Kinase Regulation by Phase Separation

Introduction

Protein phosphorylation is a process that activates biological and cellular pathways. This process is carried out by enzymes called protein kinases that add phosphates to proteins. Protein kinases are crucial drug targets involved in the onset and progression of human diseases such as cancer and Alzheimer’s disease.

Regulation of Protein Kinases

Growing evidence suggests that protein kinases are regulated spatially and temporally by the phase separation and condensation of biomolecules into cellular organelles that are not surrounded by membranes. The molecular mechanisms that govern the action of kinases in phase-separated condensates, however, are unknown. Knowledge of these mechanisms is crucial for the development of better drugs that target protein kinases.

Project Overview

To address this challenge, I have designed an interdisciplinary project that goes well beyond the state-of-the-art to explore in atomic detail the action of protein kinases intimately involved in Alzheimer’s disease and the abnormal phosphorylation of the protein Tau.

Objectives of the PhaseKin Project

The PhaseKin project aims to:

1. Reveal the specificity and reaction kinetics of protein kinases inside phase-separated condensates in vitro and in cells.
2. Decipher the dynamic conformational landscape of the protein kinases MARK2 and GSK3β by advanced NMR methods that will grant unprecedented detail on their modes of regulation.
3. Disentangle changes in population distributions and rates of interconversion between structurally distinct kinase states inside condensates.
4. Unravel the physicochemical basis of kinase drug partitioning into condensates.

Innovation and Impact

The highly innovative nature of the project is devised to delve into the heart of protein kinase function and to revolutionize our knowledge about the chemistry of drug-kinase interactions. Findings from the PhaseKin project will provide critical guidance in the development of more efficacious and specific drugs which target protein kinases.