期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2104148118
关键词
protein aggregation and assembly; Sup35 yeast prion protein; amyloid beta peptide; atomic force microscopy; Saccharomyces cerevisiae
资金
- Biotechnology and Biological Sciences Research Council, United Kingdom [BB/J008001/1, BB/M02427X/1, BB/S003312/1]
- Medical Research Council [MR/T020415/1]
- BBSRC [BB/S003312/1, BB/M02427X/1, BB/J008001/1] Funding Source: UKRI
- UKRI [MR/T020415/1] Funding Source: UKRI
Amyloid seeds are nanometer-sized protein particles that can accelerate amyloid formation through a surface catalysis mechanism without propagating the specific amyloid conformation associated with the seeds. This allows for cross-seeded assembly reactions involving nonhomologous proteins and rationalizes the molecular mechanism of the cross-seeding phenomenon as a manifestation of aberrant surface activities by amyloid seeds.
Amyloid seeds are nanometer-sized protein particles that accelerate amyloid assembly as well as propagate and transmit the amyloid protein conformation associated with a wide range of protein misfolding diseases. However, seeded amyloid growth through templated elongation at fibril ends cannot explain the full range of molecular behaviors observed during cross-seeded formation of amyloid by heterologous seeds. Here, we demonstrate that amyloid seeds can accelerate amyloid formation via a surface catalysis mechanism without propagating the specific amyloid conformation associated with the seeds. This type of seeding mechanism is demonstrated through quantitative characterization of the cross-seeded assembly reactions involving two nonhomologous and unrelated proteins: the human A beta 42 peptide and the yeast prion-forming protein Sup35NM. Our results demonstrate experimental approaches to differentiate seeding by templated elongation from nontemplated amyloid seeding and rationalize the molecular mechanism of the cross-seeding phenomenon as a manifestation of the aberrant surface activities presented by amyloid seeds as nanoparticles.
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