Misfolded prion proteins are the originators of some previously incurable neurological diseases in humans and animals. But only now have researchers succeeded in mapping their structure almost down to the atom. With the help of cryo-electron microscopy, they made it possible for the first time to see how the amino acid chains of a variant of scrapie are structured and arranged. The images reveal, among other things, that the protein fibrils are made up of stacks of subunits with a structure similar to that of leaflets, which promote the attachment of further molecules to the ends. The exact decoding of the prion structure could help to prevent the development of these infectious protein misfoldings.
Be it the bovine “madness” BSE, the sheep disease scrapie, the chronic wasting disease (CWD) which is rampant among deer or the Creutzfeld-Jacob disease in humans: All of these neurological ailments are caused by prions – misfolded versions of proteins that also occur naturally occur in the brain and body. But as soon as normal proteins come into contact with a disease-causing prion, they also change their shape and become pathogenic. Prions are therefore among the most infectious proteins of all: Just one milligram can contain a billion lethal doses, as Allison Kraus from Case Western Reserve University and her colleagues report. In the meantime, some protein aggregates typical of Alzheimer’s, amyotrophic lateral sclerosis (ALS) or Parkinson’s are suspected of having a prion-like effect, although the infectivity is primarily noticeable in the rapid multiplication of these structures in the brain of those affected.
View into a prion fibril
However, how a prion is structured in detail and how it causes other proteins to take over this misfolding has so far hardly been clarified. “The detailed 3D structures that drive this pathological process have remained elusive so far,” say the scientists. “There was no data on the folding of the monomers within the infectious prion proteins, nor was there any knowledge of how the various prions differ structurally.” Now, however, Kraus and her colleagues have succeeded in locating one of these disease-causing prions almost down to the atomic level for the first time map and map down. This was made possible with cryo-electron microscopy. To do this, they first isolated the molecules of a strain of the scrapie prion adapted to hamsters, cooled them abruptly with liquid nitrogen and then scanned the whole thing with electron beams.
The recordings of thousands of such prions enabled the research team to decipher the structure of these misfolded proteins and to reconstruct them in a 3D model with almost atomic accuracy. It turns out that the elongated fibrils of the prion consist of innumerable identical, perfectly stacked subunits. Each of these monomers effectively forms a sprout of the fibril and facilitates the attachment of further sprouts from amino acid chains to the ends of the fiber, as the team reports. The individual monomers consist of amino acids, the secondary structure of which corresponds to a beta sheet – a flat, concertina-like folded disc, the twisted strands of which are held in shape by, among other things, disulfide bridges.
Species-specific differences
A first comparison of this prion with a second variant found in mice showed that the structure of the two differed in essential points: “The fibril cross-section shows clear differences at the fibril ends where the misfolding occurs,” report Kraus and their colleagues. “In addition, these prion versions present potential ligands with different lateral surfaces.” The team believes that some of these structural differences could explain why most prions can only be transferred to a limited extent or not at all between different animal species. In addition, such differences could also be behind the different neurological symptoms that are caused by the different prions.
“The detailed structures of the prions provide us with a new basis for understanding and tackling these previously incurable diseases,” says Kraus. “It’s now getting easier to hypothesize and test how prions become these highly infectious and deadly protein structures.”
Source: Allison Kraus (Case Western Reserve University, Cleveland) et al., Molecular Cell, doi: 10.1016 / j.molcel.2021.08.011