. coli, B. pseudomallei and P. luminescens. When delivered to host cells Cif triggers cell cycle arrests at either the G2/M or G1/S phase transitions. Studying proteins such as this is important for both understanding host-pathogen interactions (the molecular basis of disease) and the host cell processes themselves. For instance, a deregulated cell cycle is often linked to development of cancer, and proteins that regulate the cell cycle are one of the most targeted sets of molecules by the pharmaceutical industry. How Cif actually brings about its effect in host cells is not currently understood, although recent studies have delivered significant insights into how this might occur. One powerful approach to determining how a protein functions is to look at its structure. This can be visualised using techniques such as X-ray crystallography, in addition to other biophysical methods. Also important for understanding Cif function is identifying the protein's molecular targets within host cells, characterising the interaction and ultimately determining the structure of molecules together. This would generate a picture of a complex responsible for transducing an effect that leads to host cell cycle arrest and may have long-term application for the development of novel therapeutics targeting host-pathogen interactions and also carcinogenesis.

Publications

10 25 50