Abstract
Liquid–liquid phase separation has drawn attention as many neurodegeneration or cancer-associated proteins are able to form liquid membraneless compartments (condensates) by liquid–liquid phase separation. Furthermore, there is rapidly growing evidence that disease-associated mutation or post-translational modification of these proteins causes aberrant location, composition or physical properties of the condensates. It is ambiguous whether aberrant condensates are always causative in disease mechanisms, however they are likely promising potential targets for therapeutics. The conceptual framework of liquid–liquid phase separation provides opportunities for novel therapeutic approaches. This review summarises how the extensive recent advances in understanding control of nucleation, growth and composition of condensates by protein post-translational modification has revealed many possibilities for intervention by conventional small molecule enzyme inhibitors. This includes the first proof-of-concept examples. However, understanding membraneless organelle formation as a physical chemistry process also highlights possible physicochemical mechanisms of intervention. There is huge demand for innovation in drug development, especially for challenging diseases of old age including neurodegeneration and cancer. The conceptual framework of liquid–liquid phase separation provides a new paradigm for thinking about modulating protein function and is very different from enzyme lock-and-key or structured binding site concepts and presents new opportunities for innovation.
Highlights
Liquid–liquid phase separation (LLPS) has emerged as the mechanism underlying the formation of many membraneless organelles (MLOs)
liquid phase separation have emerged in neurodegeneration and cancer
physical properties of condensates formed by liquid
Summary
Liquid–liquid phase separation (LLPS) has emerged as the mechanism underlying the formation of many membraneless organelles (MLOs). As control of condensate composition is linked with condensate biochemical function, achieving the correct composition is important [82] It is likely there are disease-related PTM enzymes which alter client partition into condensates which would be conventional targets for small molecule drugs (Figure 1B). PAR polymerases are a conventional target for small molecules and inhibitors reduce TDP-43-associated pathology in in vitro neurons, a very promising result demonstrating control of nucleation as a therapeutic target [90] Another specific molecular example is Nephrin phosphorylation leading to the Nephrin signalling MLO [92]. Our work identified lipoamide as a stress granule LLPS modulating compound, with physicochemical effects in vitro and specific effects on stress granules in cells [66] This suggests that small molecules that reach high concentration by partition to specific condensates could alter LLPS. Perhaps partition to in vitro condensates or phenotypic screens for effects on condensates in cells
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