PXD032402

PXD032402 is an original dataset announced via ProteomeXchange.

Title	Cryo-EM Structures of Prion protein filaments from Gerstmann-Sträussler-Scheinker disease
Description	Aggregation of the prion protein (PrP) and formation of PrP amyloid (APrP) is severe in some Prion diseases. In the dominantly inherited prion protein amyloidosis known as Gerstmann-Sträussler-Scheinker (GSS) disease, plaques made of PrP amyloid are a distinct feature. The TTC to TCC mutation in Prion protein gene (PRNP), resulting in a phenylalanine to serine amino acid substitution at PrP residue 198, causes a severe amyloidosis in a well-studied GSS variant. The neuropathologic phenotype of this neurodegenerative disease is characterized by the presence of numerous extracellular APrP plaques and intracytoplasmic tau neuronal inclusions which are identical to neurofibrillary tangles of Alzheimer disease. Using cryogenic electron microscopy (cryo-EM), we determined for the first time the structures of filaments of human APrP, isolated post-mortem from the brain of a symptomatic PRNP F198S mutation carrier. We report that in GSS (F198S) APrP filaments are composed of dimeric, trimeric and tetrameric left-handed protofilaments with their protomers sharing a common protein fold. The protomers in the cross-β spines consist of sixty-two amino acids and span from glycine 80 to phenylalanine 141, adopting a previously unseen spiral fold with a thicker outer layer and a thinner inner layer. Each protomer comprises nine short β-strands. The β1 and β8 strands as well as the β4 and β9 strands are engaged in a steric zipper. The new data, obtained by Cryo-EM, provide insights into the complexity of the structure of pathogenic PrP, and reveal the difference of PrP’s structure in brain disease versus that of recombinant PrP, highlighting the urgency of extending our knowledge of the structure of the amyloid filaments involved in human neurodegenerative diseases.
HostingRepository	PRIDE
AnnounceDate	2022-07-18
AnnouncementXML	Submission_2022-07-18_07:02:47.849.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD032402
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Emma Doud
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue; deamidated residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2022-03-18 09:15:00	ID requested
⏵ 1	2022-07-18 07:02:48	announced

Hallinan GI, Ozcan KA, Hoq MR, Cracco L, Vago FS, Bharath SR, Li D, Jacobsen M, Doud EH, Mosley AL, Fernandez A, Garringer HJ, Jiang W, Ghetti B, Vidal R, ussler-Scheinker disease. Acta Neuropathol, 144(3):509-520(2022) [pubmed]

submitter keyword: Cryo-EM Structures of Prion protein filaments from Gerstmann-Sträussler-Scheinker disease

Amber Mosley
contact affiliation	Biochemistry and Molecular Biology, Indiana University School of Medicine
contact email	almosley@iu.edu
lab head
Emma Doud
contact affiliation	Indiana University School of Medicine
contact email	edoud@iu.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD032402
     1. Label: PRIDE project
     2. Name: Cryo-EM Structures of Prion protein filaments from Gerstmann-Sträussler-Scheinker disease