![]() PrP Sc is considered infectious because it transmits its pathogenic conformation by templating the conversion of other native PrP C monomers to PrP Sc in a self-propagating fashion. Prion diseases are caused when the native form of the prion protein (PrP C) misfolds and aggregates to form the amyloid structure called PrP Sc. Increasing evidence suggests that these protein conformational disorders are caused by a similar etiological mechanism, in which the amyloid that forms represents an infectious, self-templating structure that is often described as prion-like. The misfolding of proteins to form cross-β sheet amyloid structures is characteristic of a variety of diseases, including many neurodegenerative disorders, such as Alzheimer's disease. 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. Moreover, our data support the hypothesis that the variants differentially interact with the molecular chaperone Sis1. 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 prion. Here, we used a set of prion variants to show the complex web of interactions involved in the propagation of distinct aggregate structures. Previous work with yeast prions has provided tremendous insight into how distinct prion conformers can cause such phenotypic variability. The different conformations of prion strains are responsible for modulating disease progression, pathology, and transmission. In prion diseases, these different amyloid conformations are called prion strains. Interestingly, the proteins that misfold in these diseases tend to form a wide variety of distinct aggregate structures. Protein conformational disorders, including many neurodegenerative diseases, result when a protein misfolds and undergoes a conformational change to form self-templating aggregates, called amyloid. This helps reveal the complex interdependent factors that influence how a particular amyloid structure may dictate disease pathology and progression. 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. Our analysis also revealed a striking difference in the ability of these variants to interact with the chaperone Sis1. Remarkably, such differences did not result in variation in aggregate stability. ![]() This included regions outside of the canonical prion-forming domain of Rnq1. Remarkably, we found that the variants require different, non-contiguous regions of the Rnq1 protein for both prion propagation and induction. Here, we examined a set of yeast prion variants of the prion that differ in their ability to induce the formation of another yeast prion called. Yet, it remains largely unclear what other factors might account for the widespread phenotypic variation seen with aggregation-prone proteins. Aggregate stability has been found to be a key determinant of the diverse pathological consequences of different prion strains. In prion diseases, these different structures, called prion strains (or variants), confer dramatic variation in disease pathology and transmission. Amyloidogenic proteins associated with a variety of unrelated diseases are typically capable of forming several distinct self-templating conformers.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |