O Instituto Nacional de Biologia Estrutural e Bioimagem (INBEB) realiza no dia 9 de setembro mais uma edição do Seminário INBEB. O convidado é o pesquisador indiano Samrat Mukhopadhyay, do Indian Institute of Science Education and Research (IISER), que falará sobre o processo de separação de fases observado na proteína príon. O evento acontece a partir das 14h, no auditório do Bloco N, CCS/UFRJ.

Mukhopadhyay é conhecido por seus estudos sobre proteína prion, proteínas intrinsicamente desordenadas, mau enovelamento de proteínas e agregações, e temas relacionados. Já publicou em revistas científicas como Nature Communications, Proceedings of the National Academy of Sciences (PNAS). É membro do Conselho Editorial dos periódicos Biophysical Journal (Cell Press), Journal of Cellular Biochemistry (Wiley) e Essays in Biochemistry (Biochemical Society, de Londres).

 

Seminário “Prion Protein Biology Through the Lens of Liquid-Liquid Phase Separation: A Tale of an Intrinsically Disordered Tail”
Palestrante: Samrat Mukhopadhyay
Data e hora: 09 de setembro, às 14h
Local: Auditório do Bloco N, CCS/UFRJ
Entrada franca

Resumo da apresentação

Liquid-liquid phase separation (LLPS) of intrinsically disordered proteins/regions (IDPs/IDRs) into intracellular biomolecular condensates is involved in critical cellular functions. However, aberrant phase transitions are associated with debilitating neurodegenerative diseases. We show that the prion protein (PrP) can undergo LLPS via weak, multivalent, transient intermolecular interactions between the N-terminal IDR that resembles a yeast prion-like domain comprising five glycine-rich octapeptide repeats and a hydrophobic segment. An intriguing disease-associated amber stop codon mutation (Y145Stop) yields a C-terminally truncated intrinsically disordered fragment that is associated with Gerstmann-Sträussler-Scheinker syndrome and familial cerebral amyloid angiopathy. We demonstrate that Y145Stop spontaneously phase-separates into highly dynamic liquid droplets under physiological conditions. Our bioinformatic, spectroscopic, microscopic, and mutational studies coupled with single-droplet vibrational Raman spectroscopy revealed highly dynamic internal organization within condensates and illuminated the critical molecular drivers of LLPS of Y145Stop. We also show that Y145Stop exhibits a reentrant phase behavior in the presence of RNA. Upon aging, these highly dynamic liquid droplets undergo a liquid-to-solid phase transition into highly ordered, beta-rich, amyloid aggregates that exhibit a characteristic autocatalytic self-templating behavior. Therefore, LLPS-mediated amyloid formation can potentially represent a noncanonical phase transition pathway to self-replicating prions. The propensity for this aberrant phase transition is much lower for the full-length PrP indicating an evolutionarily conserved role of the folded C-terminal domain. I will also discuss our recent results on spatiotemporal modulation in complex coacervation of PrP and alpha-synuclein into multicomponent, multiphasic, hollow condensates. These multicomponent condensates can act as reaction crucibles to catalyze the amyloid conversion of these functional assemblies into pathological aggregates associated with overlapping neuropathological features. I will also discuss our latest work on the characterization of biomolecular condensates using ultrasensitive vibrational Raman spectroscopy.

Referências

• "Single-Droplet Surface-Enhanced Raman Scattering Decodes the Molecular Determinants of Liquid-Liquid Phase Separation" A. Avni, A. Joshi, A. Walimbe, S. G. Pattanashetty & S. Mukhopadhyay* Nature Communications, 2022, 13, 4378. https://www.nature.com/articles/s41467-022-32143-0
• "Spatiotemporal Modulations in Heterotypic Condensates of Prion and α-Synuclein Control Phase Transitions and Amyloid Conversion" A. Agarwal, L. Arora, S.K. Rai, A. Avni & S. Mukhopadhyay* Nature Communications, 2022, 13, 1154. https://www.nature.com/articles/s41467-022-28797-5
• "Prion Protein Biology Through the Lens of Liquid-Liquid Phase Separation". A. Agarwal* & S. Mukhopadhyay*. J. Mol. Biol. 2022, 434, 167368. https://doi.org/10.1016/j.jmb.2021.167368
• "An intrinsically disordered pathological prion variant Y145Stop converts into self-seeding amyloids via liquid-liquid phase separation". A. Agarwal, S.K. Rai, A. Avni & S. Mukhopadhyay*. Proc. Natl. Acad. Sci. U. S. A. 2021, 118, 45, e2100968118. https://doi.org/10.1073/pnas.2100968118