Nav: Home

Newly deciphered structure suggests how infectious prions replicate

September 08, 2016

Infectious prions or PrPSc--misfolded versions of the normal cellular prion protein PrPC--convert their normal counterparts into copies of themselves and thereby cause fatal disease. How this conversion works at the molecular level has remained largely a mystery. A study published on September 8th in PLOS Pathogens reports the three-dimensional structure of a large part of PrPSc. The structure argues against existing theories of conversion and suggests how the process might actually work.

The discovery of the structure of DNA in 1953 made it immediately obvious how DNA could be copied, or replicated. The three-dimensional structure of PrPSc has remained elusive, but the hope is that its discovery would likewise promote the understanding of prion replication, as well as lead to the development of structure-based therapeutic interventions. Convinced that the structure of what they call 'infectious conformers'--PrPSc from the brain of diseased animals--will be most informative, a team led by Holger Wille and Howard Young from the University of Alberta in Edmonton, Canada, and Jesús Requena from the University of Santiago de Compostela, Spain, is applying electron cryomicroscopy (cryo-EM) to the problem.

In this study, they used cryo-EM to record and analyze the structure of PrPSc isolated from the brain of infected mice. Prion-infected mouse and human brains contain a mix of different versions of PrPSc because different types of molecules such as lipids and sugars have been attached to the core protein. The heterogeneity of these modified brain-derived PrPSc makes it difficult to analyze their structure. To avoid this difficulty, the researchers started with PrPSc molecules that were truncated to delete the attachment of one type of modification, the so-called GPI lipid anchor. By using as a source the brains of transgenic mice expressing a GPI-anchorless form of the prion protein, they were able to analyze a more homogeneous version of PrPSc that nonetheless retained its ability to cause disease and convert normal cellular prion proteins.

In the diseased brain, PrPSc molecules are often arranged in fibrils. The cryo-EM images of the mouse GPI-anchorless PrPSc fibrils, and their subsequent analysis, showed that they consist of two intertwined protofilaments of defined volume. As cryo-EM preserves the native structure of specimens, this information sets a structural restraint for the conformation of GPI-anchorless PrPSc, with the implication that PrPSc molecules can form protofilaments with the observed dimensions only if they are folded up onto themselves.

Based on their own analyses (and consistent with data from related studies), the researchers conclude that the cryo-EM data reveal a four-rung ß-solenoid architecture as the basic element for the structure of the mammalian prion GPI-anchorless PrPSc. ß-solenoids are protein structures that consist of an array of repetitive elements with secondary structures that are predominantly beta sheets. These PrPSc beta-sheet rungs, the researchers propose, serve as templates for new unfolded PrPSc molecules.

What they have learned about the structure of GPI-anchorless PrPSc and its four-rung ß solenoid architecture, the researchers say, allows them to rule out all previously proposed templating mechanisms for the replication of infectious prions in vivo. Discussing their ideas for the conversion of PrPC to PrPSc, the researchers note that the molecular forces responsible for the templating are fundamentally similar to those operating during the replication of DNA. "Because the exquisite specificity of the A:T and G:C pairings is lacking", they conclude that "a much more complex array of forces controls the pairing of the pre-existing and nascent ß-rungs".

"Templating based on a four-rung ß-solenoid architecture", they say, "must involve the upper- and lowermost ß-solenoid rungs [which] are inherently aggregation-prone". "Once an additional ß-rung has formed", they propose, "it creates a fresh "sticky" edge ready to continue templating until the incoming unfolded PrP molecule has been converted into another copy of the infectious conformer".

The researchers acknowledge that higher resolution structures and resolution of structures of other PrPSc molecules will be needed. Nonetheless, they conclude, "we present data based on cryo-EM analysis that strongly support the notion that GPI-anchorless PrPSc fibrils consist of stacks of four-rung ß-solenoids. Two of such protofilaments intertwine to form double fibrils [...]. The four-rung ß-solenoid architecture of GPI-anchorless PrPSc provides unique and novel insights into the molecular mechanism by which mammalian prions replicate".
-end-
In your coverage please use this URL to provide access to the freely available article in PLOS Pathogens: http://dx.doi.org/10.1371/journal.ppat.1005835

Please contact plospathogens@plos.org if you would like more information.

Funding: This project has been supported by grants from the Alberta Prion Research Institute / Alberta Innovates Bio Solutions (201100010; 201100011; 201300012; 201300024), the Alberta Livestock & Meat Agency (2012A001R), the Canada Foundation for Innovation (NIF 21633 and IOF 21633 awards to D. Westaway), the European Commission grant FP7 222887 "Priority", a Spanish Ministry of Education grant (BFU2006-04588/BMC), and Spanish Ministry of Economy and Competitiveness grants (BFU2013-48436-C2-1-P & TIN2012-37483-C03-02). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: MRV is an employee of FEI Company (Eindhoven, The Netherlands), this does not alter our adherence to all PLoS Pathogens policies on sharing data and materials.

Citation: Vázquez-Fernández E, Vos MR, Afanasyev P, Cebey L, Sevillano AM, Vidal E, et al. (2016) The Structural Architecture of an Infectious Mammalian Prion Using Electron Cryomicroscopy. PLoS Pathog 12(9): e1005835. doi:10.1371/journal.ppat.1005835

PLOS

Related Brain Articles:

Study describes changes to structural brain networks after radiotherapy for brain tumors
Researchers compared the thickness of brain cortex in patients with brain tumors before and after radiation therapy was applied and found significant dose-dependent changes in the structural properties of cortical neural networks, at both the local and global level.
Blue Brain team discovers a multi-dimensional universe in brain networks
Using a sophisticated type of mathematics in a way that it has never been used before in neuroscience, a team from the Blue Brain Project has uncovered a universe of multi-dimensional geometrical structures and spaces within the networks of the brain.
New brain mapping tool produces higher resolution data during brain surgery
Researchers have developed a new device to map the brain during surgery and distinguish between healthy and diseased tissues.
Newborn baby brain scans will help scientists track brain development
Scientists have today published ground-breaking scans of newborn babies' brains which researchers from all over the world can download and use to study how the human brain develops.
New test may quickly identify mild traumatic brain injury with underlying brain damage
A new test using peripheral vision reaction time could lead to earlier diagnosis and more effective treatment of mild traumatic brain injury, often referred to as a concussion.
This is your brain on God: Spiritual experiences activate brain reward circuits
Religious and spiritual experiences activate the brain reward circuits in much the same way as love, sex, gambling, drugs and music, report researchers at the University of Utah School of Medicine.
Brain scientists at TU Dresden examine brain networks during short-term task learning
'Practice makes perfect' is a common saying. We all have experienced that the initially effortful implementation of novel tasks is becoming rapidly easier and more fluent after only a few repetitions.
Balancing time & space in the brain: New model holds promise for predicting brain dynamics
A team of scientists has extended the balanced network model to provide deep and testable predictions linking brain circuits to brain activity.
New view of brain development: Striking differences between adult and newborn mouse brain
Spikes in neuronal activity in young mice do not spur corresponding boosts in blood flow -- a discovery that stands in stark contrast to the adult mouse brain.
Map of teenage brain provides evidence of link between antisocial behavior and brain development
The brains of teenagers with serious antisocial behavior problems differ significantly in structure to those of their peers, providing the clearest evidence to date that their behavior stems from changes in brain development in early life, according to new research led by the University of Cambridge and the University of Southampton, in collaboration with the University of Rome Tor Vergata in Italy.

Related Brain Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Anthropomorphic
Do animals grieve? Do they have language or consciousness? For a long time, scientists resisted the urge to look for human qualities in animals. This hour, TED speakers explore how that is changing. Guests include biological anthropologist Barbara King, dolphin researcher Denise Herzing, primatologist Frans de Waal, and ecologist Carl Safina.
Now Playing: Science for the People

#SB2 2019 Science Birthday Minisode: Mary Golda Ross
Our second annual Science Birthday is here, and this year we celebrate the wonderful Mary Golda Ross, born 9 August 1908. She died in 2008 at age 99, but left a lasting mark on the science of rocketry and space exploration as an early woman in engineering, and one of the first Native Americans in engineering. Join Rachelle and Bethany for this very special birthday minisode celebrating Mary and her achievements. Thanks to our Patreons who make this show possible! Read more about Mary G. Ross: Interview with Mary Ross on Lash Publications International, by Laurel Sheppard Meet Mary Golda...