To coax the protein to change shapes, the researchers increased the concentration of a soapy solution that mimics the lipids found in different nerve cell membranes in the brain. Alpha-synuclein is known to bind to membranes on nerve cells, and lipids are a large component of those membranes.
At a low concentration, the "lipid" molecules remained separate but at higher concentration, small and then larger blobs of molecules form. The shape of the alpha-synuclein kept pace the extended helix could latch onto lipid-mimics as monomers or in a large cylinder-shaped blob, whereas the bent helix wrapped itself around smaller lipid-mimic balls or could create formations with lipid-mimic monomers.
"Others have found the protein to be in a bent helix or in an extended helix, but what we are showing here directly is that the shape can actively change," Deniz says. "It starts off in an unfolded state, and as we increase the concentration of the lipid mimics, the protein reacts to what is in effect a different binding partner, even though it is the same small molecule at different concentrations. It switches back and forth into different states.
"This is perhaps the most complex protein folding-binding system that has been studied to date using single-molecule FRET," he says.
This ability of alpha-synuclein to be switched into alternative shapes could play a significant role in regulating formation of disease-related aggregates, as well as enabling its function. Hence, one next step for the research team is to figure out which form of alpha-synuclein may accelerate formation of the types of protein aggregates found in Alzheimer's disease plaque and in
|Contact: Keith McKeown|
Scripps Research Institute