Professors Lin Guo and Rohit Pappu will visit for a talk on May 2, 2023.
*Hidden complexities of condensates formed by simple systems*
Application of the physics of associative macromolecules has led to growing recognition that condensates, even of relatively simple systems, form via hierarchies of processes governed by sequence-encoded molecular grammars that go beyond LLPS. The talk will present data and results from experiments and simulations that highlight the importance of phase separation coupled to percolation for systems governed by homotypic interactions, and the relevance of the coupling between microphase and macrophase separation in systems where homotypic and heterotypic interactions work together. Broader implications for complex multicomponent systems will also be discussed.
by Professor Rohit Pappu
Washington University in St. Louis
Department of Biomedical Engineering
*Reversing Aberrant Phase Transitions of ALS-linked Disease Protein: FUS*
Liquid-liquid phase separation (LLPS) mediates the formation of diverse membraneless organelles, such as stress granules (SGs) in the cytoplasm. Despite clear biological utility, dysregulated liquid-liquid phase separation can be detrimental. For example, phase-separated stress granules enrich RNA-binding proteins (RBPs), such as TDP-43 and FUS, which have an intrinsic tendency to form fibrils that are closely tied to fatal neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Therefore, it is important to understand how cells regulate the liquid-liquid phase separation of biomolecular condensates, which includes maintaining beneficial phases and simultaneously preventing pathological phase separation and fibrillization. As RNA-binding proteins localize mainly in the nucleus, the phase separation of FUS and TDP-43 can be regulated by both nuclear import receptors and short RNAs. For example, we found that phase separation of FUS can be regulated by Karyopherinβ2 (Kapβ2), which recognizes the proline/tyrosine–nuclear localization signal (PY-NLS) at the C-terminus of FUS protein. On the other hand, phase separation of TDP-43 can be regulated by the Importina/Karyopherinb1 complex, which binds to the canonical NLS of TDP-43. In vivo, Kapβ2 prevents FUS accumulating in stress granules, restores nuclear FUS localization and function. By preventing and reversing aberrant FUS phase transition and cytoplasmic localization, Kapβ2 is able to rescue neurodegeneration caused by disease-linked FUS. Our results indicate that regulating FUS LLPS by nuclear import receptors could be potential therapeutic strategy for ALS/FTD.
by Professor Lin Guo
Thomas Jefferson University
Department of Biochemistry and Molecular Biology