Cluster of Excellence –
University of Freiburg

Cover Story for Chemical Biology

New publication in ChemBioChem

Phosphatases are a class of signalling molecules that have important roles in health and disease. Progress in understanding the complex biological roles of phosphatases is hindered by the dearth of molecular tools to modulate their activity. Prof. Dr. Maja Köhn and her team in the Signalling Research Excellence Clusters BIOSS and CIBSS have combined their expertise in chemistry and biology to address this need for specific modulators of phosphatase activity. Their results are described in recent cover story in the journal ChemBioChem.

Reversible protein phosphorylation is a key way in which signals are relayed into and within the cell. Kinases add phosphate groups to proteins, and phosphatases remove them. Therefore, the output of many signalling pathways is determined by the balance between the activity of these enzymes. Variability in the catalytic sites of different kinases has enabled the development of many specific modulators of kinases, which are now well-established for use in research and in cancer therapy. In contrast, the highly similar catalytic site of phosphatases presents a challenge for the development of specific modulators of their activity. Hence, researchers currently have few means to dissect the function phosphatases in health and disease.

The group of Prof. Dr. Maja Köhn has pioneered a strategy to target phosphatases: instead of targeting their activity site, they synthesize peptides to target the interaction of phosphatases with their regulatory proteins. When this interaction is disrupted, the phosphatase is liberated and its activity unleashed. In their current study, the team has developed optimized peptides for specifically modulating the activity of the PP1 phosphatase. Prototypes of their peptide have already been shown to have a biological effect in samples from patients with heart failure.  The optimised version of the peptide, called PDP-Nal, is highly specific for PP1 and has enhanced stability. The authors used this peptide to dissect the role of PP1 in the MAP Kinase signalling pathway. Specifically, they found that the MEK enzyme in the MAP Kinase pathway is a direct substrate of PP1, whereas other players in the pathway are modulated indirectly by PP1. 

“We hope this strategy for targeting phosphatases will open up new possibilities for investigating the function of phosphatases, and possibly even targeting deregulated phosphatase activity in disease.” says Prof. Dr. Maja Köhn.

 

Original Publication:

Interrogating PP1 Activity in the MAPK Pathway with Optimized PP1‐Disrupting Peptides.
Wang Y, Hoermann B, Pavic K, Trebacz M, Rios P, Köhn M. (2018).
Chembiochem. 2019 Jan 2;20(1):66-71

https://onlinelibrary.wiley.com/doi/full/10.1002/cbic.201800541