Protein assembly and trafficking in eukaryotic cells

Lead Research Organisation: University of Manchester
Department Name: Life Sciences

Abstract

For cells and tissues to remain healthy they must be able to make proteins and the proteins they make must be able to function correctly in the right place. The cell has a complex machinery for ensuring that when new proteins are made they are functional and are transported to the correct location, be it within the cell or outside. The research carried out by this group will study how proteins are made and delivered to their correct location and, in particular, how this delivery process breaks down during disease. The production and delivery of proteins can be summarised into two key stages: i) ensuring proteins are made correctly and adopt the correct shape, ii) transport of the protein to the correct location.
Proteins are made as a string of amino acids that coil up or fold to adopt a characteristic three-dimensional structure. In some cases, folding is delayed to allow the elongated structure to cross membranes and enter specialised cellular compartments. We want to understand how this transfer occurs. When proteins finally fold the cell ensures that they produce the correct shape, by providing helper proteins or chaperones to aid folding. If cells are unable to carry out the correct folding of proteins disease results, including some common inherited diseases such as cystic fibrosis. Our group wants to understand in detail the reasons behind the inability of cells to fold proteins. In order to do this we need to know how proteins are folded correctly and what causes them to fold incorrectly.
Once proteins are folded they are transported through a series of membrane-bound cell compartments, which depend on the ultimate destination of the protein. The route taken by proteins to the outside of the cell is called the secretory pathway. Proteins can also enter cells, via the endocytic pathway. Selective transport of proteins is a complex process requiring proteins to be sorted and transported, akin to the process that occurs when you post a letter. We aim to determine how proteins are selected for transport, how and in what they are transported, and how this process breaks down in certain disease states. By gaining this information we will enhance both our basic knowledge of cell biology and possibly provide vital clues for the rational design of therapeutic approaches to treatment.

Technical Summary

Compartmentalisation is a fundamental aspect of eukaryotic cellular function. Naturally, this function has co-evolved with specific pathways that promote the delivery of newly synthesised proteins from the cytosol to their appropriate destination. Understanding these pathways provides the focus for the Membrane Trafficking Group within the School of Biological Sciences. Individually, we are interested in how specific aspects of this sorting machinery operate and how they are regulated. The aim of this proposal is to provide overarching support that will increase our productivity and provide added value. Specifically, the support will:
1. Provide technical and equipment support that will directly enhance the productivity of individual components.
2. Help initiate collaborative research projects, both by enabling the transfer of technical expertise between groups and by encouraging joint intellectual efforts on projects involving overlapping research interests.
This proposal forms a direct continuation of our previous MRC COGG award, which we have found to be very effective in supporting our research programmes, promoting collaborations across the Group, and attracting new investigators. As such, many of the themes of the original proposal are recalled.

Publications

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Description MRC Programme Grant G0701140
Amount £1,500,000 (GBP)
Funding ID G0701140 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 11/2008 
End 10/2013
 
Description School Visit Manchester 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Schools
Results and Impact Conducting mock UCAS interviews

Prepared students for University applications
Year(s) Of Engagement Activity 2008,2009