Structure of a Bank Vole Prion Segment in the Amyloid State

GONEN, TAMIR; SAWAYA, MICHAEL R.; ZEE, CHIH-TE; GLYNN, CALINA; EISENBERG, DAVID S.; HELGUERA G.; BOYER, DAVID R.; GALLAGHER-JONES, MARCUS; RODRÍGUEZ J. A.; CASCIO, DUILIO; MARTYNOWYCZ, MICHAEL W.; MIAO, JENNIFER; HERNANDEZ, EVELYN

Phoenix

Conferencia; American Society for Microbiology: ABRCMS; 2017

American Society for Microbiology

Prions are infectious proteins that can aggregate to cause neurodegenerative disorders.In mammals, prion diseases are a result of the misfolding and aggregation of the prionprotein (PrP). The diseases afflict various mammalian species includingCreutzfeldt-Jakob disease and fatal familial insomnia in humans, Bovine SpongiformEncephalopathy in cattle, and scrapie in sheep. The globular, non-infectious PrPC cantransform into a malignant PrPSc comprised of beta sheets that appear as fibrillar,rope-like filaments. Due to limited structural descriptions of PrPSc, no strategy has beenidentified to inhibit the harmfulness and spread of prions within or between species. Ourstudy of PrPSc structure aims to solve this problem by determining structures ofsegments that may stabilize the core of PrPSc. We examine the structure of a segmentrepresenting residues 168-176 in the wild-type sequence of bank vole PrP:QYNNQNNFV. We choose this segment because bank voles, unlike other rodents,appear to be universal acceptors of prion disease. We determine the structure of ourbank vole PrP segment by both microfocus x-ray diffraction and the electroncryo-microscopy (cryo-EM) method, microelectron diffraction (MicroED). Thesestructures are similar, but differ in resolution; 1.1Å and 0.75Å for x-ray and electrondiffraction, respectively. Our structural analysis reveals extensive hydrogen bondnetworks in this structure that may inform on the stability of fibrillar, infectious PrPSc.