Cryo-EM structure of a human prion fibril with a hydrophobic, protease-resistant core

Calina Glynn; Michael R Sawaya; Peng Ge; Marcus Gallagher-Jones; Connor W Short; Ronquiajah Bowman; Marcin Apostol; Z Hong Zhou; David S Eisenberg; Jose A Rodriguez

doi:10.1038/s41594-020-0403-y

Cryo-EM structure of a human prion fibril with a hydrophobic, protease-resistant core

Nat Struct Mol Biol. 2020 May;27(5):417-423. doi: 10.1038/s41594-020-0403-y. Epub 2020 Apr 13.

Authors

Affiliations

¹ Department of Chemistry and Biochemistry; UCLA-DOE Institute for Genomics and Proteomics; STROBE, NSF Science and Technology Center, University of California, Los Angeles, Los Angeles, CA, USA.
² Department of Biological Chemistry and Department of Chemistry and Biochemistry, UCLA-DOE Institute for Genomics and Proteomics, Howard Hughes Medical Institute, University of California Los Angeles, Los Angeles, CA, USA.
³ California NanoSystems Institute, University of California Los Angeles, Los Angeles, CA, USA.
⁴ ADRx, Thousand Oaks, CA, USA.
⁵ Department of Microbiology Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, CA, USA.
⁶ Department of Chemistry and Biochemistry; UCLA-DOE Institute for Genomics and Proteomics; STROBE, NSF Science and Technology Center, University of California, Los Angeles, Los Angeles, CA, USA. jrodriguez@mbi.ucla.edu.

Abstract

Self-templating assemblies of the human prion protein are clinically associated with transmissible spongiform encephalopathies. Here we present the cryo-EM structure of a denaturant- and protease-resistant fibril formed in vitro spontaneously by a 9.7-kDa unglycosylated fragment of the human prion protein. This human prion fibril contains two protofilaments intertwined with screw symmetry and linked by a tightly packed hydrophobic interface. Each protofilament consists of an extended beta arch formed by residues 106 to 145 of the prion protein, a hydrophobic and highly fibrillogenic disease-associated segment. Such structures of prion polymorphs serve as blueprints on which to evaluate the potential impact of sequence variants on prion disease.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Amyloid / chemistry
Animals
Cryoelectron Microscopy
Crystallography, X-Ray
Humans
Hydrophobic and Hydrophilic Interactions
Mammals
Models, Molecular
Peptide Fragments / chemistry
Peptide Hydrolases / metabolism
Prion Diseases / etiology
Prions / chemistry*
Prions / metabolism*
Protein Stability
Recombinant Proteins / chemistry
Recombinant Proteins / metabolism

Substances

Amyloid
Peptide Fragments
Prions
Recombinant Proteins
Peptide Hydrolases

Abstract

Publication types

MeSH terms

Substances

Grants and funding