Royal Society University Research Fellow
Description of research
Molecular Mechanisms of Genetic and Infectious Disease
1. Mechanisms of pathogenesis in Krabbe Disease
We are studying how clinically-identified mutations of the enzyme galactocerebrosidase (GALC) result in Krabbe disease, a devastating neurodegenerative disorder. GALC plays an essential role in lipid recycling thereby maintaining the lipid-rich myelin sheath that protects nerve cells. Defects in GALC lead to the accumulation of cytotoxic metabolites that elicit complex, and still only partially understood, cellular events that result in apoptosis of myelin-forming cells and progressive demyelination. Our recent structures of GALC have provided new insight into the catalytic mechanism of GALC and the molecular role of pathogenic mutations. This insight has allowed us to design small molecules that bind and stabilise GALC and identify patients that might be responsive to this form of therapy known as pharmacological chaperone therapy.
2. Host-pathogen interactions during Shigella infection
Diseases caused by bacteria, viruses and other parasites are major causes of death, disability, and social and economic disruption for millions of people. Our ability to effectively treat infectious diseases is being progressively depleted due to increasing resistance of microbes to antimicrobial drugs. A top priority today is the development of new low-cost drugs that can replace those that are becoming ineffective. An essential part of developing new therapeutics is a clear molecular understanding of how pathogens evade our immune defences and hijack our cellular components.
Our research focuses on the bacterial pathogen Shigella flexneri. This pathogen invades cells of our digestive tract and hijacks components of the actin polymerization pathway in order to aid its movement within our cells and allowing it to spread directly from cell to cell. In this way Shigella can limit its detection by our immune system. As an extra defence S. flexneri produces proteins that specifically disarm the intracellular immune response to pathogens. We study the structure, interactions and regulation of Shigella virulence proteins and the host proteins they target.
Keywords: Galactocerebrosidase, Shigella flexneri, Type III Secretion
Clinical conditions: Krabbe Disease, Shigellosis
Methodologies: Biochemistry, biophysics and structural biology
Dr Louise Boyle, Dr Stephen Graham, Prof. Randy Read, Prof. Timothy Cox
Dr Henrik Jensen, Aarhus University, Denmark
Hill, C.H., Graham, S.C., Read, R.J. and Deane J.E. (2013) “Structural snapshots illustrate the catalytic cycle of β-galactocerebrosidase, the defective enzyme in Krabbe disease” Proc. Natl Acad Sci U.S.A. 110: 20479-84.
Hermann, C., Strittmatter, L.M., Deane, J.E. and Boyle, L.H. (2013) “TAPBPR and tapasin binding to MHC class I is mutually exclusive” J. Immunol. 191: 5743-50.
Graham, S.C., Wartosch, L., Gray, S.R., Scourfield, E.J., Deane, J.E., Luzio, J.P. and Owen, D.J. (2013) “Structural basis of Vps33A recruitment to the human HOPS complex by Vps16” Proc. Natl Acad Sci U.S.A. 111:13345-50.
Abrusci, P., Vergara-Irigaray, M., Johnson, S., Beeby, M.D., Hendrixson, D., Roversi, P., Friede, M.E., Deane, J.E., Jensen, G.J., Tang, C.M., Lea, S.M. (2013) “Architecture of the major component of the Type III secretion system export apparatus” Nat. Struct. Mol. Biol. 20:99-104.
Deane, J.E., Graham, S.C., Kim, N.N., Stein, P.E., McNair, R., Cachón-González, M.B., Cox, T.M. and Read, R.J. (2011) “Insights into Krabbe Disease from Structures of Galactocerebrosidase” Proc. Natl Acad. Sci. U.S.A. 108: 15169-73.
Deane, J.E., Abrusci, P. Johnson, S. and Lea, S.M. (2010) “Timing is Everything: the regulation of type III secretion” Cell. Mol. Life Sci. 67: 1065-75.