Pick up a prion: Solid state NMR spots the differences

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  • Published: Nov 15, 2017
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: Pick up a prion: Solid state NMR spots the differences

Cerebral amyloid angiopathy

Schematic model for the [hu] amyloid core based on the combination of solid-state NMR and tilted-beam transmission electron microscopy data Credit: Jaroniec et al/Nature Communications

Researchers in the USA have used solid-state nuclear magnetic resonance (NMR) spectroscopy to study the rogue protein, Y145Stop, involved in familial human cerebral amyloid angiopathy (CAA). This hereditary neurodegenerative condition is one of the family of prion diseases that afflict mammals and include bovine spongiform encephalopathy (often referred to colloquially as "mad cow disease"), Creutzfeldt-Jakob disease in humans, their equivalents in cats, mice, hamsters and other animals.

Writing in the journal Nature Communications, Christopher Jaroniec, professor of chemistry and biochemistry at The Ohio State University, and his colleagues explain how this research is the first to examine forms of the protein in three different species. Specifically the team used solid state NMR to look at the proteins underlying CAA in humans, the mouse, and the hamster. Although all three prions have almost identical amino acid sequences, they reveal themselves to have distinct three-dimensional structures at the atomic level. The findings highlight the fact that minor alterations in single amino acids can cause profound differences in structure and function among this family of proteins, the team suggests.

Revealing the plaque

"The large-scale differences in the structures and transmission characteristics of these proteins - caused by what amounts to seemingly insignificant differences in the positions of a few carbon and hydrogen atoms - are quite remarkable," Jaroniec explains. The new work offers the possibility of using these proteins as models for understanding the fundamental aspects of how prion diseases can be transferred from species to species, their cross-species transmission mechanism, in other words. The research also underscores the utility of solid-state NMR spectroscopy for imaging the structures of proteins associated with these diseases. The aims of the study were not to develop a new test for CAA nor to helping in finding treatments rather it was aimed at understanding the wider realm of transmissible prionic diseases.

It was previously known that within the body of someone with CAA, the associated protein molecules form plaques that lodge in blood vessel walls in the brain. In 2008, OSU scientists and their collaborators at Case Western Reserve University had performed preliminary solid-state studies of the relevant prion protein variant and narrowed down the list of essential critical amino acids for its function to about 30. Moreover, it is worth noting that there had not been until recently a detailed examination of the molecular structure of these plaques.

Subtle structure

Now, the researchers have demonstrated that a single amino acid - known by its number along the protein chain, 139 - is the key to this prion protein variant adopting a "human-like" as opposed to a "hamster-like" structure. A second amino acid, number 112 in the protein sequence, governs the structural differences between the human and mouse versions of the protein. The team has also shown that these two amino acids appear to be responsible for the emergence of structurally distinct "prion strains" within the same protein sequence.

Prion diseases are incurable and fatal. The fact that some of them are transmissible means that we need to understand the protein structures and how their form affects transmissibility if there is ever to be a possibility of finding a way to prevent their spread. The structures adopted by the brain prion proteins within the lethal plaques are thought to be critical to their ability to be transmitted between different hosts and cause disease.

"Our group is currently working on determining the high resolution molecular structures of the truncated prion protein variants associated with familial human CAA in order to gain a complete atomistic understanding of the factors underlying their transmission, and the present study is a major stepping stone in this effort," Jaroniec explains. "We hope that one day our group and other researchers will be able to use similar methodologies to unravel the structural basis of the transmissible prion diseases," he adds.

Related Links

Nature Commun 2017, 8, online: "Species-dependent structural polymorphism of Y145Stop prion protein amyloid revealed by solid-state NMR spectroscopy"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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