The role of the O-GlcNAc posttranslational modification in neurodegeneration

Research

The 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.

My 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

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

Wong, E., G. Vaaje-Kolstad, A. Ghosh, R. Hurtado-Guerrero, P.V. Konarev, A.F. Ibrahim, D.I. Svergun, V.G. Eijsink, N.S. Chatterjee, and D.M. van Aalten, The Vibrio cholerae colonization factor GbpA possesses a modular structure that governs binding to different host surfaces. Plos Pathogens, 2012. 8(1): p. e1002373.

 Schimpl, M., V.S. Borodkin, L.J. Gray, and D.M. van Aalten, Synergy of peptide and sugar in O-GlcNAcase substrate recognition. Chemistry & biology, 2012. 19(2): p. 173-8.

 Pathak, S., V.S. Borodkin, O. Albarbarawi, D.G. Campbell, A. Ibrahim, and D.M. van Aalten, O-GlcNAcylation of TAB1 modulates TAK1-mediated cytokine release. The EMBO journal, 2012. 31(6): p. 1394-404.

 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.