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Professor Luke Chamberlain

Strathclyde Institute of Pharmacy and Biomedical Sciences

Personal statement

PROTEIN PALMITOYLATION: EXPLORING THE MECHANISMS AND OUTCOMES OF AN ESSENTIAL POST-TRANSLATIONAL MODIFICATION

Palmitoylation (or S-acylation) is a dynamic post-translational modification of eukaryotic proteins. Palmitoylation has many effects on modified proteins, including regulating intracellular sorting, protein-protein interactions, membrane binding, membrane micro-localisation, and stability. A diverse array of proteins is regulated by palmitoylation, including: Ras, Src family kinases, Galpha subunits of heterotrimeric G proteins, G protein-coupled receptors, ion channels, AMPA and NMDA glutamate receptors, and membrane fusion proteins.

Recent work identified a family of 24 'DHHC' palmitoyltransferases that regulate cellular palmitoylation dynamics, and mutations in the genes encoding these proteins have been linked with cancer, schizophrenia, and mental retardation.

To understand how DHHC proteins and palmitoylation contribute to physiology and pathophysiological states, the major research questions being addressed by members of the group are aimed at delineating: (1) How DHHC proteins are regulated. (2) The general principles of DHHC-substrate specificity. (3) How palmitoylation affects the trafficking and function of substrate proteins. (4) New molecules that modulate DHHC protein activity.

We employ a range of techniques to explore the regulation and outcomes of protein palmitoylation, including live-cell imaging (FRAP, iFRAP), image deconvolution and quantitative analyses of fluorescence covariance, yeast-based protein interaction platforms (split-ubiquitin system), and protein palmitoylation assays (radiolabelling, acyl RAC, and click chemistry).

Publications

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)
http://dx.doi.org/10.1016/j.expneurol.2018.06.014
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)
http://dx.doi.org/10.1242/jcs.222257
Toll-like receptor 3 activation impairs excitability and synaptic activity via TRIF signalling in immature rat and human neurons
Ritchie Louise, Tate Rothwelle, Chamberlain Luke H., Robertson Graham, Zagnoni Michele, Sposito Teresa, Wray Selina, Wright John A., Bryant Clare E., Gay Nicholas J., Bushell Trevor J.
Neuropharmacology Vol 135, pp. 1-10, (2018)
http://dx.doi.org/10.1016/j.neuropharm.2018.02.025
Tracking intracellular uptake and localisation of alkyne tagged fatty acids using Raman spectroscopy
Jamieson Lauren E., Greaves Jennifer, McLellan Jayde A., Munro Kevin R., Tomkinson Nicholas C.O., Chamberlain Luke H., Faulds Karen, Graham Duncan
Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy Vol 197, pp. 30-36, (2018)
http://dx.doi.org/10.1016/j.saa.2018.01.064
The C-terminal domain of zDHHC2 contains distinct sorting signals that regulate intracellular localisation in neurons and neuroendocrine cells
Salaun Christine, Ritchie Louise, Greaves Jennifer, Bushell Trevor J., Chamberlain Luke H.
Molecular and Cellular Neuroscience Vol 85, (2017)
http://dx.doi.org/10.1016/j.mcn.2017.07.007
Peptide array–based screening reveals a large number of proteins interacting with the ankyrin-repeat domain of the zDHHC17 S-acyltransferase
Lemonidis Kimon, MacLeod Ruth, Baillie George S., Chamberlain Luke H.
Journal of Biological Chemistry Vol 292, pp. 17190-17202, (2017)
http://dx.doi.org/10.1074/jbc.M117.799650

more publications

Projects

Impact Acceleration Account - University Of Strathclyde 2012 / R120526-226
Chamberlain, Luke (Principal Investigator)
Period 01-Oct-2012 - 31-Mar-2017
ANALYSIS OF ZDHHC17 INTERACTION NETWORKS AND PROTEIN INTERACTIONS LINKED TO NEURODEGENERATION
Chamberlain, Luke (Principal Investigator)
Period 07-May-2018 - 06-May-2021
Doctoral Training Partnership (DTP - University of Strathclyde) | McLellan, Jayde
Tomkinson, Nicholas (Principal Investigator) Chamberlain, Luke (Co-investigator) McLellan, Jayde (Research Co-investigator)
Period 01-Oct-2015 - 01-Apr-2019
Protein palmltoylation in adipocytes: Role in insulin action
Chamberlain, Luke (Principal Investigator)
Period 01-Oct-2011 - 30-Sep-2014
Fatty Acid Specificity in the DHHC Family of S-Acyltransferases: From Mechanisms to Functional Outcomes
Chamberlain, Luke (Principal Investigator) Tomkinson, Nicholas (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."
Period 30-Sep-2014 - 06-May-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."
Period 01-Nov-2012 - 29-Feb-2016

more projects

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Strathclyde Institute of Pharmacy and Biomedical Sciences
Hamnett Wing John Arbuthnott Building

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