Research project: Understanding the role of lipid-protein interactions in the intracellular localisation of proteins and its role in muscular dystrophy.

The mis-regulation of protein trafficking is linked to a number of diseases including congenital muscular dystrophy. These classes of diseases arise due to the miss-localisation of glycosyltransferases within the Endoplasmic Reticulum (ER)/Golgi Apparatus(GA). It is thought that the N-terminal transmembrane domain plays a key role in the localisation of glycosyltransferases within these compartments. Typically the transmembrane domains of ER/GA resident proteins are shorter than those of proteins resident in the plasma membrane. This, and the absence of any clear sequence motifs, has led to the suggestion that it is the interaction of the N-terminal transmembrane domains with the characteristic bilayer composition of these intracellular compartments which leads to their correct localisation.
We are employing a broad spectrum of biophysical techniques to understand how the surrounding lipid environment influences the structure, oligomeric state and lateral segregation of glycosyltransferases. In particular we exploiting the potential of solid-state NMR to characterise these molecular properties whilst the protein is resident in its native lipid bilayer. These studies aim to provide valuable insights into the retention of glycosyltransferases and other proteins within the ER/GA aiding our understanding of a number of diseases including muscular dystrophy.

Funding

Wellcome Trust Career Development Fellowship (Jan 2007-2011)