Figure 1. Model showing preferential seeding of specific [PSI⁺] variants by [PIN⁺] variants at different temperatures. Very high and high [PIN⁺] prion domains are cartooned as parallel in register β sheets (black bars) with non-β sheet loops in variant-specific positions. The Sup35 prion domain (gray) is preferentially cross seeded into parallel in register β sheets³⁸ (gray bars) by different lengths of β sheet regions available in high and very high [PIN⁺]. In the left, Sup35 is shown to first bind to the [PIN⁺] aggregates (step 1). Only then does the [PIN⁺] amyloid region convert the Sup35 into amyloid (step 2). Due to the interference of its non-β sheet loop, very high [PIN⁺] preferentially seeds strong [PSI⁺], with a small β-sheet core which is vulnerable to sheering and the production of the smaller aggregates characteristic of strong [PSI⁺]. High [PIN⁺], which has a larger uninterrupted β-sheet region, preferentially seeds weak [PSI⁺] with a large β-sheet core. At 4 °C, soluble Sup35 is shown forming a nucleus that interferes with the initial β sheet conversion even when seeded by high [PIN⁺]. This results in the formation of a smaller β sheet-core and the induction of strong [PSI⁺]. Evidence for the in vitro formation of such a Sup35 nucleus at 4 °C has been presented.³⁵