Charakterisierung der Sumoylierung von p35, dem Aktivator der Zyklin-abhängigen Kinase 5 (Cdk5), und der daraus resultierenden funktionellen Konsequenz

Characterisation of the sumoylation of p35, an activator of the cyclin-dependent kinase 5 (Cdk5), and the resulting functional consequence

von Anja Büchner
Dissertation
Datum der mündl. Prüfung:2013-04-29
Erschienen:2013-05-28
Betreuer:Prof. Dr. Mathias Bähr
Gutachter:Prof. Dr. Mathias Bähr
Gutachter:Prof. Dr. Sigrid Hoyer-Fender
Zum Verlinken/Zitieren: http://dx.doi.org/10.53846/goediss-3866

 

 

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For the central nervous system development and neuron-specific functions, including neurite outgrowth as well as synaptic function and plasticity, cyclin-dependent kinase (Cdk) 5 has a central role. Cdk5 activity requires binding to the neuron-specific activator p35. p35 redistribution as well as misregulation of Cdk5 activity is followed by cell death in several models of neurodegeneration. SUMO (small ubiquitin related modifier) regulates protein/protein interactions. We demonstrated a covalently binding of SUMO2 to p35 in cells using both biochemical and FRET/FLIM-based approaches. We also identified the two major SUMO acceptor lysines in p35. Different degrees of oxidative stress resulted in differential p35 sumoylation levels. A change in p35 sumoylation could be a direct link between oxidative stress, altered activity of Cdk5 and neurodegenerative diseases. Functionally, sumoylation of p35 does not interfere with the binding to Cdk5, but increased the activity of the p35/Cdk5 complex. This resulted in nucleocytoplasmic translocation of p35. In this thesis we identified p35 as a novel neuronal SUMO target. The sumoylation of p35 provides a regulatory mechanism for the rapid modulation of p35/Cdk5 localisation and activity in physiological situations as well as in diseases. Therefore, through the sumoylation of p35, we identified a novel activity-dependent way, which is controlled by sumoylation and induced subcellular localisation of proteins.
Keywords: sumoylation
 
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