A penny for your prions

North Carolina State University researchers have discovered a link between copper and the normal functioning of prion proteins, which are associated with transmissible spongiform encephalopathy diseases such as Cruetzfeldt-Jakob in humans or "mad cow" disease in cattle. Their work could have implications for patients suffering from these diseases, as well as from other prion-related diseases such as Alzheimers or Parkinson's.

Prion proteins, or PrPs, are commonly found in brain tissue and throughout the central nervous system. In humans or animals with prion diseases, these proteins deform and aggregate, creating clumps of PrPs that interfere with the nervous system's ability to function normally. A team of NC State physicists, led by Miroslav Hodak and Jerry Bernholc, has found that when PrPs bind with copper in the human body, their structure becomes more stable and less likely to misfold or aggregate.

"We believe that a prion protein's normal function is to serve as a copper buffer in the human body, binding with copper ions and keeping those ions from damaging human tissue," Hodak says. "We wanted to determine whether this was the normal function of the prion, and then look at how that binding affected the prion's structure."

The researchers created a 3-D model of the PrP using supercomputers at Oak Ridge National Laboratories. With the model, they determined that PrPs can bind up to four copper ions apiece, depending on the concentration of copper present. They also found that when the PrPs bind to the copper ions, the structure of the protein changes, becoming more stable.

Their results are published online this week in Proceedings of the National Academy of Sciences.

"Prion proteins are unusual in that half of the protein has a well-defined structure, but the other half of it -- where the binding occurs -- is a flexible, random tangle," Hodak says. "When we looked at the so-called 'random' portion of the PrP where that binding occurs, we found that the copper ions lend stability to the overall protein. This stability may play a role in preventing PrPs from misfolding or aggregating -- which indicates that with prion diseases, copper binding may be beneficial."

Note to editors: An abstract of the paper follows.

"Cu2+ Binding to the Prion Protein: Functional Implications and the Role of Copper"

Authors: Miroslav Hodak, and Robin Chisnell, North Carolina State University; Wenchang Lu and Jerry Bernholc, North Carolina State University and Oak Ridge National Laboratories

Published: Online the week of June 22, 2009, in Proceedings of the National Academy of Sciences

Abstract: The prion protein (PrP) is responsible for a group of neurodegenerative diseases called the transmissible spongiform encephalopathies. The normal function of PrP has not yet been discovered, but indirect evidence suggests a linkage to its ability to bind copper. In this article, low-copper-concentration bindings of Cu2+ to PrP are investigated by using a recently developed hybrid density functional theory (DFT)/DFT method. It is found that at the lowest copper concentrations, the binding site consists of 4 histidine residues coordinating the copper through _ imidazole nitrogens. At higher concentrations, 2 histidines are involved in the binding, one of them in the axial position. These results are in good agreement with existing experimental data. Comparison of free energies for all modes of coordination shows that when enough copper is available, the binding sites will spontaneously rearrange to accommodate more copper ions, despite the fact that binding energy per copper ion decreases with concentration. These findings support the hypothesis that PrP acts as a copper buffer in vivo, protecting other proteins from the attachment of copper ions. Using large-scale classical molecular dynamics, we also probe the structure of full-length copper-bound PrP, including its unfolded N-terminal domain. The results show that copper attachment leads to rearrangement of the structure of the Cu-bonded octarepeat region and to development of turns in areas separating copperbound residues. These turns make the flexible N-terminal domain more rigid and thus more resistant to misfolding. The last result suggests that copper binding plays a beneficial role in the initial stages of prion diseases.

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June 25, 2009