Abstract
Prion-like behaviour is attracting much attention due to the growing evidences that amyloid-like self-assembly may reach beyond neurodegeneration and be a conserved functional mechanism. The best characterized functional prions correspond to a subset of yeast proteins involved in translation or transcription. Their conformational promiscuity is encoded in Prion Forming Domains (PFDs), usually long and intrinsically disordered protein segments of low complexity. The compositional bias of these regions seems to be important for the transition between soluble and amyloid-like states. We have proposed that the presence of cryptic soft amyloid cores embedded in yeast PFDs can also be important for their assembly and demonstrated their existence and self-propagating abilities. Here, we used an orthogonal approach in the search of human domains that share yeast PFDs compositional bias and exhibit a predicted nucleating core, identifying 535 prion-like candidates. We selected seven proteins involved in transcriptional or translational regulation and associated to disease to characterize the properties of their amyloid cores. All of them self-assemble spontaneously into amyloid-like structures able to propagate their polymeric state. This provides support for the presence of short sequences able to trigger conformational conversion in prion-like human proteins, potentially regulating their functionality.
Highlights
A broad range of human pathologies, ranging from neurodegenerative conditions such as Alzheimer’s and Parkinson’s diseases, to non-neuronal disorders such as type II diabetes and cataracts, are associated with protein misfolding and aggregation into amyloid-like structures[1]
The information on the common features shared by yeast Prion Forming Domains (PFDs) has fueled the development of algorithms aimed to identify similar prion-like domains (PrLDs) and the proteins that contain them at the proteome level[9,10,11,12,13,14,15,16,17]
We have recently proposed that, in addition to composition, the presence of soft amyloid cores inside PFDs and PrLDs could be important for their assembly[28,29]
Summary
A broad range of human pathologies, ranging from neurodegenerative conditions such as Alzheimer’s and Parkinson’s diseases, to non-neuronal disorders such as type II diabetes and cataracts, are associated with protein misfolding and aggregation into amyloid-like structures[1]. We have recently proposed that, in addition to composition, the presence of soft amyloid cores inside PFDs and PrLDs could be important for their assembly[28,29] We rationalized that these assembly-nucleating regions should be longer than classical amyloid stretches, in such a way that the amyloid potential would be more diffusely distributed; each residue having an average lower potency, but with more residues contributing to the assembling force. In our view, the aggregation of prion-like domains shares mechanistic features with those of classical amyloidogenic proteins This notion was implemented in pWALTZ, an algorithm that predicts the 21-residues long sequence stretch with the highest average amyloid potential in PrLDs14,15. This concept was further validated experimentally by demonstrating the existence of such soft amyloid stretches in the prion domains of four of the best characterized yeast prions[30], as well as in the predicted PrLD of the Rho termination factor of Clostridium botulinum[31], which later led to the discovery of the first bacterial prion-like protein[32]
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