| Summary |
Cells contain membrane-enclosed organelles that compartmentalize cellular constituents and regulate biochemical processes. A growing body of exciting research now reveals that there is also an alternative mechanism of spatiotemporally-controlled intracellular compartmentalization and organization through biomolecular condensate formation via macromolecular phase separation of proteins and nucleic acids into noncanonical membraneless organelles with emergent material properties. These functional liquid-like biomolecular condensates can undergo aberrant irreversible phase transitions into gel-like or solid-like amyloid aggregates associated with a range of debilitating human diseases [1,2]. Our longstanding interest in prion biology led us to discover that the prion protein (PrP) (well-known for its association with mad cow disease and Creutzfeldt-Jakob disease) can undergo phase separation via weak, multivalent, transient intermolecular interactions between the N-terminal domain. An intriguing disease-associated amber stop codon mutation (Y145Stop) of PrP yields a C-terminally truncated intrinsically disordered fragment. We demonstrated that this fragment spontaneously phase-separates into highly dynamic liquid droplets under physiological conditions [3]. Upon aging, these liquid droplets undergo a liquid-to-solid phase transition into highly ordered, b-rich, amyloid-like aggregates that exhibit a characteristic autocatalytic self-templating behavior. The propensity for the aberrant phase transition is much lower for the full-length PrP indicating an evolutionarily conserved role of the folded C-terminal domain. Our recent results also showed intriguing spatiotemporal modulations in complex coacervation of PrP with other neuronal intrinsically disordered proteins into heterotypic, multi-component, multiphasic, multilayered condensates in the presence of RNA [4,5]. I will also discuss our surface-enhanced Raman scattering (SERS), single-molecule FRET (Förster resonance energy transfer), and homoFRET studies that capture exquisite molecular details of in-vitro-reconstituted biomolecular condensates and cellular stress granules derived from neuronal RNA-binding proteins that are associated with Amyotrophic Lateral Sclerosis [6-8].
1. Mukhopadhyay Nature Chemistry (News & Views) (2021) 13, 1028-1030.
2. Dogra et al. J. Am. Chem. Soc. (2019) 141, 20380-20389.
3. Agarwal et al. Proc. Natl. Acad. Sci. (2021) 118, 45, e2100968118.
4. Agarwal et al. Nature Communications (2022) 13, 1154.
5. Rai et al. Proc. Natl. Acad. Sci. (2023) 120, e2216338120.
6. Avni et al. Nature Communications (2022) 13, 4378.
7. Joshi et al. Nature Communications (2023) 14, 7331.
8. Joshi et al. bioRxiv (2024).
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