The physical basis of how prion conformations determine strain phenotypes

Abstract

A principle that has emerged from studies of protein aggregation is that proteins typically can misfold into a range of different aggregated forms. Moreover, the phenotypic and pathological consequences of protein aggregation depend critically on the specific misfolded form. A striking example of this is the prion strain phenomenon, in which prion particles composed of the same protein cause distinct heritable states. Accumulating evidence from yeast prions such as [PSI+] and mammalian prions argues that differences in the prion conformation underlie prion strain variants. Nonetheless, it remains poorly understood why changes in the conformation of misfolded proteins alter their physiological effects. Here we present and experimentally validate an analytical model describing how [PSI+] strain phenotypes arise from the dynamic interaction among the effects of prion dilution, competition for a limited pool of soluble protein, and conformation-dependent differences in prion growth and division rates. Analysis of three distinct prion conformations of yeast Sup35 (the [PSI+] protein determinant) and their in vivo phenotypes reveals that the Sup35 amyloid causing the strongest phenotype surprisingly shows the slowest growth. This slow growth, however, is more than compensated for by an increased brittleness that promotes prion division. The propensity of aggregates to undergo breakage, thereby generating new seeds, probably represents a key determinant of their physiological impact for both infectious (prion) and non-infectious amyloids.

Ultrasonication-dependent production and breakdown lead to minimum-sized amyloid fibrils

“…Once the nucleus is formed, the growth phase proceeds via the incorporation of the monomers into the ends of seed fibrils in a template-dependent manner (9). Under normal extension conditions without the fragmenting effect of ultrasonication, the energy landscape is broad, and might be modulated by additional mechanisms including breaking down and rejoining reactions especially for long fibrils (22)(23)(24)(25), resulting in a wide range of fibril lengths (black line in Fig. 1).…”

“…The position of the energy minimum and the steepness of the landscape of fragmentation would be determined by a balance between the elongation kinetics and fragmentation efficiency, the latter of which is presumably determined by the frequency of ultrasonication pulses. Additionally, the intrinsic physical properties such as fragility of individual fibrils (23,(25)(26)(27) and intensity of ultrasonication would affect the equilibrated fibril size.…”

Structural fingerprints and their evolution during oligomeric vs. oligomer-free amyloid fibril growth

“…5(b)), has been experimentally observed in other systems, and is an integral part of nucleated polymerization models of amyloid fibril growth. 29 As a result, scattering intensity reports the predominant increases in the number-averages of aggregates within an essentially stationary aggregate peak. Light scattering intensity increases also correlated well with the total amount of aggregates obtained via ultracentrifugation, further buttressing our conclusion.…”

Failure of Aβ(1-40) amyloid fibrils under tensile loading

“…Initially solely associated with severe disorders [1], amyloid protein materials are now recognized also as common protein structures with important biological functional roles [1][2][3] as bacterial coatings [1], protective materials in egg envelopes of several fish species and insects [4,5] and scaffold for catalytic reactions [6]. Amyloid protein materials often result from protein misfolding pathways that generate fibrillar aggregates with a common core structure consisting of an elongated stack of beta-strands stabilized by a dense network of hydrogen bonds [7].…”