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Research Overview

Much information is now available on which genes are implicated in particular diseases. Genes are the instruction book, but the proteins they code for are what we're interested in. They are the molecular machines of the cell and the targets of therapeutic drugs.

After genes are coded into proteins, the proteins are then ‘decorated’ with multiple chemicals, called post-translational modifications (PTMs). PTMs alter protein behaviour/function. The Synapse Proteomics Group focus on defining protein PTMs and how they affect protein function.

The proteins we are particularly interested in are crucial for the formation of vesicles. Vesicles are tiny 'cells within cells' which are made from the cell membrane. Vesicles are used to store neurotransmitter in the brain, and vesicle formation is also necessary for the transport and degradation of crucial environmental signalling molecules, e.g. those involved in inflammation.

The high fidelity production of vesicles is a crucial cellular process that is important for many diseases, but detailed mechanistic information on the proteins involved is still lacking. We aim to fill in these critical gaps in our knowledge so we can develop better treatments for such diverse diseases as epilepsy, Alzheimer's, and childhood leukaemia.

Developing treatments for diseases requires knowledge of the genes involved, the proteins they code for and how to target those proteins with drugs to change the disease state. Specific extra knowledge is required to know the best way to attack the problem. We need knowledge of what the disease-related protein does and which enzymes and binding partners influence the protein function. The Synapse Proteomics Group uses advanced technology to identify enzyme pathways and map interacting protein partners for disease-related proteins.

Lab Head

0 D8 A9973

Mark Graham

Group Leader, Synapse Proteomics
Available for Student Supervision

Group Leader, Synapse Proteomics and Honours Student Coordinator

View full bio

Team Members

Jesse Wark
Research Assistant

Research Projects

Diseases of neurotransmission

The synapse is centre stage for many brain diseases. Many disease-related genes have been identified that code for proteins involved in neurotransmitter release, synapse morphology, and synaptic plasticity. A major focus of the Synapse Proteomics Group is the synaptic vesicle cycle proteins involved in disease.

Endocytosis in neurotransmission

Endocytosis is a fundamental process that occurs in all eukaryotic cells. Defects in endocytosis limit the ability of a cell to internalise molecules and properly respond to environmental queues. Defects in endocytosis also affect exocytosis and intracellular trafficking because these processes are reliant on the proper sorting of the exocytic machinery during endocytosis. This is particularly important in the brain where cyclic exocytosis and endocytosis is required to maintain neurotransmission. The most well understood mode of endocytosis is clathrin-mediated endocytosis (CME). CME involves the formation of a lattice-like clathrin coat over the budding vesicle. Clathrin assembly proteins are responsible for making vesicles of a consistent size and shape. We are focused on defining the molecular mechanism of events during assembly of the clathrin coat, including the signalling events mediated by post-translational modifications.

A better understanding of neurotransmission will help us determine what goes wrong in a range of diseases like epilepsy, autism and Alzheimer’s disease. It also tells us about normal learning and memory.

CME Proteins

AP180 and CALM are a major focus of our group. Both are clathrin assembly proteins. AP180 is only found in brain and forms small vesicles in the synapses of neurons. The mechanism of clathrin assembly by AP180 is not yet well understood. The gene for AP180 has been implicated in bipolar disorder.

CALM is found in all cells of the body where it is involved in receptor internalisation which has implications for both Alzheimer’s and leukaemia. The fusion of CALM and AF10 via chromosomal translocation causes an acute leukaemia. A better understanding of CALM function may lead to therapeutics that can better target and potentially prevent the aberrant functions of this fusion product.

Polymorphisms in the gene for CALM have been found in Alzheimer’s patients. CALM may have a role the clearance of amyloid plaques or the processing of amyloid precursor protein (APP). CALM is known to be involved in APP-trafficking, so it could contribute to Alzheimer’s by trafficking APP to where it can break down and eventually form plaques. Understanding how CALM works will allow us to achieve the ultimate goal of finding subtle ways to regulate endocytosis and modulate its function to treat these diseases.

Follow the phosphate

Post-translational modification, which is the addition of molecules to a protein after it has been made, often significantly changes protein function. Therefore, rather than directly targeting a disease-related protein with a drug, it is possible to change protein function by targeting the enzymes involved in protein post-translational modification. We study protein phosphorylation, since it is the most common post-translational modification. We measure changes to the level of phosphate on both individual proteins and sometimes thousands of proteins at once to determine normal phosphorylation signalling that occurs presynaptically during neurotransmission. Phospho-signalling directed at disease-related proteins is picked up in these screens. The phospho-signalling pathways can potentially be exploited as a targeted way to treat disease.

We have identified novel activity-dependent signalling to proteins involved in Alzheimer’s disease, autism and epilepsy. Our signalling network data also fills in a major gap in our fundamental knowledge of presynaptic neurotransmission and this is where we aim to add significantly to global efforts to model brain function.


Site-specific glycan-peptide analysis for determination of N-glycoproteome heterogeneity.

Parker BL, Thaysen-Andersen M, Solis N, Scott NE, Larsen MR, Graham ME, Packer NH, Cordwell SJ (2013) J. Proteome Res. 12:5791-800. PMID: 24090084

Kruppel-associated Box (KRAB)-associated Co-repressor (KAP-1) Ser-473 Phosphorylation Regulates Heterochromatin Protein 1β (HP1-β) Mobilization and DNA Repair in Heterochromatin.

Bolderson E, Savage KI, Mahen R, Pisupati V, Graham ME, Richard DJ, Robinson PJ, Venkitaraman AR and Khanna KK (2012). J. Biol. Chem. 287:28122-31. PMID: 22715096

A novel method for the simultaneous enrichment, identification, and quantification of phosphopeptides and sialylated glycopeptides applied to a temporal profile of mouse brain development.

Palmisano G, Parker BL, Engholm-Keller K, Lendal SE, Kulej K, Schulz M, Schwämmle V, Graham ME, Saxtorph H, Cordwell SJ, Larsen MR (2012). Mol. Cell. Proteomics, 11:1191-202.

PMID: 22843994

Phosphorylation of syndapin I F-BAR domain at two helix-capping motifs regulates membrane tubulation.

Quan A, Xue J, Wielens J, Smillie KJ, Anggono V, Parker MW, Cousin MA, Graham ME, Robinson PJ (2012). Proc. Natl Acad. Sci. USA, 109:3760-5. PMID: 22355135

Calcineurin selectively docks with the dynamin Ixb splice variant to regulate activity-dependent bulk endocytosis.

Xue J, Graham ME, Novelle AE, Sue N, Gray N, McNiven MA, Smillie KJ, Cousin MA, Robinson PJ (2011). J. Biol. Chem., 286:30295-303. PMID: 21730063

A novel post-translational modification in nerve terminals: O-linked N-acetylglucosamine phosphorylation.

Graham ME, Thaysen-Andersen M, Bache N, Craft GE, Larsen MR, Packer NH, Robinson PJ (2011). J. Proteome Res., 10:2725-33. PMID: 21500857

Phosphorylation of dynamin II at serine-764 is associated with cytokinesis.

Chircop M, Sarcevic B, Larsen MR, Malladi CS, Chau N, Zavortink M, Smith CM, Quan A, Anggono V, Hains PG, Graham ME, Robinson PJ (2011). Biochim. Biophys. Acta, 1813:1689-99. PMID: 21195118

Autophosphorylation and ATM activation: additional sites add to the complexity.

Kozlov SV, Graham ME, Jakob B, Tobias F, Kijas AW, Tanuji M, Chen P, Robinson PJ, Taucher-Scholz G, Suzuki K, So S, Chen D, Lavin MF (2011). J. Biol. Chem., 286:9107-19. PMID: 21149446

Differential phosphorylation of dynamin I isoforms in subcellular compartments demonstrates the hidden complexity of phosphoproteomes.

Chan LS, Hansra G, Robinson PJ, Graham ME (2010). J. Proteome Res., 9:4028-37. PMID: 20560669

The in vivo phosphorylation sites of rat brain dynamin I.

Graham ME, Anggono VA, Bache N, Larsen MR, Craft GE and Robinson PJ (2007). J. Biol. Chem. 282:14695-707. PMID: 16648848

Protein composition of catalytically active human telomerase from immortal cells.

Cohen SB, Graham ME, Lovrecz GO, Bache N, Robinson PJ and Reddel RR (2007). Science 315:1850-1853. PMID: 17395830

Involvement of novel autophosphorylation sites in ATM activation.

Kozlov SV, Graham ME, Peng C, Chen P, Robinson PJ and Lavin, M. F. (2006). EMBO J. 25:3504-14. PMID: 16858402

Phosphorylation of Ser19 alters the conformation of tyrosine hydroxylase to increase the rate of phosphorylation of Ser40.

Bevilaqua LR, Graham ME, Dunkley PR, von Nagy-Felsobuki EI and Dickson PW. (2001). J. Biol. Chem. 276:40411-40416. PMID: 11502746

Major Achievements


Co-discovered the phosphorylation-regulated function of the endocytic fission protein dynamin 1 in endocytosis. Led the team that defined the dynamin 1 phosphorylation sites and their importance to endocytosis.


Discovered novel irradiation-sensitive phosphorylation sites on the DNA damage response protein ATM.


Co-discovered the protein components of active human telomerase.


Demonstrated that phosphorylation sites in identical contexts on multiple protein isoforms can have very different regulation.


Discovered a completely new post-translational modification (O-GlcNAc-phosphate) on the brain specific clathrin assembly protein AP180.


First to synthesise O-GlcNAc-phosphate modified peptides.