Palm-TACs: palmitoylation targeting chimaeras. Genetic and pharmacological reagents to specifically target protein S-Palmitoylation
Lead Research Organisation:
University of Glasgow
Department Name: College of Medical, Veterinary, Life Sci
Abstract
Context
Proteins are molecular machines that perform different jobs in a cell. When they need to adapt to their environment, cells change the way that proteins work by having enzymes make chemical changes to these proteins in a controlled manner. We are particularly interested in a type of protein chemical change called 'palmitoylation'. In this process, fat molecules are added to proteins, altering either how the protein works or where it goes within the cell. Palmitoylation plays an important role in many physiological processes in all types of organisms. For example, how hard and fast our hearts beat, how cells respond to hormones, memory generation in the brain, plant growth and virus replication are all controlled by palmitoylation.
Challenge
Palmitoylation is controlled by the actions of two families of enzymes in the cell: palmitoyl acyl transferases add fat molecules to proteins, and thioesterases remove these fat molecules. We understand very little about what controls these processes, and the tools available to manipulate palmitoylation are very poor quality, impeding progress in this field. We have designed a strategy to deliver thioesterases to different places in a cell using a targeting unit called a nanobody. In this paradigm the nanobody acts as the 'delivery driver' and delivers the thioesterase to one specific protein in the cell. When we use a nanobody to deliver a thioesterase, the thioesterase does the job it is programmed to do and removes the fat molecule from a protein. These nanobody reagents therefore give us the ability to control whether one individual protein gets palmitoylated or not.
Aims & Objectives
In this project, in two separate workpackages, we will develop and test this technology. First, we will refine and expand the use of nanobodies to deliver thioesterases to different proteins in cells. We will evaluate which thioesterases can be delivered by nanobodies, and the breadth and specificity of nanobody-mediated control of palmitoylation. We will develop new nanobodies to deliver thioesterases to new protein targets and use chemical genetic approaches to control when a nanobody will deliver a thioesterase to its target. Second, we will develop small molecules that do the same job as the nanobody, acting as delivery agents to bring a thioesterase together with one particular protein. These agents will be the first step towards developing molecules that can control palmitoylation of a protein in a living organism.
Potential Applications & Benefits
This project will create a set of tools that can precisely control a specific chemical change in a single protein within a living organism using genetic and compound-based methods. The exceptional control over how the proteins behave made possible by this technology will have applications in both basic scientific research and medicine. We expect that the methods developed in this study can be easily adapted to target other chemical changes to proteins in numerous situations.
Relevance to the BBSRC long-term research and innovation priorities
This proposal aligns to multiple BBSRC long-term objectives, offering world-class ideas, innovation, and the potential for impact. Embedded in curiosity and basic bioscience discovery, the proposal will innovate by producing small molecules that paves the way to access an entirely new class of drugs, with the potential for world-changing impact in both experimental and clinical settings.
Proteins are molecular machines that perform different jobs in a cell. When they need to adapt to their environment, cells change the way that proteins work by having enzymes make chemical changes to these proteins in a controlled manner. We are particularly interested in a type of protein chemical change called 'palmitoylation'. In this process, fat molecules are added to proteins, altering either how the protein works or where it goes within the cell. Palmitoylation plays an important role in many physiological processes in all types of organisms. For example, how hard and fast our hearts beat, how cells respond to hormones, memory generation in the brain, plant growth and virus replication are all controlled by palmitoylation.
Challenge
Palmitoylation is controlled by the actions of two families of enzymes in the cell: palmitoyl acyl transferases add fat molecules to proteins, and thioesterases remove these fat molecules. We understand very little about what controls these processes, and the tools available to manipulate palmitoylation are very poor quality, impeding progress in this field. We have designed a strategy to deliver thioesterases to different places in a cell using a targeting unit called a nanobody. In this paradigm the nanobody acts as the 'delivery driver' and delivers the thioesterase to one specific protein in the cell. When we use a nanobody to deliver a thioesterase, the thioesterase does the job it is programmed to do and removes the fat molecule from a protein. These nanobody reagents therefore give us the ability to control whether one individual protein gets palmitoylated or not.
Aims & Objectives
In this project, in two separate workpackages, we will develop and test this technology. First, we will refine and expand the use of nanobodies to deliver thioesterases to different proteins in cells. We will evaluate which thioesterases can be delivered by nanobodies, and the breadth and specificity of nanobody-mediated control of palmitoylation. We will develop new nanobodies to deliver thioesterases to new protein targets and use chemical genetic approaches to control when a nanobody will deliver a thioesterase to its target. Second, we will develop small molecules that do the same job as the nanobody, acting as delivery agents to bring a thioesterase together with one particular protein. These agents will be the first step towards developing molecules that can control palmitoylation of a protein in a living organism.
Potential Applications & Benefits
This project will create a set of tools that can precisely control a specific chemical change in a single protein within a living organism using genetic and compound-based methods. The exceptional control over how the proteins behave made possible by this technology will have applications in both basic scientific research and medicine. We expect that the methods developed in this study can be easily adapted to target other chemical changes to proteins in numerous situations.
Relevance to the BBSRC long-term research and innovation priorities
This proposal aligns to multiple BBSRC long-term objectives, offering world-class ideas, innovation, and the potential for impact. Embedded in curiosity and basic bioscience discovery, the proposal will innovate by producing small molecules that paves the way to access an entirely new class of drugs, with the potential for world-changing impact in both experimental and clinical settings.
