ayout 1 - EMBL Grenoble

EMBL Research at a Glance 2009
Maja Köhn
PhD 2005 MPI for Molecular
Physiology, Dortmund.
Postdoctoral work at Harvard
University, Cambridge,
Massachusetts.
Group leader at EMBL since
2007.
Investigation of phosphatases using chemical
biology tools
Previous and current research
Protein dephosphorylation by protein phosphatases (PPs) is fundamental to a vast number of cellular
signalling processes and thus to physiological functions. Impairment of these processes contributes
to the development of human diseases such as cancer and diabetes. The investigation of
phosphatases is challenging, mainly due to their broad substrate specificity and the lack of tools
to selectively study particular phosphatases. Therefore, knowledge of phosphatase function and
substrate interaction is generally still quite limited. Our main interest is thus to control and investigate
phosphatases with the help of chemical tools, based on phosphoinositide and peptide
synthetic organic chemistry as well as protein semisynthesis, and also with molecular biology approaches.
We are currently focussing on protein tyrosine phosphatases (PTPs) and dual specificity
phosphatases (DSPs).
We are working on the design of inhibitors for PTPs based on chemical modification of protein/peptide
substrates in a way that they a) cannot be dephosphorylated and b) show an increased
half-life in the body. Thus, upon binding, the phosphatase cannot fulfil its function and is bound
to the modified substrate with natural high affinity. In this way, one does not have to rely on the
random discovery of effector molecules by, for example, exhaustive screening of large compound libraries. In addition, we are looking into
other possible natural substrates of phosphatases such as phosphoinositides. Working on new synthetic strategies to simplify access to these
compounds as well as their analogues is necessary in order to be able to control the function of lipid phosphatases in cells.
In case the substrate specificity of a PTP/DSP is not known, screening of focussed peptide libraries that are designed based on for example
structural data of the phosphatase is necessary. When applying the above described strategy, the discovery of artificial or even natural substrates
will lead to an inhibitor of the phosphatase of interest. Here, we are particularly interested in the PRL family of phosphatases, which
is involved in several types of cancer. In addition to creating effector molecules using synthetic organic chemistry, we also apply protein semisynthesis
and molecular biology approaches to obtain information about natural substrates, regulation and networks of these phosphatases.
Future projects and goals
We are interested in further developing chemical methods to stabilise (phospho-)peptides and in working on novel cell penetration concepts.
We are planning on modifying phosphatases semisynthetically in order to control their function, not through effector molecules but intrinsically.
Developing effector molecules for the highly non-specific PSTPs is a long-term goal. The activity of these phosphatases is controlled
not only by specificity, but also by cofactors and cellular localisation, which adds to the challenge of finding tools to selectively target these
phosphatases in the context of the cell.
Selected references
Jonkheijm, P., Weinrich, D., Köhn, M., Engelkamp, H., Christianen,
P.C., Kuhlmann, J., Maan, J.C., Nusse, D., Schroeder, H., Wacker,
R., Breinbauer, R., Niemeyer, C.M. & Waldmann, H. (2008).
Photochemical surface patterning by the thiol-ene reaction. Angew
Chem Int Ed Engl., 7, 21-2
Köhn, M., Gutierrez-Rodriguez, M., Jonkheijm, P., Wetzel, S.,
Wacker, R., Schroeder, H., Prinz, H., Niemeyer, C.M., Breinbauer, R.,
Szedlacsek, S.E. & Waldmann, H. (2007). A microarray strategy for
mapping the substrate specificity of protein tyrosine phosphatase.
Angew Chem Int Ed Engl., 6, 7700-7703
Watzke, A., Köhn, M., Gutierrez-Rodriguez, M., Wacker, R.,
Schroder, H., Breinbauer, R., Kuhlmann, J., Alexandrov, K.,
Niemeyer, C.M., Goody, R.S. & Waldmann, H. (2006). Site-selective
protein immobilization by Staudinger ligation. Angew Chem Int Ed
Engl., 5, 108-112
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