Kenneth Lindegaard Madsen – University of Copenhagen

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Center for Synthetic Biology > Meet the Researchers > Kenneth Lindegaard Madsen

Kenneth Lindegaard Madsen

Associate Professor

Molecular Neuropharmacology Group
Department of Neuroscience and Pharmacology
Faculty of Health Sciences

kennethma@sund.ku.dk 

Kenneth Lindegaard Madsen's research group focuses on studying the reconstitution of membrane proteins into larger, organized protein scaffolds of key importance for neuronal signalling processes. The outcome of their research might to be a key in building synthetic biological systems of scaffolded membrane protein complexes.

Research
Our research includes studies on PDZ domain mediated neuronal scaffolding interactions and BAR (Bin/amphyphysin/Rvs) domain mediated protein-lipid interactions. Of particular interest is the PDZ domain protein PICK1 (protein interacting with C kinase 1), whose scaffolding capacities show great potential for building organized, synthetic biological systems containing proteins that are studied in other labs within the center. 

Figure: Illustration of the scaffolding protein PICK1 binding the C-terminal tail of the dopamine transporter (blue) via the PDZ domain (green). The crescent shaped BAR domain (turquoise) serves to shape the membrane into high curvature to facilitate vesicle budding.

The work has both provided novel important insights into the cellular function of PICK1 and led to the identification of the first small molecule inhibitor of the PICK1 PDZ domain. The compound represents a possible lead in future development of therapeutics against neuropathic pain and stroke and, thus, the study strongly corroborate the potential of targeting intracellular protein-protein interactions in CNS-related diseases. 

Collaborations within the Center for Synthetic Biology
Dimitrios Stamou
Nikos Hatzakis
Lise Arleth
Karen Martinez
Björn Hamberger
Birger Lindberg Møller
Claus Løland
Ulrik Gether

CV

2013-present Associate professor, Molecular Neuropharmacology group. Department of Pharmacology and Neuroscience,  Faculty  of Health and Medical Sciences, University of Copenhagen
2010-2013 Post Doc, Molecular Neuropharmacology group, Department of Pharmacology and Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen. Fellowship from FSS
2008-2010 Post Doc, Molecular Neuropharmacology group, funded by KU Programme of Excellence in ‘Biomolecular scaffolding of neurotransmitter transporters and receptors’.
2005-2008

PhD thesis, Molecular Neuropharmacology group, Faculty of Health Sciences, University of Copenhagen

2002-2004 MSc in Biochemistry , Molecular Neuropharmacology Group, (thesis supervisor: Professor, M.D. Ulrik Gether).
1998-2001 BSc in Biochemistry, University of Copenhagen
1994-1997 BSc in Geography, University of Copenhagen

Publications

Erlendsson, S. and Madsen, K.L. Membrane binding and modulation of the PDZ domain of PICK1 Membranes 5(4), 597-615 doi:10.3390/membranes5040597 (2015) I.F. not available

Karlsen, M.L., Thorsen, T.S., Johner, N., Ammendrup-Johnsen, I., Erlendsson, S., Tian, X., Simonsen, J.B., Høiberg-Nielsen, R., Christensen, N.M., Khelashvili, G., Streicher, W., Teilum, K., Vestergaard, B., Weinstein, H., Gether, U., Arleth, L. and Madsen, K.L. Structure of Dimeric and Tetrameric Complexes of the BAR Domain Protein PICK1 Determined by Small-Angle X-Ray Scattering. Structure. 23(7):1258-70. doi:10.1016/j.str.2015.04.020 (2015)

Rathje, M., Fang, H., Bachman, J.L., Gether, U., Huganir, R.L., Madsen, K.L. Reply to Wilkinson et al.: Concerning the use of pHluorin-tagged GluA2 as a reporter for NMDA-induced AMPA receptor recycling. Proceedings of the National Academy of Sciences USA 111, E305-E305, doi:10.1073/pnas.1320452111 (2014)


Pinheiro, P. S, Jansen, A.M., de Wit, H., Tawfik, B., Madsen, K.L., Verhage, M., Gether, U., and Sorensen, J.B.The BAR Domain Protein PICK1 Controls Vesicle Number and Size in Adrenal Chromaffin Cells. Journal of Neuroscience 34, 10688-10700, doi:10.1523/jneurosci.5132-13.2014 (2014).

Holst, B., Madsen, K.L., Jansen, A.M., Jin, C., Rickhag, M., Lund, V.K., Jensen, M., Bhatia, V., Sorensen, G., Madsen, A.N. Xue, Z., Møller, S. K., Woldbye, D., Qvortrup, K., Huganir, R., Stamou, D., Kjaerulff, O., Gether, U. PICK1 Deficiency Impairs Secretory Vesicle Biogenesis and Leads to Growth Retardation and Decreased Glucose Tolerance. Plos Biology 11, doi:10.1371/journal.pbio.1001542 (2013).

Rickhag, M., Hansen, F.H., Sorensen, G., Strandfelt, K.N., Andresen, B., Gotfryd, K., Madsen, K.L., Klewe, I.V., Ammendrup-Johnsen, I., Eriksen, J., Newman, A. H., Fuechtbauer, E.-M., Gomeza, J.,Woldbye, D. P. D., Woertwein, G., Gether, U.A C-terminal PDZ domain-binding sequence is required for striatal distribution of the dopamine transporter (vol 4, pg 1580, 2013). Nature Communications 4, doi:10.1038/ncomms3589 (2013).

Madsen, K. L., Thorsen, T. S., Rahbek-Clemmensen, T., Eriksen, J. & Gether, U.  Protein Interacting with C Kinase 1 (PICK1) Reduces Reinsertion Rates of Interaction Partners Sorted to Rab11-dependent Slow Recycling Pathway.Journal of Biological Chemistry 287, 12293-12308, doi:10.1074/jbc.M111.294702 (2012).

Thorsen, T. S., Madsen, K. L., Rebola, N., Rathje, M., Anggono, V., Bach, A., Moreira, I. S., Stuhr-Hansen, N., Dyhring, T., Peters, D., Beuming, T., Huganir, R., Weinstein, H., Mulle, C., Strømgaard, K., Rønn, L. C. B. and Gether, U. Identification of a small-molecule inhibitor of the PICK1 PDZ domain that inhibits hippocampal LTP and LTD. Proceedings of the National Academy of Science of the United States of America 107(1), 413-418, doi:10.1073/pnas.0902225107, (2010).

Hatzakis, N. S., Bhatia, V.K., Larsen, J., Madsen, K.L., Bolinger, P.-Y., Kunding, A.H., Castillo, J., Gether, U., Hedegard, P., and Stamou, D. How curved membranes recruit amphipathic helices and protein anchoring motifs. Nature Chemical Biology 5, 835-841, doi:10.1038/nchembio.213 (2009).

Bhatia, V. K., Madsen, K.L., Bolinger, P.-Y., Kunding, A., Hedegard, P., Gether, U., and Stamou, D.Amphipathic motifs in BAR domains are essential for membrane curvature sensing. EMBO Journal 28, 3303-3314, doi:10.1038/emboj.2009.261 (2009).