Deadly folding mistake: Molecular mechanism of prion protein oligomerization at atomic resolution

August 16, 2013

(Phys.org) —Mad cow disease and its cousin Creutzfeld-Jakob disease cause fatal spongy changes in brain tissue. Today, we know that these diseases are caused by prions, proteins that are folded incorrectly. A team of German researchers have now been able to follow how the diseased proteins aggregate and "infect" healthy ones on the atomic scale. Their report appears in the journal Angewandte Chemie.

How can a disease that is caused by a protein instead of a virus or bacterium be contagious? It is clear that incorrectly folded prion proteins must be able to deform their correctly folded analogues and to change their spatial structure. They transfer their own incorrect shape to the healthy proteins. Normally, these proteins exist as monomers that are mostly wound into an alpha helix. When incorrectly folded, the protein has many regions containing beta sheets, structures that resemble an accordion, and has a tendency to self-assemble into larger aggregates. These cannot be broken down and thus form deposits in the brain's tissue.

How this process works in detail has now been clarified. Kai Schlepckow and Harald Schwalbe at the Goethe University Frankfurt am Main have successfully used time-resolved NMR spectroscopic studies to follow what is happening to every individual amino acid as the prion aggregate—an extremely complex process.

Their most interesting revelation is that the aggregation occurs in two steps. First, oligomers are formed from five to eight units. In the second step, these aggregate further into molecules made of up to 40 units that form fibrous structures. The first oligomerizations initially affect proteins in a largely unfolded state. Certain regions of the protein stiffen as the oligomerization proceeds. Different regions of the protein participate in different phases of the aggregation.

The researchers hope to use their new understanding to better determine what role is played by the specific mutations in the that seem to fuel initiation of this process. This may also provide a starting point for the development of effective drugs.

Explore further: Cellular stress can induce yeast to promote prion formation

More information: Schwalbe, H. and Goethe, J. Molecular Mechanism of Prion Protein Oligomerization at Atomic Resolution, Angewandte Chemie International Edition. dx.doi.org/10.1002/anie.201305184

Related Stories

Cellular stress can induce yeast to promote prion formation

July 23, 2011

It's a chicken and egg question. Where do the infectious protein particles called prions come from? Essentially clumps of misfolded proteins, prions cause neurodegenerative disorders, such as mad cow/Creutzfeld-Jakob disease, ...

The ribosome: A new target for antiprion medicines

July 2, 2013

New research results from Uppsala University, Sweden, show that the key to treating neurodegenerative prion diseases such as mad cow disease and Creutzfeldt-Jakob disease may lie in the ribosome, the protein synthesis machinery ...

Recommended for you

Findings illuminate animal evolution in protein function

July 27, 2015

Virginia Commonwealth University and University of Richmond researchers recently teamed up to explore the inner workings of cells and shed light on the 400–600 million years of evolution between humans and early animals ...

New polymer able to store energy at higher temperatures

July 30, 2015

(Phys.org)—A team of researchers at the Pennsylvania State University has created a new polymer that is able to store energy at higher temperatures than conventional polymers without breaking down. In their paper published ...

How to look for a few good catalysts

July 30, 2015

Two key physical phenomena take place at the surfaces of materials: catalysis and wetting. A catalyst enhances the rate of chemical reactions; wetting refers to how liquids spread across a surface.

Yarn from slaughterhouse waste

July 29, 2015

ETH researchers have developed a yarn from ordinary gelatine that has good qualities similar to those of merino wool fibers. Now they are working on making the yarn even more water resistant.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.