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Saturday, 10 September 2016

Glimpse of Notorious Prion Protein Shape Revealed

Molecular architecture of an infectious mammalian prion. (Image Credit: ESTER VAZQUEZ-FERNANDEZ, HOWARD YOUNG, HOLGER WILLE, JESUS REQUENA, Source: The Scientist)

Structural Biologists has been deciphering many unknown molecular structures within the cell. But until now the notorious candidate – the mammalian prion was missing. The reason for this late discovery was the insoluble nature and tendency to aggregate of prions. Now researchers have overcome these difficulties and came forward with the structure of shortened form of infectious Prion protein, commonly known as PrPSc.

The research has published in this week’s Plos Pathogens.

Giuseppe Legname of Scuola Internazionale Superiore di Studi Avanzati in Trieste, Italy (who was not involved in this study) said "For the first time, we have a structure of an infectious mammalian prion. It's a very important paper."

The co-author of the research Jesús Requena of the University of Santiago de Compostela in Spain said, “What we have done is to obtain a very simple, very preliminary idea of what the structure of these mammalian prions is.”

The Research:

Requena and colleagues have generated a short form of PrPSc by injecting laboratory strain of prions into transgenic mice that had expressed truncated form of normal cellular prion protein PrPc. This cellular form is different from the diseased form by the absence of membrane anchor protein. Naturally the cellular form transforms in diseased form, leading to a disease called Creutzfeldt-Jakob that is usually seen in scrapie in sheep, mad cow disease and even in humans.

In shortened PrPSc there is an absence of membrane anchor which helped the researchers to isolate homogeneous population of PrPSc. Confirmation was made by infecting it to wild type mouse which then developed prion disease.

The authors in the study used electron cryomicroscopy (cryo-EM) on PrPSc molecules which formed amyloid fibrils in the brain of infected animals. Researchers took multiple pictures including hundreds of fibrils each to generate the 3D reconstruction of the fibrils. The results shown that PrPSc is four-rung β solenoid, like a spring with four turns.

Holger Wille, from University of Alberta, Canada and the co-author of the study confirmed this structure with X-ray diffraction techniques which showed same four-rung β solenoid structure. “When you get the same result with different techniques, it makes you confident that you’re on the right track,” he said.

The authors now looking ahead of how PrPc is turning into PrPSc. There are lots more to reveal as the authors said.

Source: The Scientist


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