Professor Luke Chamberlain

Strathclyde Institute of Pharmacy and Biomedical Sciences

Personal statement

PROTEIN S-ACYLATION IN HEALTH AND DISEASE

S-acylation (aka palmitoylation), the reversible attachment of fatty acids onto cysteine residues, regulates a diverse array of proteins and impacts fundamental cellular processes such as signalling, membrane traffic, communication, and growth and division. Defects in S-acylation are linked with cancer, diabetes, and CNS disorders such as intellectual disability, epilepsy, Huntington’s disease and neuronal ceroid lipofuscinosis. In addition, S-acylation is required for infection and virulence of some viruses and parasites. As a result, there is growing interest in the therapeutic potential of targeting the S-acylation machinery, with a major goal being the development of isoform-selective inhibitors against the 23 zDHHC S-acyltransferase enzymes.

RESEARCH IN THE CHAMBERLAIN LAB

The research that we are undertaking aims to unravel the multitude of functions that S-acylation plays in cellular pathways, in particular, signalling and membrane traffic. In addition, we aim to understand how defects in S-acylation contribute to disorders such as intellectual disability, epilepsy, neurodegeneration, cancer and diabetes. Through this work we hope to identify novel drug targets and new drug treatments for these conditions. We use a wide range of techniques including chemical biology (click chemistry), confocal microscopy, proteomics, and behavioural analyses.

Our research falls into two major programmes:

1. S-acylation and cell function in health and disease

(i) How does dynamic S-acylation of key signalling and trafficking proteins regulate cell pathways and how does disruption of this process cause disease?

(ii) What are the molecular effects of S-acylation that underlie protein regulation?

(iii) Does acyl chain heterogeneity provide functionally distinct pools of the same protein?

2. The zDHHC family of S-acyltransferases

(i) What are the substrate networks of individual zDHHC enzymes, and how is enzyme-substrate specificity encoded?

(ii) How do zDHHC enzymes select specific acyl-CoAs from a mixed population?

(iii) How do multiple zDHHC enzyme isoforms coordinate protein S-acylation at the level of a single intracellular organelle?

(iv) What are the cellular and molecular changes that underlie disease phenotypes caused by ZDHHC mutations?

(v) Can we develop isoform-selective chemical modulators of the zDHHC enzyme family?

 

RESEARCH OPPORTUNITIES


We would be delighted to hear from post-doctoral researchers interested in developing fellowhsip proposals that can be hosted in our lab. We can offer support and mentorship for fellowship applications.

We are also happy to speak with prospective PhD students who have secured funding.

All enquiries can be directed to luke.chamberlain@strath.ac.uk

Publications

Regulatory effects of post-translational modifications on zDHHC S-acyltransferases
Zmuda Filip, Chamberlain Luke H
Journal of Biological Chemistry (2020)
https://doi.org/10.1074/jbc.REV120.014717
The linker domain of the SNARE protein SNAP25 acts as a flexible molecular spacer that ensures efficient S-acylation
Salaun Christine, Greaves Jennifer, Tomkinson Nicholas C O, Chamberlain Luke H
Journal of Biological Chemistry Vol 295, pp. 7501-7515 (2020)
https://doi.org/10.1074/jbc.RA120.012726
Disruption of the Zdhhc9 intellectual disability gene leads to behavioural abnormalities in a mouse
Kouskou Marianna, Thomson David M, Brett Ros R, Wheeler Lee, Tate Rothwelle J, Pratt Judith A, Chamberlain Luke H
Experimental Neurology Vol 308, pp. 35-46 (2018)
https://doi.org/10.1016/j.expneurol.2018.06.014
S-acylation regulates the trafficking and stability of the unconventional Q-SNARE STX19
Ampah Khamal K, Greaves Jennifer, Shun-Shion Amber S M, Asnawi Asral W B A, Lidster Jessica A, Chamberlain Luke H, Collins Mark O, Peden Andrew A
Journal of Cell Science (2018)
https://doi.org/10.1242/jcs.212498
Fam49/CYRI interacts with Rac1 and locally suppresses protrusions
Fort Loic, Batista José Miguel, Thomason Peter A, Spence Heather J, Whitelaw Jamie A, Tweedy Luke, Greaves Jennifer, Martin Kirsty J, Anderson Kurt I, Brown Peter, Lilla Sergio, Neilson Matthew P, Tafelmeyer Petra, Zanivan Sara, Ismail Shehab, Bryant David M, Tomkinson Nicholas C O, Chamberlain Luke H, Mastick Grant S, Insall Robert H, Machesky Laura M
Nature Cell Biology Vol 20, pp. 1159-1171 (2018)
https://doi.org/10.1038/s41556-018-0198-9
LIF-dependent survival of embryonic stem cells is regulated by a novel palmitoylated Gab1 signalling protein
Sutherland Linda, Ruhe Madeleine, Gattegno-Ho Daniela, Mann Karanjit, Greaves Jennifer, Koscielniak Magdalena, Meek Stephen, Lu Zen, Waterfall Martin, Taylor Ryan, Tsakiridis Anestis, Brown Helen, Maciver Sutherland K, Joshi Anagha, Clinton Michael, Chamberlain Luke H, Smith Austin, Burdon Tom
Journal of Cell Science (2018)
https://doi.org/10.1242/jcs.222257

more publications

Projects

Industrial Case Account - University of Strathclyde 2019 | Galindo, Alex
Tomkinson, Nick (Principal Investigator) Chamberlain, Luke (Co-investigator) Galindo, Alex (Research Co-investigator)
01-Jan-2019 - 01-Jan-2023
Analysis of the substrate network and neurodevelopmental functions of the intellectual disability
Chamberlain, Luke (Principal Investigator)
01-Jan-2019 - 30-Jan-2022
ANALYSIS OF ZDHHC17 INTERACTION NETWORKS AND PROTEIN INTERACTIONS LINKED TO NEURODEGENERATION
Chamberlain, Luke (Principal Investigator)
07-Jan-2018 - 09-Jan-2021
Doctoral Training Partnership (DTP - University of Strathclyde) | McLellan, Jayde
Tomkinson, Nick (Principal Investigator) Chamberlain, Luke (Co-investigator) McLellan, Jayde (Research Co-investigator)
01-Jan-2015 - 26-Jan-2019
Fatty Acid Specificity in the DHHC Family of S-Acyltransferases: From Mechanisms to Functional Outcomes
Chamberlain, Luke (Principal Investigator) Tomkinson, Nick (Co-investigator)
"The cells in our body contain a diverse array of different proteins that coordinate and drive specific pathways, such as cell growth and division. These proteins are subjected to strict modes of regulation to ensure that they are able to perform their specific functions as and when required. One prominent mechanism of protein regulation is via chemical modification and a variety of different molecules are added to proteins that affect their activity. One modification that is receiving increasing interest is S-acylation, the attachment of fatty acids onto proteins, which is catalysed by a family of twenty-four DHHC enzymes. Dysfunction of DHHC enzymes has been linked with many important disorders, including diabetes, Huntington's disease, schizophrenia, intellectual disability and cancer.

The fatty acids that are added to S-acylated proteins can be diverse and it is likely that different fatty acids affect proteins in different ways. Despite this, we currently know very little about the mechanisms that specify the chemical identity of fatty acids added to individual S-acylated proteins, and how fatty acid identity impacts protein function. Therefore the aim of this research is to promote a major advance in this poorly understood aspect of S-acylation. To do this, we have brought together experts in Chemistry and Biology with the goal of using novel chemical probes to determine: (a) if different DHHC enzymes preferentially add distinct types of fatty acids onto S-acylated proteins, (b) what features of DHHC enzymes underlie their fatty acid specificity, and (c) how different fatty acids affect the localisation of proteins to different regions of the cell and their function in specific cellular pathways. In addition to shedding light on an important but poorly understood aspect of cell biology, this research may also highlight new strategies to design selective modulators of DHHC enzymes to treat a range of clinical conditions."
30-Jan-2014 - 06-Jan-2018
Molecular dissection of DHHC protein targeting and its importance for post-synaptic palmitoylation dynamics
Chamberlain, Luke (Principal Investigator) Bushell, Trevor (Co-investigator)
"Genes present within the DNA of living organisms encode for the production of specific proteins. The thousands of proteins that are produced within a single cell interact to drive a multitude of pathways, such as cell growth and division. Protein modifications can enhance protein diversity beyond that encoded at the DNA level. For example, many proteins are modified by the attachment of the fatty acid palmitate, a process termed palmitoylation.

Communication between neurons, specialised cells in the brain, underlies every movement, thought and sensation; this neuronal communication occurs at specialised sites termed synapses. Palmitoylation of several proteins that are essential for neuronal communication mediates their targeting to synapses; modulating the extent of this targeting affects synaptic communication. It is well established that changes in synaptic communication are important for events such as learning and memory. Despite the importance of palmitoylation for normal synaptic function, there is very little known about how the enzymes that mediate palmitoylation reactions are regulated in neurons. Recent work identified a family of 24 'DHHC' proteins that are responsible for essentially all cellular palmitoylation activity. The importance of DHHC proteins for normal brain function is highlighted by work linking genetic mutations in these proteins with schizophrenia and mental retardation.

This research project will focus on DHHC2, which is one of the most highly expressed DHHC proteins in brain. Furthermore, DHHC2 is targeted to synaptic regions, where it has been shown to palmitoylate a protein called PSD95; this protein plays an important role in stabilising neurotransmitter receptors and is therefore essential for synaptic communication. Palmitoylation of PSD95 by DHHC2 leads to an increase in synaptic targeting of PSD95, which in turn affects synaptic dynamics of neurotransmitter receptors. In this project, we will investigate the mechanisms that regulate DHHC2 movement to synapses where it palmitoylates PSD95. Furthermore, we will examine how interfering with the mobility of DHHC2 at synapses impacts neuronal communication. This work will play a major role in delineating how palmitoylation dynamics are regulated at synapses and the downstream effects of this regulation on neurotransmitter receptor dynamics.

There is currently much interest in DHHC proteins as potential drug targets for the treatment of diverse human disorders, thus delineating the mechanisms whereby specific DHHC proteins regulate cellular dynamics is of major importance."
01-Jan-2012 - 29-Jan-2016

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Address

Strathclyde Institute of Pharmacy and Biomedical Sciences
Hamnett Wing

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