Nucleated Conformational Conversion and the Replication of Conformational Information by a Prion Determinant

Abstract

Prion proteins can serve as genetic elements by adopting distinct physical and functional states that are self-perpetuating and heritable. The critical region of one prion protein, Sup35, is initially unstructured in solution and then forms self-seeded amyloid fibers. We examined in vitro the mechanism by which this state is attained and replicated. Structurally fluid oligomeric complexes appear to be crucial intermediates in de novo amyloid nucleus formation. Rapid assembly ensues when these complexes conformationally convert upon association with nuclei. This model for replicating protein-based genetic information, nucleated conformational conversion, may be applicable to other protein assembly processes.

The yeast prion protein Ure2: Structure, function and folding

“…Another commonly described feature is that the length of the lag time decreases with increasing protein concentration in an approximately exponential relationship. In fact, for Ure2 [36,102] and also for Sup35 [103], the relationship between increasing protein concentration and decreasing lag time is linear. This may reflect a variation in mechanism, the oligomeric nature of the native state, or simply the choice of reaction conditions [36,101,103].…”

“…In fact, for Ure2 [36,102] and also for Sup35 [103], the relationship between increasing protein concentration and decreasing lag time is linear. This may reflect a variation in mechanism, the oligomeric nature of the native state, or simply the choice of reaction conditions [36,101,103]. Nevertheless, a common feature of the various models is the involvement of partially-folded (or misfolded) intermediate states, implying that the mechanism of amyloid or prion formation is related to the pathway by which the protein folds (or misfolds).…”

[PSI+] prion generation in yeast: characterization of the ‘strain’ difference

“…The conformational rearrangement of monomers may either occur spontaneously and then be ®xed in polymer structure (Jarrett and Lansbury, 1993) or, alternatively, be directly catalysed by polymer at the moment of accretion (Horwich and Weissman, 1997). As a modi®cation of the latter model, it was proposed that the prion conformation is adopted concomitantly with assembly, via molten oligomeric intermediates (Serio et al, 2000).…”

Kinetic theory of amyloid fibril templating

“…While fibrils can grow either by the attachment of single proteins to the fibril ends, or by the coalescence of small oligomers, [15][16][17][18] this paper addresses only the former process. There are two reasons for this simplification.…”