Distinguished iNANO Lecture: Nanoscale imaging of protein self-assembly: From molecular hole-punchers to suicide protection in the immune system

The lecture is cancelled

Professor Bart Hoogenboom, London Centre for Nanotechnology, University College London

Nanoscale imaging of protein self-assembly: From molecular hole-punchers to suicide protection in the immune system

Atomic force microscopy (AFM) enables us to visualise how biomolecules self-assemble into functional machines. A biomedically most relevant example of such self-assembly is that of pore forming proteins. These proteins are secreted as monomers that bind to membranes and assemble into giant oligomeric transmembrane pores. They are used by bacteria to gain access to nutrients and/or to kill host cells, and by our immune system to attack rogue and invading cells. 

Using AFM, we have shown that pore forming proteins can be effective in piercing membranes even without assembling complete pores, and more generally mapped out pathways of membrane pore formation [1,2]. Of particular interests are our findings on perforin, secreted by killer lymphocytes and as such a key weapon in cancer immunotherapies. We find that perforin slices its way into target membranes effectively like a can-opener [2]. Importantly, we can directly correlate nanoscale experiments on model membranes with cell-based assays. In doing so, we have identified how lipid order and charge determine the effectiveness of perforin pore formation and provide our own immune cells with a shield against the perforin they secrete [3]. 

Finally, for immune proteins of the complement system in serum, we have mapped the kinetics of assembly of the membrane attack complex at single-molecule level and characterised pore formation both on model membranes and on live bacteria [4,5].

1. Leung et al., eLife 3, e04247 (2014).
2. Leung et al., Nature Nanotechnology 12 (5), 467-473 (2017).
3. Rudd-Schmidt et al., Nature Communications 10 (1), 5396 (2019).
4. Parsons et al., Nature Communications 10 (1), 2066 (2019).
5. Heesterbeek et al., EMBO Journal 38, e99852 (2019).

Host: Associate Professor Mingdong Dong, Interdisciplinary Center, Aarhus University