Amyloidogenic proteins associated with a variety of unrelated diseases are typically capable of forming several distinct self-templating conformers. In prion diseases, these different structures, called prion strains (or variants), confer dramatic variation in disease pathology and transmission. Aggregate stability has been found to be a key determinant of the diverse pathological consequences of different prion strains. Yet, it remains largely unclear what other factors might account for the widespread phenotypic variation seen with aggregation-prone proteins. Here, we examined a set of yeast prion variants of the [ RNQ +] prion that differ in their ability to induce the formation of another yeast prion called [ PSI +]. Remarkably, we found that the [ RNQ +] variants require different, non-contiguous regions of the Rnq1 protein for both prion propagation and [ PSI +] induction. This included regions outside of the canonical prion-forming domain of Rnq1. Remarkably, such differences did not result in variation in aggregate stability. Our analysis also revealed a striking difference in the ability of these [ RNQ +] variants to interact with the chaperone Sis1. Thus, our work shows that the differential influence of various amyloidogenic regions and interactions with host cofactors are critical determinants of the phenotypic consequences of distinct aggregate structures. This helps reveal the complex interdependent factors that influence how a particular amyloid structure may dictate disease pathology and progression. Author Summary Protein conformational disorders, including many neurodegenerative diseases, result when a protein misfolds and undergoes a conformational change to form self-templating aggregates, called amyloid. Interestingly, the proteins that misfold in these diseases tend to form a wide variety of distinct aggregate structures. In prion diseases, these different amyloid conformations are called prion strains. The different conformations of prion strains are responsible for modulating disease progression, pathology, and transmission. Previous work with yeast prions has provided tremendous insight into how distinct prion conformers can cause such phenotypic variability. Here, we used a set of [ RNQ +] prion variants to show the complex web of interactions involved in the propagation of distinct aggregate structures. We found that several different non-adjacent regions of Rnq1, even outside the prion-forming domain, make varying contributions to the propagation of distinct variants of the [ RNQ +] prion. Moreover, our data support the hypothesis that the [ RNQ +] variants differentially interact with the molecular chaperone Sis1. These data strongly suggest that the variable phenotypic manifestations of different aggregate conformations depend upon a unique set of primary structural elements and differential interactions with host cofactors.
【초록키워드】 pathology, Diseases, Variation, variant, Transmission, Proteins, progression, variants, Disease progression, Protein, Region, stability, amyloid, molecular, disease, Strains, Critical, yeast, Interaction, Hypothesis, Analysis, structures, conformational change, Propagation, strain, manifestation, phenotypic variation, cofactors, cofactor, Support, determinant, Factor, disorders, These data, complex, domain, Variability, conformation, help, aggregation, disease pathology, phenotypic, aggregate, prion, element, aggregates, chaperone, Host, widespread, consequence, responsible, examined, involved, provided, unique, variety, conformational, induce, canonical, PSI, neurodegenerative, modulating, 【제목키워드】 Region, Diversity, strain, Extensive,