Ubiquitylation and degradation of postsynaptic scaffold proteins

• Applicant: Professor Dr. Hans-Jürgen Kreienkamp
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: from 2007 to 2012
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 35615435

A series of multi-domain proteins constitute the scaffold of the postsynaptic density (PSD) in excitatory synapses of the mammalian brain, including different members of the Shank and SAPAP families. Changes in the molecular composition of the PSD are fundamental to synaptic development and plasticity. Neuronal activity induces degradation of several selected PSD components by the ubiquitin/proteasome system (UPS), including Shank and SAPAP subtypes. Using in vivo stimulation protocols, we intend to analyze the kinetics and substrate specificity of UPS activity at the postsynaptic site. In cellular and in vitro assays, we will investigate the molecular mechanisms contributing to ubiquitylation and proteasomal targeting of Shank and SAPAP family members. In this context, we will particularly focus on sharpin, a protein that interacts with both Shank and ubiquitin through different motifs. In cells, the Shank/sharpin interaction is stabilized by proteasome inhibition, indicating that Shank/sharpin complexes are subject to rapid degradation. We will investigate whether sharpin acts as part of an E3 ligase complex for postsynaptic proteins, or if it plays a role in targeting ubiquitylated substrates to proteasomes. The outlined research will help to unravel the role of the UPS in activity-induced modulation of the synapse, which may contribute to learning and memory.

• DFG Programme: Research Units
• Subproject of: FOR 885: Neuronal Protein Turnover
• Participating Person: Professor Dr. Stefan Kindler