PhD BSc(Hons)

Interrogating the structures and interactions of biomacromolecules using biophysical techniques

The regulation of the complement system and disease

Amno acids and protein structure (Molecules Genes and Cells 1; The Dynamic Cell 2)

Biophysical techniques (Protein, Structure and Funcrion 3; Biochemical Techniques  4; Biophysical Chemistry 4/5)

Pore-forming proteins (Membrane Biology 4)

Molecular engineering (Biomacromolecules 4/5)

Structural biology of the complement system (Structural Biology 4)

Tutorials and Synoptic Exam (Biochemistry Honours)

We work on the “complement system”, a first line of immune defense against microbial invasion of the human body. We are interested in two key aspects of complement – its remarkable speed of activation, and its potentially hazardous ability to punch holes in cell membranes. We are also interested in designing drugs to combat the effects of complement when it attacks our own cells.

 We work on one of Nature's most dangerous examples of a molecular positive-feedback loop. This is the APC (for alternative pathway of complement), which is vital to the extraordinary responsiveness of the complement system but can also injure our own cells. The APC has just six, initially inactive, protein components yet it can identify a bacterial cell and coat it with one hundred million copies of the human C3b protein within ten minutes. Thereafter the C3b-coated bacterial cell is eaten (phagocytosed) by a guardian cell or undergoes rupture (cytolysis, see below). We are particularly interested in how this potentially explosive process is controlled. We currently focus on factor H, a glycoprotein of 155 kD that regulates the APC selectively on self cells while allowing it to proceed unchecked on bacterial cells.

A second goal is to understand the fascinating self-assembly process whereby the membrane-attack complex is formed from inactive soluble complement components circulating in the blood. Production of C3b (see above) triggers formation of C5b. C5b acts as a platform for non-enzymatic (ATP and GTP-independent) assembly of a complex that first associates with a nearby membrane, then penetrates it via a molecular flick-knife mechanism and finally carves a hole through the membrane forming a water-filled pore. We focus on C6 and C7 that bind in succession to nascent C5b and guide the complex to the membrane surface.

We use the tools of chemistry, structural biology and biophysics to tackle these complex processes in atomic detail and with mathematical precision. An ultimate ambition is to produce a robust atomic resolution model of the entire complement system by combining all of the data collected on complement by our lab and other labs around the world.  This will be used to predict accurately the consequences of genetic variations amongst its various components; many of these are strongly linked to disease affording opportunities to design therapeutic interventions.