Research project Clostridial neurotoxins, deadly toxins that also can heal -How do these large proteins bind to, and

The clostridial neurotoxins perform all of their key functions at or in the membrane. In spite of this, the membrane itself has generally been neglected in studies. We will generate the first structural insights on how the clostridial toxins function on the membrane and in the membrane.

We will study:

• How the soluble translocation domain is transformed into a transmembrane pore, capable of moving entire proteins across the membrane
• How binding to cell surface receptors at the membrane occurs
• The total binding avidity of the clostridial neurotoxins to intact neuronal cells, and how distinct interactions contribute to the total avidity
• The structures, receptors, substrates, lipid interactions of recently identified, novel toxins

We will employ recent method developments and advances which include: Single-particle cryo-EMQuartz crystal microbalance biosensors

The structure and mechanism of the enigmatic translocation of the clostridial neurotoxins across the membrane and receptor binding at the membrane surface are complex, high risk/high gain questions. We will decipher how the soluble toxins are transformed into transmembrane channels capable of translocating entire proteins across the lipid bilayer.