Prion Protein Prolines 102 and 105 and the Surrounding Lysine Cluster Impede Amyloid Formation.

摘要: Human prion diseases can have acquired, sporadic, or genetic origins, each of which results in the conversion protein (PrP) to transmissible, pathological forms. The disease Gerstmann-Straussler-Scheinker syndrome arise from point mutations prolines 102 105. However, structural effects these two prolines, and thereof, on PrP misfolding are not well understood. Here, we provide evidence that individual Pro-102 Pro-105 noncyclic aliphatic residues such as Gerstmann-Straussler-Scheinker-linked leucines promote vitro formation amyloid with extended protease-resistant cores reminiscent infectious prions. This effect was enhanced by additional charge-neutralizing four nearby lysine comprising so-called central cluster. Substitution proline accelerated spontaneous no longer slower than scrapie-seeded formation. Thus, Pro-105, lysines cluster, impede PrP, implicating key modulators disease-associated types amyloid.