Establishing a structure-function relationship between biomolecular condensates and protein degradation

Dr Janet Kumita; Dept of Pharmacology, University of Cambridge

Our bodies contain some 100,000 proteins that enable or regulate essentially every biochemical process on which our lives depend. To maintain healthy proteostasis, cells have evolved intricate quality control networks that identify aberrant and damaged components and destroy them. For this to occur, cells need to spatially organise their components to promote specific reactions and processes. The rapid formation and dissolution of membraneless, biomolecular condensates (BCs) is key to many biological roles, including autophagy, the cell’s waste disposal machinery. BCs contain an array of different biomolecules and, depending on their biological function, they can be very fluid in nature or they can have a more gel-like composition; therefore the dynamics and physical attributes of BCs appear to be closely linked with their biological roles. But how does the cell control the phase boundaries within live cells and how do they know when to form droplets in the right place at the right time? Here we are exploring the design of novel proteins comprising molecular adhesive peptides to drive liquid-liquid-phase separation (LLPS) and consensus tetratricopeptide repeat units (CTPR) to endow the droplets with functional capabilities in order to create well defined BCs. We want to characterise the physico-chemical properties of these LLPS-CTPR designs in vitro and relate these attributes to their ability to induce autophagosome formation and subsequent protein degradation in cells. We hope to establish a structure-function relationship that will enable rational design of artificial phase-separating molecules that can drive the removal of disease-causing proteins from the cell.

Janet Kumita completed her undergraduate degree in Biochemistry at the University of Waterloo  and her PhD in Chemistry at the University of Toronto. In 2003, she was awarded an NSERC Postdoctoral Fellowship and joined Prof. Sir Christopher Dobson’s group in the Department of Chemistry at the University of Cambridge, investigating how extracellular molecular chaperones modulate the amyloid formation of proteins associated with neurodegenerative diseases and systemic amyloidosis. Janet spent 17 years working closely with the Dobson group, but in 2020 she moved to the Department of Pharmacology to work with Prof. Laura Itzhaki. In January 2022, Janet was awarded a MRC Career Development Award and became a Group Leader in the Department of Pharmacology. Her research looks at deciphering the underlying mechanisms of protein self-assembly in order to find therapeutic strategies to combat neurodegenerative disorders.