A systematic survey identifies prions and illuminates sequence features of prionogenic proteins

By S. Alberti, Randal Halfmann, Oliver D. King, A. Kapila, Susan Lindquist. Cell, 2009

982 citations recorded by the source corpus.

SUMMARY Prions are proteins that convert between structurally and functionally distinct states, one or more of which is transmissible. In yeast, this ability allows them to act as non-Mendelian elements of phenotypic inheritance. To further our understanding of prion biology, we conducted a bioinformatic proteome-wide survey for prionogenic proteins in S. cerevisiae, followed by experimental investigations of 100 prion candidates. We found an unexpected amino acid bias in aggregation-prone candidates and discovered that 19 of these could also form prions. At least one of these prion proteins, Mot3, produces a bona fide prion in its natural context that increases population-level phenotypic heterogeneity. The self-perpetuating states of these proteins present a vast source of heritable phenotypic variation that increases the adaptability of yeast populations to diverse environments.

Subfields: Molecular Biology, Neurology, Nutrition and Dietetics

View Paper: https://www.semanticscholar.org/paper/848e5a9f1733ff8499d7ce3f4e54f83706597b23

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Citations in the corpus

A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation. (2015, positive): “LC domains are also present in yeast prion proteins, which have the ability to interconvert into fibers rather than a liquid state (Alberti et al., 2009).”
Stress granules as crucibles of ALS pathogenesis (2013, background): “These domains are typically enriched in uncharged polar amino acids (such as asparagine, glutamine, and tyrosine) and glycine (Alberti et al., 2009; King et al., 2012).”
Phase separation of a yeast prion protein promotes cellular fitness (2018, background): “The N-terminal region of Sup35 is intrinsically disordered and can be divided into two parts: an N-terminal prion domain (N) and a charged middle domain (M) (20, 21) (Fig.”
A molecular grammar governing the driving forces for phase separation of prion-like RNA binding proteins (2018, neutral): “that they contain a small subset of amino acids includingpolar residues, such as glycine, glutamine, and serine, as well as aromatic residues, generally tyrosine (Alberti et al., 2009; Kato et al., 2012; Malinovska et al., 2015).”
Identification of a selective and direct NLRP3 inhibitor to treat inflammatory disorders (2017, methodology): “ 4 G), a method for detecting large protein oligomers in studying prions (Alberti et al., 2009; Hou et al., 2011).”
Liquid-Liquid Phase Separation in Disease. (2019, background): “In this framework, IDRs and IDPs can be described as polymers consisting of two fundamental units: stickers and spacers (152).”
PLAAC: a web and command-line application to identify proteins with prion-like amino acid composition (2014, methodology): “A subsequent algorithm called PAPA (Toombs et al. , 2010, 2012) that uses AA scores derived from a random mutagenesis screen can downweigh many of the apparent false positives from Alberti et al. (2009), and can give sharper predictions for the re-sults of point mutations (Kim et al. , 2013).”
Cell-Free Formation of RNA Granules: Low Complexity Sequence Domains Form Dynamic Fibers Within Hydrogels (2012, background): “Lindquist and colleagues recently described dozens of new, ultrastable amyloids formed in yeast, many derived from the LC sequences associated with transcription factors and RNA-binding proteins (Alberti et al., 2009).”
Cell-free formation of RNA granules: bound RNAs identify features and components of cellular assemblies. (2012, background): “More recently, the Lindquist laboratory has provided compelling evidence that many different yeast proteins are able to be converted into permanently aggregated, prion-like structures (Alberti et al., 2009).”
MAVS Forms Functional Prion-Like Aggregates To Activate and Propagate Antiviral Innate Immune Response (2011, methodology): “1Department of Molecular Biology 2Department of Cell Biology 3Howard Hughes Medical Institute University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA *Correspondence: zhijian.chen@utsouthwestern.edu DOI 10.1016/j.cell.2011.06.041”
The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease (2012, methodology): “Subsequently, a refined algorithm was developed that used a hidden Markov model able to identify regions that have the unusual amino acid composition characteristic of known yeast prions (Alberti et al., 2009; Cushman et al., 2010).”