The Hunt for Ancient Prions: Archaeal Prion-Like Domains Form Amyloid-Based Epigenetic Elements

Abstract

Prions, proteins that can convert between structurally and functionally distinct states and serve as non-Mendelian mechanisms of inheritance, were initially discovered and only known in eukaryotes, and consequently considered to likely be a relatively late evolutionary acquisition. However, the recent discovery of prions in bacteria and viruses has intimated a potentially more ancient evolutionary origin. Here we provide evidence that prion-forming domains exist in the domain archaea, the last domain of life left unexplored with regard to prions. We searched for archaeal candidate prion-forming protein sequences computationally, described their taxonomic distribution and phylogeny, and analyzed their associated functional annotations. Using biophysical in vitro assays, cell-based and microscopic approaches, and dye-binding analyses, we tested select candidate prion-forming domains for prionogenic characteristics. Out of the 16 tested, 8 formed amyloids, and 6 acted as protein-based elements of information transfer driving non-Mendelian patterns of inheritance. We also identified short peptides from our archaeal prion candidates that can form amyloid fibrils independently. Lastly, candidates that tested positively in our assays had significantly higher tyrosine and phenylalanine content than candidates that tested negatively, an observation that may help future archaeal prion predictions. Taken together, our discovery of functional prion-forming domains in archaea provides evidence that multiple archaeal proteins are capable of acting as prions—thus expanding our knowledge of this epigenetic phenomenon to the third and final domain of life and bolstering the possibility that they were present at the time of the last universal common ancestor (LUCA).

Evolution of sequence traits of prion-like proteins linked to amyotrophic lateral sclerosis (ALS)

“…Also, it is important to bear in mind that the PLAAC program for identification of prion-like composition was trained on data obtained from experiments on S. cerevisiae proteins. However, there has been some success in using the PLAAC program to identify prion-forming domains in other eukaryotes, and in bacteria and archaea ( Chakrabortee et al, 2016 ; Harrison, 2019 ; Kim et al, 2013 ; Sideri et al, 2017 ; Yuan & Hochschild, 2017 ; Zajkowski et al, 2021 ), but there may be other prion-forming domain compositions that are not sampled during the evolution of budding yeasts ( An, Fitzpatrick & Harrison, 2016 ; Wang & Harrison, 2021 ).…”

Melatonin: Regulation of Prion Protein Phase Separation in Cancer Multidrug Resistance

“…Prions and prion-like molecules have likely assumed central roles in early chemical evolutionary processes preceding the Last Universal Common Ancestor (LUCA), which eventually resulted in present-day living systems [ 246 , 247 ]. The ability of prions to efficiently replace their non-aggregate native state by assembling short peptides into β-sheet amyloid aggregates with high structural stability and resistance to hostile, extreme environments may have facilitated self-replication, catalytic activities, and analogical information transfer in protein-based, self-propagating, information-processing biomolecules in early life forms ~3.9 billion years ago [ 248 , 249 , 250 ].…”

Structural Bases of Prion Variation in Yeast

“…This protein behaves as a functional amyloid in Aplysia , but in yeast acts as a bona fide prion giving phenotypically different variants. The Sup35 system also revealed the prion behavior of some mammalian [ 58 ], plant [ 59 ], archaeal [ 60 ] and baculovirus [ 61 ] proteins.…”