Amyloids or prions? That is the question

Abstract

Despite major efforts devoted to understanding the phenomenon of prion transmissibility, it is still poorly understood how this property is encoded in the amino acid sequence. In recent years, experimental data on yeast prion domains allow to start at least partially decrypting the sequence requirements of prion formation. These experiments illustrate the need for intrinsically disordered sequence regions enriched with a particularly high proportion of glutamine and asparagine. Bioinformatic analysis suggests that these regions strike a balance between sufficient amyloid nucleation propensity on the one hand and disorder on the other, which ensures availability of the amyloid prone regions but entropically prevents unwanted nucleation and facilitates brittleness required for propagation.

Keywords: AD, Alzheimer's disease; CJD, Creutzfeldt-Jakob disease; PD, Parkinson's disease; PFD, prion forming domain; Q/N-rich domains; TSE, transmissible spongiform encephalopathy; amyloids; fALS, familial amyotrophic lateral sclerosis; neurodegenerative diseases; prions; protein intrinsic disorder; yeast.

Figure 1.

Two models for amyloid structure formation in Q/N-rich prion-like domains. The compositional model relies on the establishment a large number of weak interactions whereas the amyloid-stretch model proposes the existence of a preferential short nucleating sequence whose amyloid propensity is modulated by its structural context.

Figure 2.

Balance between amyloid and structural propensities in natural amino acids. Residues rendering ordered and disordered 21-residues long homo-polymers according to FoldIndex are shown in green and yellow circles, respectively. The amyloid propensity of these stretches was calculated with Waltz. The four more over-represented residues in yeast PFDs are circled by discontinuous lines, red indicates odd ratios > 4.0 and blue odd ratios > 1.5, relative to the composition of the protein universe.