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.

“This type of transition package is widely used in academia,” Jordan said, “but these are extraordinary budgetary times. I am asking the chancellor to review the contract to ensure compliance with university policies, rules and regulations.”

Nielsen resigned as provost effective May 22 to return to the faculty. He is being paid his provost salary during a six-month period in which he is preparing himself to resume his faculty responsibilities. Before serving as provost for over four years, Nielsen served as dean of the College of Natural Resources for four years.

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In a new paper published in Proceedings of the Royal Society B, North Carolina State University biologist Rob Dunn and colleagues examine the concept of coextinction, or the domino effect of extinctions caused by species loss. For example, each fig species tends to be pollinated by a single fig wasp such that the loss of one should result in the loss of the other.

Mathematical models suggest that coextinctions due to the actions of humans are very common, the paper asserts. Yet, counterintuitively, there have been few reported cases of coextinction in the scientific literature.

“What we know about coextinctions presents a kind of paradox. The models suggest thousands of coextinctions have already occurred and that hundreds of thousands may be on the horizon. Yet we have observed few such events,” Dunn says. “So we’re not sure if all of these coextinctions are happening and not being tracked, or if parasites and mutualist species are better able to switch partners than we give them credit for, or something in between. Maybe some of the specialized relationships – like between the figs and fig wasps – aren’t so specialized.”

Moreover, Dunn says, the models, if crudely accurate, suggest that the number of parasite coextinctions greatly outweighs the number of host extinctions.

“Since the diversity of parasitic or affiliated species – which may include viruses, ticks, lice and bacteria, and butterflies, but also so-called mutualists such as the crops pollinated by honey bees or the bees themselves – is several orders of magnitude greater than that of their hosts, the numbers of coextinctions are also expected to be far greater than the number of extinctions of host species,” Dunn says.

This numbers game alone presents strong evidence to suggest that coextinctions are more important than the original host extinctions themselves. But the paper also examines other costs of coextinction – including the losses of biological diversity, unique species traits and what we can learn about evolutionary history.

But, regardless of whether we care at all about the loss of such species and their traits and roles, there is something even scarier about the consequences of coextinction.

“There is a distinct possibility that declines in host species could drive parasite species to switch onto alternative hosts, which in turn could escalate the rate of emerging pathogens and parasites both for humans and our domesticated animals and plants,” Dunn says. “Put simply, when a host becomes rare, its parasites and mutualists have two choices: jump ship to another host or go extinct. Either situation is a problem.”

Dunn noted that the regions where new human diseases, such as bird flu, are emerging coincide with the regions where the most mammal and bird species are endangered. “We have long talked about the negative consequences of the endangerment of the species we love,” he says, “but getting left with their parasites is a consequence no one bargained for.”

The paper concludes by calling for better study and understanding of coextinction, and for documenting cases of coextinction when they are discovered. It also calls for more study into the interactive effects of the different reasons for extinction – habitat loss, species invasion, overkill and coextinctions, not to mention climate change – to gauge how they affect each other.

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Note: An abstract of the paper follows.

“The sixth mass coextinction: are most endangered species parasites and mutualists?”

Authors: Robert R. Dunn and Nyeema C. Harris, North Carolina State University; Robert K. Colwell, University of Connecticut; Lian Pin Koh, Institute of Terrestrial Ecosystems, ETH Zurich; Navjot S. Sodhi, University of Singapore and Harvard University

Published: May 27, 2009, in Proceedings of the Royal Society B

Abstract: The effects of species declines and extinction on biotic interactions remain poorly understood. The loss of a species is expected to result in the loss of other species that depend on it (coextinction), leading to cascading effects across trophic levels. Such effects are likely to be most severe in mutualistic and parasitic interactions. Indeed, models suggest that coextinction may be the most common form of biodiversity loss. Paradoxically, few historical or contemporary coextinction events have actually been recorded. We review the current knowledge of coextinction by: (i) considering plausible explanations for the discrepancy between predicted and observed coextinction rates; (ii) exploring the potential consequences of coextinctions; (iii) discussing the interactions and synergies between coextinction and other drivers of species loss, particularly climate change; and (iv) suggesting the way forward for understanding the phenomenon of coextinction, which may well be the most insidious threat to global biodiversity.

“Discovery and Recovery: Death in Natural Environments,” being held June 1-5 at NC State, will help law enforcement officers hone their investigative skills through a combination of classroom instruction and hands-on field exercises. The workshop – funded by a grant from the National Institute of Justice – includes lectures and presentations each morning at the NC State College of Textiles, followed by afternoon field exercises at NC State’s Lake Wheeler Road Field Laboratories.

Media wishing to attend the workshop and hone their own skills in covering crime scenes are invited to do so. Lectures will take place each day from approximately 9 to 11 a.m. in room 2221 at NC State’s College of Textiles on Centennial Campus. Field exercises will run from approximately 12:30 to 5 p.m. at the Lake Wheeler Road Field Laboratories each day, except Friday. Media wishing to cover the workshop should contact Caroline Barnhill in the NC State News Services office at caroline_barnhill@ncsu.edu or 919/515-6251 for more information.

The “Discovery and Recovery” workshop is co-sponsored by NC State, the North Carolina Program for Forensic Sciences, the N.C. Office of State Archaeology Research Center and the N.C. Justice Academy. Dr. Ann H. Ross, associate professor of anthropology at NC State, and Dr. Billy Oliver, an archaeologist and NC State adjunct professor in sociology and anthropology, are co-directors of the forensic program and are coordinating the workshop. They will be joined by Dr. David Hinks, associate professor of textile engineering, chemistry and science; Dr. Wes Watson, associate professor of entomology; and Dr. Jason Byrd, director of operations for the Office of the Medical Examiner in Daytona Beach, Fla.

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