I have a longstanding fascination with how the information encoded in the sequence of amino acids in a protein chain is realised in the 3-D structure of a folded, active protein.
My graduate work was on the mechanism of action of the molecular chaperones GroEL and GroES, essential proteins in bacterial cells that help other proteins to fold correctly. This work (in Bristol with Professor Tony Clarke) focused on aspects of the mechanistic enzymology of these large, ATP-hydrolysing molecular machines. I then cross-trained into cryo-EM at Birkbeck College London with Professor Helen Saibil FRS, again on GroEL/GroES but now trying to understand how conformational change drives chaperone function.
Current projects focus on the folding of membrane proteins, especially outer membrane proteins (OMPs) of the bacterial outer membrane. The outer membrane of Gram-negative bacteria is a key part of their defence against the environment in which they live, and is a crucial factor in their (growing) resistance to antibiotics. In a fantastic collaboration with Professor Sheena Radford FRS here in Leeds, we are working on the structure and function of the β-barrel assembly machinery, or BAM complex. BAM is an integral membrane protein complex of five proteins, and it's required for the correct folding and insertion of a wide range of OMPs into the lipid bilayer of the outer membrane. We are currently working hard to understand the molecular mechanisms by which different OMPs transit the BAM complex on their way into their native lipid environment. We're also beginning to work on the structures of several OMP substrates, as the lab's interest in antimicrobial resistance more widely grow.
Of course, when protein folding goes wrong, misfolded proteins often aggregate, and for some proteins in some conditions, ordered amyloid-like aggregates are formed, causing a range of devastating diseases in humans such as Alzheimer's and Parkinson's diseases. The lab is working to understand the structure of these ordered protein aggregates, and understand how such protein aggregation induces cytotoxicity.