Abstract
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 Aβ42 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.
Highlights
Koloteva-Levine, Nadejda, Aubrey, Liam D., Marchante, Ricardo, Purton, Tracey J., Hiscock, Jennifer R., Tuite, Mick F. and Xue, Wei-Feng (2021) Amyloid particles facilitate surface-catalyzed cross-seeding by acting as promiscuous nanoparticles
We demonstrate that amyloid seeds can accelerate amyloid formation via a surface catalysis mechanism without propagating the specific amyloid conformation associated with the seeds
In order to test whether such a general surface-catalyzed mechanism can explain and rationalize the molecular mechanism of amyloid cross-seeding and to show that the seeding and templating activities of amyloid seeds can potentially be mechanistically uncoupled, we investigated the cross-seeding interactions between two unrelated amyloidogenic proteins: human Aβ42 fibril-seeds (Aβ42s) that is associated with Alzheimer disease [2] and the amyloid-forming protein Sup35NM that is a component of a prion-based epigenetic switch in the yeast Saccharomyces cerevisiae [7]
Summary
Koloteva-Levine, Nadejda, Aubrey, Liam D., Marchante, Ricardo, Purton, Tracey J., Hiscock, Jennifer R., Tuite, Mick F. and Xue, Wei-Feng (2021) Amyloid particles facilitate surface-catalyzed cross-seeding by acting as promiscuous nanoparticles. 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 crossseeded assembly reactions involving two nonhomologous and unrelated proteins: the human Aβ42 peptide and the yeast prion– forming protein Sup35NM. The slow nucleation-dependent process that converts normally soluble protein or peptide precursors into their amyloid conformation [3] can be bypassed through the addition of preformed amyloid particles, the seeds This phenomenon, which effectively accelerates amyloid growth and propagates the amyloid conformation, is called seeding. The seeded growth of amyloid, as well as transmissible forms of amyloid known as prions, via the templated addition of monomer units or small oligomers to the ends of preformed fibril seeds [4,5,6] is known as fibril elongation (Fig. 1A)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
