(6jw) Protein Condensation in Nature: Functional or Pathological?

It is well established that protein condensation is associated with numerous neurodegenerative diseases and cancer. Recently it was discovered that P-granules exhibited liquid-liquid phase separation during C. elegans germ cell development. Another example of functional protein condensation is during cell division, where within short time scales, highly dynamic network of microtubules is nucleated. Protein self-assemblies is shown to promote microtubules nucleation by enhancing the local concentration and consequently, lowering the nucleation barrier for this process. These discoveries provided new insights on the functional aspects of protein condensates. In this study, we first explore a pathological pathway for protein condensation. We demonstrate how the p53, essential tumor suppressor protein, can form anomalous liquid condensates which can initiate nucleation of pathological amyloid fibrils. We further exhibit that crowding condition mimicking inside cell environment, can alter the ability of these condensates to nucleate fibrils. To gain deeper understanding of cell mechanisms to control protein condensation, we focus on a family of carrier proteins known as importins, which control the cytoplasm-nucleus transport of cargos such as p53, spindle assembly factors (SAFs), etc. We find out that aside from regular function of importins for transport, they can regulate liquid-liquid phase separation of some cargo proteins. Surprisingly, for some of the cargo proteins, the self-association is linked with the function. To investigate this, we focus on an essential microtubule nucleator, known as TPX2, which exhibits self-association on microtubules surface in ex vivo conditions, and rapid liquid-liquid phase separation in vitro. Recent study demonstrated that the self-association of TPX2 is directly linked to its ability to nucleate new microtubules. Here, we demonstrate a molecular picture on how importins can prevent TPX2 phase separation in vitro. Thus, controlling the nucleation ability of TPX2 in ex vivo conditions. Our data will provide details on how protein condensation can act both as pathological and functional pathways and demonstrate one possible route on cell mechanism to tune these processes.

Research Interests:

Biological liquid liquid phase separation, Biophysical characterization of protein condensates, Mechanisms underlying development of neurodegenerative diseases from protein condensates, Preventing toxic protein aggregation as a pathway for cell survival (exploring new therapeutics)

Teaching Interests:

Protein biophysics, Thermodynamics, Applied mathematics to chemical engineering, fluid dynamics, separation processes in chemical engineering