Open AccessMechanism of misfolding of the human prion protein revealed by a pathological mutation
Author(s) -
Máximo Sanz-Hernández,
Joseph D. Barritt,
Jens Sobek,
Simone Hornemann,
Adriano Aguzzi,
Alfonso De Simone
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2019631118
Subject(s) - protein aggregation , prion protein , mutation , protein folding , mechanism (biology) , amyloid (mycology) , fibril , mutant , chemistry , amyloid fibril , microbiology and biotechnology , biology , biochemistry , disease , amyloid β , gene , medicine , inorganic chemistry , pathology , philosophy , epistemology
Significance The misfolding and aggregation into amyloid fibrils of the prion protein (PrP) have been strongly linked with a group of neurodegenerative disorders that include the mad cow disease. Currently, the molecular origins of the prion diseases are unknown, including the underlying mechanisms of PrP misfolding and the regions promoting its aggregation. Here, we identified the structural basis by which the folded domain of the human PrP converts into amyloids. We showed that this process is promoted by intermediate species forming as a result of the pathological mutation T183A, and that POM antibodies are able to suppress completely the aggregation process by blocking the misfolding mechanism. This study thereby suggests possible molecular strategies to inhibit PrP aggregation into amyloids.