Navigation Links
Scripps research study reveals structural dynamics of single prion molecules

The new findings, which are being published the week of February 12 in an online edition of the Proceedings of the National Academy of Sciences, offer significant insights into normal folding mechanisms as well as those that lead to abnormal amyloid fibril conversion. The new insights may lead to the discovery of novel therapeutic targets for neurodegenerative diseases.

Intriguingly, certain prions and amyloids can play beneficial roles. The subject of the new study, Sup35, enables protein-based inheritance in yeast. When this prion protein misfolds, it converts into self-perpetuating amyloid fibrils, thus altering its function in an inheritable manner. The research team used a combination of advanced biophysical methods to investigate these processes.

"By focusing on single unfolded prions, we were able to define the dynamics of two distinct regions or domains that determine conversion dynamics," said Ashok A. Deniz, a Scripps Research scientist who led the study. "Our research techniques can now be used to probe the structures of other amyloidogenic proteins. This could prove important in understanding the basic biology of amyloid formation, as well as in designing strategies against misfolding diseases."

Interestingly, the new study revealed that yeast prion protein Sup35 lacks a specific, static structure in its native collapsed state. Instead, the compact protein fluctuates among several different structures before forming intermediate shapes during the amyloid assembly process.

The intermediate stages of the process are critically important, Deniz noted: "No single native unfolded protein is capable of initiating the amyloid cascade because of this constant shape-shifting. To start the amyloid conversion process, it has to first convert to an intermediate species, consisting of multiple protein molecules. This insight may be important to finding potential new therapeutic targets for disease-causing amyloids."

To define the dynamic structural details of individual prions, Deniz and his colleagues employed several novel technologies including single-molecule fluorescence resonance energy transfer (SM-FRET) and fluorescence correlation spectroscopy (FCS).

Fluorescence resonance energy transfer is a highly sensitive tool used to measure molecular structure and dynamics such as in single proteins at the angstrom level, a measurement unit used to define molecular distances (a 10th of a millionth of a millimeter). Fluorescence correlation spectroscopy is a high resolution technique that measures time fluctuations in fluorescent emissions from tagged proteins, which provided information about changes in shape of Sup35 taking place on the nanosecond timescale (billionths of seconds).

A third technology, single molecule fluorescence coincidence, was used in an unusual way-to prove that the protein species under scrutiny were not oligomeric (consisting of multiple proteins in an aggregate). The technology, based on measuring fluorescence bursts from individual tagged proteins, enabled the scientists to determine that the proteins being studied were, in fact, single monomers and not aggregates.

Deniz said that future work with yeast prion mutants might resolve some of the questions that remain unanswered. "Our laboratory has spent a great deal of time in improving these techniques, and we have used them to uncover some very intriguing information about this particular monomer," he said. "This combination of techniques can now be used to study other amyloidogenic proteins, including prions, particularly small assemblies and intermediate stages of the aggregation process. These are currently considered the most toxic forms of amyloid-disease associated proteins."

While mammalian prion proteins are different from those of yeast in their amino acid sequence, they do share some basic features, including their ability to catalyze the conversion to a myloid fibers. Some studies suggest that prions may also play key roles in certain critical processes such as long-term memory. Other authors of the study, A Natively Unfolded Yeast Prion Monomer Adopts An Ensemble of Collapsed and Rapidly Fluctuating Structures, are Samrat Mukhopadhyay and Edward A. Lemke of The Scripps Research Institute; and Susan Lindquist and Rajaraman Krishnan of the Whitehead Institute for Biomedical Research.


'"/>

Source:Scripps Research Institute
Technorati Profile


Related biology news :

1. Scripps scientists find potential for catastrophic shifts in Pacific ecosystems
2. To Stop Evolution: New Way Of Fighting Antibiotic Resistance Demonstrated By Scripps Scientists
3. Scripps research scientists identify infertility molecule
4. Scripps research scientists solve structure of a critical innate immune system protein
5. New Scripps Oceanography project to study sediments and ecosystem restoration in Venice lagoon
6. Scripps Research study reveals new activation mechanism for pain sensing channel
7. Scripps research team discovers a chemical pathway that causes mice to overeat and gain weight
8. Scripps research study shows humans and plants share common regulatory pathway
9. Scripps research team sheds light on long-sought cold sensation gene
10. Columbia research lifts major hurdle to gene therapy for cancer
11. U of M researcher examines newly emerging deadly disease
Post Your Comments:
*Name:
*Comment:
*Email:


(Date:4/18/2017)... -- Socionext Inc., a global expert in SoC-based imaging and computing solutions, ... which features the company,s hybrid codec technology. A demonstration utilizing TeraFaces ... will be showcased during the upcoming Medtec Japan at Tokyo Big ... Las Vegas Convention Center April 24-27. ... Click here for an image of ...
(Date:4/13/2017)... April 13, 2017 According to a new market ... Identity Analytics, Identity Administration, and Authorization), Service, Authentication Type, Deployment Mode, Vertical, ... Market is expected to grow from USD 14.30 Billion in 2017 to ... of 17.3%. ... MarketsandMarkets Logo ...
(Date:4/11/2017)... April 11, 2017 No two people ... at the New York University Tandon School of ... have found that partial similarities between prints are ... in mobile phones and other electronic devices can ... The vulnerability lies in the fact that fingerprint-based ...
Breaking Biology News(10 mins):
(Date:10/11/2017)... ... October 11, 2017 , ... At its national board meeting ... I. Sheikh, the co-founder, CEO and chief research scientist of Minnesota-based Advanced Space ... membership in ARCS Alumni Hall of Fame . ASTER Labs is a ...
(Date:10/11/2017)... ... October 11, 2017 , ... Personal eye wash is a basic first aid supply ... a time. So which eye do you rinse first if a dangerous substance enters both ... Duo Eye Wash with its unique dual eye piece. , “Whether its dirt and ...
(Date:10/11/2017)... ... October 11, 2017 , ... Proscia Inc ... hosting a Webinar titled, “Pathology is going digital. Is your lab ready?” with ... adoption best practices and how Proscia improves lab economics and realizes an increase ...
(Date:10/11/2017)... LAGUNA HILLS, Calif. , Oct. 11, 2017 ... London (ICR) and University of ... prognostic tool to risk-stratify patients with multiple myeloma (MM), in ... nine . The University of Leeds ... by Myeloma UK, and ICR will perform the testing services ...
Breaking Biology Technology: