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Department of Pharmacology

 
Supervisors: Dr Janet Kumita and Prof Laura Itzhaki
Industrial Partner: Transition Bio
Non-Academic Partner Supervisor: Dr Will Arter
Industrial Partner Website: transitionbio.com
Project ID: 00078
 
Project Summary

Cells promote specific reactions and processes within distinct regions by controlling the spatiotemporal organisation of the intracellular components. Often physical segregation by membranes are involved; however, membraneless, subcellular structures can also be formed by liquid-liquid phase separation (LLPS). Biological processes mediated by LLPS include cell signaling, stress adaption and protein degradation. How and why cells use these biomolecular condensates (BCs) is far from understood, but diverse roles are being increasingly validated in vivo. The highly concentrated protein environment of BCs allows for enhanced reaction rates, and their liquid-like nature promotes dynamic exchange of constituents with the cytoplasm. Important to their behaviours, BCs have different physicochemical properties, highly influenced by “client” proteins that are not crucial for LLPS but are still recruited into them. But how does the sequestering of client proteins alter the BCs physicochemical state and impact their biological functions?

The Kumita and Itzhaki labs are developing artificial multi-valent proteins capable of LLPS with the aim of building multifunctional BCs to harness cellular degradation pathways to destroy disease-related proteins. This PhD
project will exploit our artificial condensate designs, consisting of “molecular adhesives” to drive LLPS combined with our versatile consensus-designed tetratricopeptide repeats (CTPRs) to engineer in multitarget binding properties, to study how the BC environment alters protein-protein interactions, condensate formation and stability, both in vitro and in cells, and is vital in the ubiquitin-proteasome system and autophagy-related LLPS. In order to gain mechanistic insights, cutting-edge analytical tools are required; therefore, we have partnered with Transition Bio, a global company developing one-of-a-kind technologies, including droplet microfluidic approaches and cellular platforms, to characterise condensates and their modulation, in molecular detail. With computational platforms that apply machine learning, we can also optimise and create novel designs of our CTPR-LLPS system. The impact of the physico-chemical propertiesof our BCs will be evaluated in cell models, provide a novel system for developing Transition Bio capabilities.