University of Dundee

Professor Daan van Aalten FRSE

The role of the O-GlcNAc posttranslational modification in neurodegeneration
Position: 
Professor of Biological Chemistry
Address: 
School of Life Sciences, University of Dundee, Dundee
Full Telephone: 
+44 (0) 1382 384979, int ext 84979
Email: 

Research

Figure 1The modification of serines/threonines on cytosolic proteins in higher eukaryotes with O-linked N-acetylglucosamine (O-GlcNAc) is an essential, abundant and dynamic post-translational modification (see Figure 1)

 O-GlcNAc has been implicated in a wide range of cellular processes, including transcription, the cell cycle, signal transduction networks and protein folding, and shows interplay with regulatory protein phosphorylation. Despite recent biochemical and structural advances, our understanding of the precise functional implications of O-GlcNAc is still limited and we do not understand how O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase (OGA), single essential genes in metazoa, together build the dynamic O-GlcNAc proteome. Interestingly, O-GlcNAc appears to be particularly abundant in the brain and recent proteomics studies have identified O-GlcNAc on proteins that are involved in the development and progression of neurodegenerative diseases - Tau in Alzheimer's disease, the PrP prion protein in Creutzfeldt-Jakob disease and a-synuclein in Parkinson's disease.

Figure 2My lab aims to transform our understanding of the mechanisms, regulation and functional implications of the O-GlcNAc modification in the brain and neurodegenerative disease using a multidisciplinary chemical, biochemical, structural and cell biological approach.We determined the crystal structures and mechanisms O-GlcNAcase - the enzyme that removes the O-GlcNAc modification, and O-GlcNAc transferase (Figure 2), providing the first insights into how these enzyme recognise their substrates

Figure 3Figure 4

 

Using these structural data, we then developed low nanomolar, cell permeable inhibitors (GlcNAcstatins, Figure 3) of O-GlcNAcase that are now widely used to probe the role of O-GlcNAc in live cells, and in our lab to study the role of O-GlcNAc on proteins linked to neurodegenerative diseases and neuronal outgrowth (Figure 4).

 

 

In addition to our work on O-GlcNAc, we collaborate with several members in the unit to uncover molecular mechanisms underlying signal transduction and human diseases, for instance determining the structures of a the TAB1 pseudophosphatase with the laboratory of Philip Cohen, protein kinases in collaboration with the laboratory of Dario Alessi and protein involved in the mRNA methyl cap with the laboratory of Vicky Cowling

Teaching

4A07 - Protein Structure and Function

Publications

Kapuria, V., Rohrig, U. F., Bhuiyan, T., Borodkin, V. S., van Aalten, D. M., Zoete, V. and Herr, W. (2016) Proteolysis of HCF-1 by Ser/Thr glycosylation-incompetent O-GlcNAc transferase:UDP-GlcNAc complexes. Genes & development. 30, 960-972

Raich, L., Borodkin, V., Fang, W., Castro-Lopez, J., van Aalten, D. M., Hurtado-Guerrero, R. and Rovira, C. (2016) A Trapped Covalent Intermediate of a Glycoside Hydrolase on the Pathway to Transglycosylation. Insights from Experiments and Quantum Mechanics/Molecular Mechanics Simulations. Journal of the American Chemical Society. 138, 3325-3332

Swamy, M., Pathak, S., Grzes, K. M., Damerow, S., Sinclair, L. V., van Aalten, D. M. and Cantrell, D. A. (2016) Glucose and glutamine fuel protein O-GlcNAcylation to control T cell self-renewal and malignancy. Nature immunology. 17, 712-720

Trapannone, R., Mariappa, D., Ferenbach, A. T. and van Aalten, D. M. (2016) Nucleocytoplasmic human O-GlcNAc transferase is sufficient for O-GlcNAcylation of mitochondrial proteins. The Biochemical journal

Trapannone, R., Rafie, K. and van Aalten, D. M. (2016) O-GlcNAc transferase inhibitors: current tools and future challenges. Biochemical Society transactions. 44, 88-93

Fang, W., Robinson, D. A., Raimi, O. G., Blair, D. E., Harrison, J. R., Lockhart, D. E., Torrie, L. S., Ruda, G. F., Wyatt, P. G., Gilbert, I. H. and van Aalten, D. M. (2015) N-myristoyltransferase is a cell wall target in Aspergillus fumigatus. ACS Chem Biol. 10, 1425-1434

Jank, T., Eckerle, S., Steinemann, M., Trillhaase, C., Schimpl, M., Wiese, S., van Aalten, D. M., Driever, W. and Aktories, K. (2015) Tyrosine glycosylation of Rho by Yersinia toxin impairs blastomere cell behaviour in zebrafish embryos. Nat Commun. 6, 7807

Kazlauskaite, A., Martinez-Torres, R. J., Wilkie, S., Kumar, A., Peltier, J., Gonzalez, A., Johnson, C., Zhang, J., Hope, A. G., Peggie, M., Trost, M., van Aalten, D. M., Alessi, D. R., Prescott, A. R., Knebel, A., Walden, H. and Muqit, M. M. (2015) Binding to serine 65-phosphorylated ubiquitin primes Parkin for optimal PINK1-dependent phosphorylation and activation. EMBO Rep. 16, 939-954

Mariappa, D., Selvan, N., Borodkin, V. S., Alonso, J., Ferenbach, A. T., Shepherd, C., Navratilova, I. H. and van Aalten, D. M. (2015) A mutant O-GlcNAcase as a probe to reveal global dynamics of protein O-GlcNAcylation during Drosophila embryonic development. Biochem J. 470, 255-262

Mariappa, D., Zheng, X., Schimpl, M., Raimi, O., Ferenbach, A. T., Muller, H. A. and van Aalten, D. M. (2015) Dual functionality of O-GlcNAc transferase is required for Drosophila development. Open Biol. 5

Ostrowski, A., Gundogdu, M., Ferenbach, A. T., Lebedev, A. A. and van Aalten, D. M. (2015) Evidence for a Functional O-Linked N-Acetylglucosamine (O-GlcNAc) System in the Thermophilic Bacterium Thermobaculum terrenum. J Biol Chem. 290, 30291-30305

Pathak, S., Alonso, J., Schimpl, M., Rafie, K., Blair, D. E., Borodkin, V. S., Schuttelkopf, A. W., Albarbarawi, O. and van Aalten, D. M. (2015) The active site of O-GlcNAc transferase imposes constraints on substrate sequence. Nat Struct Mol Biol. 22, 744-750

Selvan, N., Mariappa, D., van den Toorn, H. W., Heck, A. J., Ferenbach, A. T. and van Aalten, D. M. (2015) The Early Metazoan Trichoplax adhaerens Possesses a Functional O-GlcNAc System. J Biol Chem. 290, 11969-11982

van der Beek, S. L., Le Breton, Y., Ferenbach, A. T., Chapman, R. N., van Aalten, D. M., Navratilova, I., Boons, G. J., McIver, K. S., van Sorge, N. M. and Dorfmueller, H. C. (2015) GacA is essential for Group A Streptococcus and defines a new class of monomeric dTDP-4-dehydrorhamnose reductases (RmlD). Mol Microbiol

Zhang, N., Gordon, S. L., Fritsch, M. J., Esoof, N., Campbell, D. G., Gourlay, R., Velupillai, S., Macartney, T., Peggie, M., van Aalten, D. M., Cousin, M. A. and Alessi, D. R. (2015) Phosphorylation of synaptic vesicle protein 2A at Thr84 by casein kinase 1 family kinases controls the specific retrieval of synaptotagmin-1. J Neurosci. 35, 2492-2507

Alonso, J., Schimpl, M. and van Aalten, D. M. (2014) O-GlcNAcase: promiscuous hexosaminidase or key regulator of O-GlcNAc signaling? J Biol Chem. 289, 34433-34439

Borodkin, V. S., Schimpl, M., Gundogdu, M., Rafie, K., Dorfmueller, H. C., Robinson, D. A. and van Aalten, D. M. (2014) Bisubstrate UDP-peptide conjugates as human O-GlcNAc transferase inhibitors. Biochem J. 457, 497-502

Brand, S., Norcross, N. R., Thompson, S., Harrison, J. R., Smith, V. C., Robinson, D. A., Torrie, L. S., McElroy, S. P., Hallyburton, I., Norval, S., Scullion, P., Stojanovski, L., Simeons, F. R. C., van Aalten, D., Frearson, J. A., Brenk, R., Fairlamb, A. H., Ferguson, M. A. J., Wyatt, P. G., Gilbert, I. H. and Read, K. D. (2014) Lead Optimization of a Pyrazole Sulfonamide Series of Trypanosoma brucei N-Myristoyltransferase Inhibitors: Identification and Evaluation of CNS Penetrant Compounds as Potential Treatments for Stage 2 Human African Trypanosomiasis. Journal of Medicinal Chemistry. 57, 9855-9869

Dorfmueller, H. C., Ferenbach, A. T., Borodkin, V. S. and van Aalten, D. M. (2014) A structural and biochemical model of processive chitin synthesis. J Biol Chem. 289, 23020-23028

Lockhart, D. E., Schuettelkopf, A., Blair, D. E. and van Aalten, D. M. (2014) Screening-based discovery of Aspergillus fumigatus plant-type chitinase inhibitors. FEBS Lett. 588, 3282-3290

Speakman, C. M., Domke, T. C., Wongpaiboonwattana, W., Sanders, K., Mudaliar, M., van Aalten, D. M., Barton, G. J. and Stavridis, M. P. (2014) Elevated O-GlcNAc levels activate epigenetically repressed genes and delay mouse ESC differentiation without affecting naive to primed cell transition. Stem cells. 32, 2605-2615

Fang, W., Du, T., Raimi, O. G., Hurtado-Guerrero, R., Marino, K., Ibrahim, A. F., Albarbarawi, O., Ferguson, M. A., Jin, C. and Van Aalten, D. M. (2013) Genetic and structural validation of Aspergillus fumigatus N-acetylphosphoglucosamine mutase as an antifungal target. Bioscience reports. 33

Fang, W., Du, T., Raimi, O. G., Hurtado-Guerrero, R., Urbaniak, M. D., Ibrahim, A. F., Ferguson, M. A., Jin, C. and van Aalten, D. M. (2013) Genetic and structural validation of Aspergillus fumigatus UDP-N-acetylglucosamine pyrophosphorylase as an antifungal target. Mol Microbiol. 89, 479-493

Hahne, H., Sobotzki, N., Nyberg, T., Helm, D., Borodkin, V. S., van Aalten, D. M. F., Agnew, B. and Kuster, B. (2013) Proteome Wide Purification and Identification of O-GlcNAc-Modified Proteins Using Click Chemistry and Mass Spectrometry. J Proteome Res. 12, 927-936

Hobley, L., Ostrowski, A., Rao, F. V., Bromley, K. M., Porter, M., Prescott, A. R., MacPhee, C. E., van Aalten, D. M. and Stanley-Wall, N. R. (2013) BslA is a self-assembling bacterial hydrophobin that coats the Bacillus subtilis biofilm. Proc Natl Acad Sci U S A. 110, 13600-13605

Mariappa, D., Pathak, S. and van Aalten, D. M. (2013) A sweet TET-a-tete-synergy of TET proteins and O-GlcNAc transferase in transcription. The EMBO journal. 32, 612-613

Ostrowski, A. and van Aalten, D. M. (2013) Chemical tools to probe cellular O-GlcNAc signalling. Biochem J. 456, 1-12

Rao, F. V., Schuttelkopf, A. W., Dorfmueller, H. C., Ferenbach, A. T., Navratilova, I. and van Aalten, D. M. (2013) Structure of a bacterial putative acetyltransferase defines the fold of the human O-GlcNAcase C-terminal domain. Open Biol. 3, 130021

Striebeck, A., Robinson, D. A., Schuttelkopf, A. W. and van Aalten, D. M. (2013) Yeast Mnn9 is both a priming glycosyltransferase and an allosteric activator of mannan biosynthesis. Open Biol. 3, 130022

Urbaniak, M. D., Collie, I. T., Fang, W., Aristotelous, T., Eskilsson, S., Raimi, O. G., Harrison, J., Navratilova, I. H., Frearson, J. A., van Aalten, D. M. and Ferguson, M. A. (2013) A novel allosteric inhibitor of the uridine diphosphate N-acetylglucosamine pyrophosphorylase from Trypanosoma brucei. ACS Chem Biol. 8, 1981-1987

Dixon, M. J., Gray, A., Schenning, M., Agacan, M., Tempel, W., Tong, Y., Nedyalkova, L., Park, H. W., Leslie, N. R., van Aalten, D. M., Downes, C. P. and Batty, I. H. (2012) IQGAP proteins reveal an atypical phosphoinositide (aPI) binding domain with a pseudo C2 domain fold. J Biol Chem. 287, 22483-22496

Dorfmueller, H. C., Fang, W., Rao, F. V., Blair, D. E., Attrill, H. and van Aalten, D. M. (2012) Structural and biochemical characterization of a trapped coenzyme A adduct of Caenorhabditis elegans glucosamine-6-phosphate N-acetyltransferase 1. Acta crystallographica. Section D, Biological crystallography. 68, 1019-1029

Pathak, S., Borodkin, V. S., Albarbarawi, O., Campbell, D. G., Ibrahim, A. and van Aalten, D. M. (2012) O-GlcNAcylation of TAB1 modulates TAK1-mediated cytokine release. The EMBO journal. 31, 1394-1404

Penman, G. A., Lockhart, D. E., Ferenbach, A. and van Aalten, D. M. (2012) Purification, crystallization and preliminary X-ray diffraction data of UDP-galactopyranose mutase from Aspergillus fumigatus. Acta crystallographica. Section F, Structural biology and crystallization communications. 68, 705-708

Schimpl, M., Borodkin, V. S., Gray, L. J. and van Aalten, D. M. (2012) Synergy of peptide and sugar in O-GlcNAcase substrate recognition. Chemistry & biology. 19, 173-178

Schimpl, M., Rush, C. L., Betou, M., Eggleston, I. M., Recklies, A. D. and van Aalten, D. M. (2012) Human YKL-39 is a pseudo-chitinase with retained chitooligosaccharide-binding properties. Biochem J. 446, 149-157

Schimpl, M., Zheng, X., Borodkin, V. S., Blair, D. E., Ferenbach, A. T., Schuttelkopf, A. W., Navratilova, I., Aristotelous, T., Albarbarawi, O., Robinson, D. A., Macnaughtan, M. A. and van Aalten, D. M. (2012) O-GlcNAc transferase invokes nucleotide sugar pyrophosphate participation in catalysis. Nat Chem Biol. 8, 969-974

Wong, E., Vaaje-Kolstad, G., Ghosh, A., Hurtado-Guerrero, R., Konarev, P. V., Ibrahim, A. F., Svergun, D. I., Eijsink, V. G., Chatterjee, N. S. and van Aalten, D. M. (2012) The Vibrio cholerae colonization factor GbpA possesses a modular structure that governs binding to different host surfaces. PLoS Pathog. 8, e1002373

Rush, C.L., A.W. Schuttelkopf, R. Hurtado-Guerrero, D.E. Blair, A.F. Ibrahim, S. Desvergnes, I.M. Eggleston, and D.M. van Aalten, Natural product-guided discovery of a fungal chitinase inhibitor. Chemistry & biology, 2010. 17(12): p. 1275-81.
Dorfmueller, H.C., V.S. Borodkin, M. Schimpl, X. Zheng, R. Kime, K.D. Read, and D.M. van Aalten, Cell-penetrant, nanomolar O-GlcNAcase inhibitors selective against lysosomal hexosaminidases. Chemistry & biology, 2010. 17(11): p. 1250-5.
Zeqiraj, E., B.M. Filippi, M. Deak, D.R. Alessi, and D.M. van Aalten, Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation. Science, 2009. 326(5960): p. 1707-11.