Research Interests

Fundamental Features of Prion Proteins

Our lab uses budding yeast to study the basic steps involved in the formation of infectious protein aggregates (“prions”). Specifically, we are interested in understanding the fundamental features of prion proteins. In yeast, a growing list of proteins have the demonstrated ability to form prions. Known prion proteins often contain strikingly Q/N-rich prion domains. However, while this is a common feature among prion proteins, it is not sufficient to predict prion activity. Therefore, using a large-scale genetic screen, we have developed a bioinformatic method to predict prion propensity.

Related Publications:
  • Cascarina SM, Paul KR, Machihara S, Ross ED. Sequence features governing aggregation or degradation of prion-like proteins. PLOS Genet 2018.  Pubmed  Download PDF
  • Paul KR, Molliex A, Cascarina S, Boncella AE, Taylor J, Ross ED. Effects of mutations on the aggregation propensity of the human prion-like protein hnRNPA2B1. Mol Cell Biol 2017.  Pubmed
  • Paul KR, Hendrich CG, Waechter A, Harman MR, Ross ED. Generating new prions by targeted mutation or segment duplication. Proc Natl Acad Sci 2015.  Pubmed  Download PDF
  • Toombs JA, Petri M, Paul KR, Kan GY, Ben-Hur A, Ross ED. De novo design of synthetic prion domains. Proc Natl Acad Sci 2012. Pubmed  Download PDF
  • Toombs JA, McCarty BR, Ross ED. Compositional determinants of prion formation in yeast. Mol Cell Biol 2010.  Pubmed

Functional and Pathogenic Aggregation of Proteins with Prion-like Domains

While protein aggregation is often pathological, a growing body of research suggests that reversible interactions mediating the transient assembly of certain proteins in response to cellular stress actually improves cell survival. Many of these proteins contain prion-like domains, which are themselves drivers or modifiers of beneficial assembly. However, as this is an exciting, relatively new area of research, little is known about the physical and molecular regulators of this process. Furthermore, mutations within prion-like domains involved in functional assembly can lead to the formation of pathological aggregates. Therefore, our lab is interested in understanding how the assembly of prion-like domains can be harnessed and regulated by cells to promote cellular adaptation to unfavorable conditions, and how mutations can disrupt this process.

Related Publications:
  • Baer MH*, Cascarina SM*, Paul KR*, Ross ED. Rational tuning of the concentration-independent enrichment of prion-like domains in stress granules. J Mol Biol 2024.  Pubmed  Access Link (temporary)  *Co-first authors
  • Boncella AE*, Shattuck JE*, Cascarina SM, Paul KR, Baer MH, Fomicheva A, Lamb AK, Ross ED. Composition-based prediction and rational manipulation of prion-like domain recruitment to stress granules. Proc Nat Acad Sci 2020.  Pubmed  Download PDF  *Co-first authors
  • Cascarina SM, Ross ED. Natural and pathogenic protein sequence variation affecting prion-like domains within and across human proteomes. BMC Genom 2020.  Pubmed  Download PDF
  • Shattuck JE, Paul KR, Cascarina SM, Ross ED. The prion-like protein kinase Sky1 is required for efficient stress granule disassembly. Nat Commun 2019.  Pubmed  Download PDF
  • Kim et al.. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 2013.  Pubmed

Composition-driven Molecular Processes

Prion aggregation involves the transformation of native proteins into a new “infectious” conformation. Unlike most protein folding events, certain yeast prion proteins can misfold into their infectious form in a primary sequence-independent manner! That means that the prion domain sequences can be completely scrambled (while preserving the amino acid composition) and still retain the ability to form infectious aggregates. This suggests that some molecular processes are governed predominantly by amino acid composition.

This counter-dogmatic principle led us to ask if a central focus on amino acid composition could illuminate additional cellular and molecular processes. Therefore, we have developed a novel bioinformatic approach to link amino acid composition to protein fates and functions on a proteome-wide scale. Using this approach, we are currently exploring relationships between amino acid composition and the fundamental aspects of a protein life cycle (synthesis, abundance, and degradation), as well as defining the compositional features associated with proteins involved in known composition-driven processes.

Related Publications:
  • Cascarina SM, Ross ED. Identification of low-complexity domains by compositional signatures reveals class-specific frequencies and functions across the domains of life. PLOS Comput Biol 2024.  Pubmed  Download PDF
  • Cascarina SM, Ross ED. The LCD-Composer webserver: high-specificity identification and functional analysis of low-complexity domains in proteins. Bioinformatics 2022.  Pubmed  Download PDF
  • Cascarina SM, Ross ED. Expansion and functional analysis of the SR-related protein family across the domains of life. RNA 2022.  Pubmed  Download PDF
  • Cascarina SM, King DC, Osborne Nishimura E, Ross ED. LCD-Composer: an intuitive, composition-centric method enabling the identification and detailed functional mapping of low-complexity domains. NAR Genom & Bioinform 2021.  Pubmed  Download PDF
  • Cascarina SM, Ross ED. A proposed role for the SARS-CoV-2 nucleocapsid protein in the formation and regulation of biomolecular condensates. FASEB J 2020.  Pubmed  Download PDF
  • Cascarina SM, Elder MR, Ross ED. Atypical structural tendencies among low-complexity domains in the Protein Data Bank proteome. PLOS Comput Biol 2020.  Pubmed  Download PDF
  • Cascarina SM, Ross ED. Natural and pathogenic protein sequence variation affecting prion-like domains within and across human proteomes. BMC Genom 2020.  Pubmed  Download PDF
  • Cascarina SM, Ross ED. Proteome-scale relationships between local amino acid composition and protein fates and functions. PLOS Comput Biol 2018.  Pubmed  Download PDF

Aggregation and Protein Quality Control

The ability to generate and maintain properly folded proteins is a skill required of every known life form. Accordingly, cells possess an arsenal of factors whose purpose is to regulate the synthesis, folding, and degradation of all cellular proteins, a process referred to as protein homeostasis, or “proteostasis”. Some proteins manage to aggregate in spite of these quality control systems, yet little is known about the inherent sequence features that make prion and prion-like proteins susceptible or resistant to regulation by the proteostasis machinery. Therefore, we have developed a genetic screening pipeline that allowed us to delineate many of the features of prion-like domains leading either to aggregation or accelerated degradation. We are now trying to understand why these prion-like domains are sensitive or resistant to degradation, and which proteostasis factors are involved in regulating the stability and aggregation activity of prion-like proteins.

Related Publications:
  • Cascarina SM, Kaplan JP, Elder MR, Brookbank L, Ross ED. Generalizable compositional features influencing the proteostatic fates of polar low-complexity domains. IJMS 2021.  Pubmed  Download PDF
  • Cascarina SM, Ross ED. Aggregation and degradation scales for prion-like domains: sequence features and context weigh in. Curr Genet 2019.  Pubmed
  • Cascarina SM, Paul KR, Machihara S, Ross ED. Sequence features governing aggregation or degradation of prion-like proteins. PLOS Genet 2018.  Pubmed  Download PDF
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