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Personal profile

Overview

Molecules called proteins are responsible for virtually all the processes that occur inside the cells that make up living organisms. Proteins are incredibly diverse, and many thousands of proteins with different shapes, sizes and functions can be found inside a single cell. However, all of these are initially made as a linear chain of building blocks called amino acids. In order to become functioning proteins, this chain of amino acids must be folded up into the correct 3 dimensional shape. When the folding process goes wrong, abnormally shaped proteins are produced. These can be toxic and therefore ‘quality control’ systems operate inside cells to identify and eliminate incorrectly folded proteins. Many diseases, including cystic fibrosis and Alzheimer’s, are caused by defects in protein folding and/or a failure of the cell’s quality control processes. Our research is aimed at understanding how these quality control processes work. This may one day allow us to design new ways to treat protein folding diseases.

Research interests

Mechanisms of protein quality control and their role in disease

Research in my laboratory is aimed at understanding the mechanisms that mediate protein quality control at the endoplasmic reticulum, and how these impact upon cell survival during health and disease.

Protein quality control at the endoplasmic reticulum

The endoplasmic reticulum (ER) is the major site for the synthesis of membrane and secretory proteins. These are inserted into or across the ER membrane as extended polypeptide chains, which are then folded into their final conformation before moving along the secretory pathway. Correctly folded proteins are packaged into transport vesicles that deliver them to their final destination within the cell. Incorrectly folded proteins are potentially toxic and are therefore retained and degraded by quality control systems in the ER and at later points in the secretory pathway.

Techinques

We are addressing these questions using a range of molecular biology (molecular cloning, mutgenesis, in vitro transcription/translation), cell biology (mammalian cell culture, expression of wild type and mutant proteins, RNA interference, fluorescence microscopy) and biochemistry (electrophoresis, protein purification, cross-linking) techniques.

Related Publications

Briant, K., Koay, Y. H., Otsuka, Y. and Swanton, E. (2015). ERAD of proteins containing aberrant transmembrane domains requires ubiquitylation of cytoplasmic lysine residues. J Cell Sci 128, 4112-25.

Sun, C., Roboti, P., Puumalainen, M.R., Fryknas, M., Wang, X., D'Arcy, P., Hult, M., High, S., Linder, S. and Swanton, E. (2014) Elevation of proteasomal substrate levels sensitizes cells to apoptosis induced by inhibition of proteasomal deubiquitinases. PLoS One, 9, e108839.

McKibbin C, Mares A, Piacenti M, Williams H, Roboti P, Puumalainen M, Callan AC, Lesiak-Mieczkowska K, Linder S, Harant H, High S, Flitsch S, Whitehead RC, Swanton E. (2012) Inhibition of protein translocation at the endoplasmic reticulum promotes activation of the unfolded protein response. Biochem J. 442, 639–648.

Roboti, P., Swanton, E., High, S. (2009). Differences in endoplasmic reticulum quality control determine the cellular response to disease-associated mutants of proteolipid protein. J. Cell Sci. 122, 3942-3953

Cross, B. C., McKibbin, C., Callan, A. C., Roboti, P., Piacenti, M., Williams, H. M., Rabu, C., Wilson, C.M. Whitehead, R., Flitsch, S.L., Pool, M.R., High, S. & Swanton, E. (2009).Eeyarestatin I inhibits Sec 61-mediated protein translocation at the endoplasmic reticulum. J. Cell Sci. 122, 4393-4400.

 

Expertise related to UN Sustainable Development Goals

In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This person’s work contributes towards the following SDG(s):

  • SDG 3 - Good Health and Well-being

Research Beacons, Institutes and Platforms

  • Manchester Institute for Collaborative Research on Ageing

Keywords

  • protein quality control
  • membrane protein
  • ubiqutin
  • secretory pathway

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