Typical amyloid diseases such as Alzheimer's and Parkinson's were thought to exclusively result from de novo aggregation, but recently it was shown that amyloids formed in one cell can cross-seed aggregation in other cells, following a prion-like mechanism. Despite the large experimental effort devoted to understanding the phenomenon of prion transmissibility, it is still poorly understood how this property is encoded in the primary sequence. In many cases, prion structural conversion is driven by the presence of relatively large glutamine/asparagine (Q/N) enriched segments. Several studies suggest that it is the amino acid composition of these regions rather than their specific sequence that accounts for their priogenicity. However, our analysis indicates that it is instead the presence and potency of specific short amyloid-prone sequences that occur within intrinsically disordered Q/N-rich regions that determine their prion behaviour, modulated by the structural and compositional context. This provides a basis for the accurate identification and evaluation of prion candidate sequences in proteomes in the context of a unified framework for amyloid formation and prion propagation. Protein conformational disorders include several neurodegenerative diseases. These pathologies are initiated by conformational changes in specific polypeptides that, in many cases, result in their spontaneous self-assembly to form toxic amyloids. Prions are a subclass of amyloids with the ability to propagate in vivo, thus becoming infectious. Previous work with yeast prions has provided tremendous insight into prion propagation mechanism. These proteins contain glutamine/asparagine (Q/N) enriched prion forming domains (PFDs), which are both necessary and sufficient for propagation. We found that these domains include specific short amyloid-prone sequences, which are likely able to trigger the amyloid conversion of the complete prion protein. The amyloid potency of these short segments suffices to discriminate with high accuracy between Q/N rich domains with and without prion activity. Our data suggest a model for prions where a classical amyloid core is embedded in a sequence context that reduces the amyloid nucleation potential, resulting in sequences that are strongly dependent on seeding. This model should allow the identification of prion-like proteins in the human proteome and prediction of the deleterious effects of genetic mutations occurring in these particular proteins.