Year-end Sale % OFF 
Abstract
The early stages of protein misfolding remain incompletely understood, as most mammalian proteinopathies are only detected after irreversible protein aggregates have formed. Cross-seeding, where one aggregated protein templates the misfolding of a heterologous protein, is one mechanism proposed to stimulate protein aggregation and facilitate disease pathogenesis. Here, we demonstrate the existence of cross-seeding as a crucial step in the formation of the yeast prion [PSI+], formed by the translation termination factor Sup35. We provide evidence for the genetic and physical interaction of the prion protein Rnq1 with Sup35 as a predominant mechanism leading to self-propagating Sup35 aggregation. We identify interacting sites within Rnq1 and Sup35 and determine the effects of breaking and restoring a crucial interaction. Altogether, our results demonstrate that single-residue disruption can drastically reduce the effects of cross-seeding, a finding that has important implications for human protein misfolding disorders.
Highlights
The aggregation of heterologous proteins is implicated in many human neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS)
They are a robust model for studying the aggregation of human proteins, as yeast prions can form varying conformational “strains” that impart differing cellular phenotypes in a manner analogous to the distinct structures and pathologies formed by amyloidogenic proteins in humans[6,7,8,9]
We set out to test the cross-seeding model, which posits a physical interaction between Rnq[1] and Sup[35]
Summary
The aggregation of heterologous proteins is implicated in many human neurodegenerative diseases, including Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS). The yeast prion protein Sup[35] has provided a unique model for probing the nature of heterologous cross-seeding. In contrast to the titration model, the cross-seeding model suggests that Sup[35] and Rnq[1] physically interact during [PSI+] formation (Fig. 1B). In this manner, the misfolded and aggregated Rnq[1] in the [RNQ+] state induces Sup[35] to misfold via bending the monomer out of its native conformation or templating a spontaneously misfolded monomer into a structure that is conducive for prion propagation. We probed the functional consequences of disrupting this binding, and for the first time in any system, identified sites of interaction that are responsible for cross-seeding and facilitating the spread of aggregation between two heterologous amyloidogenic proteins
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.
