Prion and Non-prion Amyloids of the HET-s Prion forming Domain

Structural dependence of HET-s amyloid fibril infectivity assessed by cryoelectron microscopy

“…The PD is necessary and sufficient for prion formation and fibrillizes readily in vitro (9)(10)(11). The HeLo domain interacts with the PD to affect its fibrillation but as yet has no other assigned function (6).…”

Heterogeneous seeding of HET-s(218–289) and the mutability of prion structures

“…The different spacing of the equatorial diffraction maxima in PrP 27-30 with respect to HET-s(218-289) is caused by the larger diameter of PrP 27-30, which can be determined by electron microscopy (EM) and X-ray diffraction. 11,24 Fiber diffraction of PrP 27-30 showed many features consistent with a four-rung β-solenoid model derived from EM reconstructions and structural comparison, 25 which is similar to the two-rung β-solenoid structure of HET-s(218-289). 12 Concomitant with the similarities in molecular architectures, HET-s(218-289) heterogeneous seeding resembles a model of PrP adaptation.…”

“…9,10 HET-s(218-289) forms polymorphic structures depending on the pH of the fibrillization conditions. 11 At physiological pH, HET-s(218-289) readily forms biologically active prions that are well ordered enough to allow for structure determination by solid state NMR (ssNMR). 12 The infectious prion structure is a two-rung β-solenoid (see Fig.…”

Truncated forms of the prion protein PrP demonstrate the need for complexity in prion structure

“…17,18,19 Regardless of the mechanism of infectivity, it is clear that the generic stacked-sheet structure has very little infectivity if any, and is very different, both structurally and functionally, from the b-solenoidal structure. HET-s exhibits a similar polymorphism: 20 the wild-type protein at neutral pH and many mutants form b-solenoids, but other mutants and the wildtype protein at acidic pH form non-infectious 21 stacked sheets.…”

“…1B), can have a large impact on fibrillization kinetics, stability, and structure of the fibril, 20 as well as infectivity. 26 In Ab, residues [21][22][23] in the boundary between the first b-strand and the loop connecting it to the second strand are often altered in families exhibiting early-onset Alzheimer's disease. 27 Perhaps the greatest value for prion studies of at least the larger fragments of PrP lies in their use not as structural models for the active prion itself, but as templates that illustrate the phenomenon of heterogeneous seeding or deformed templating.…”