Ubiquitylation and degradation of postsynaptic scaffold proteins

突触后支架蛋白的泛素化和降解

• 批准号: 45502901
• 负责人: Professor Dr. Hans-Jürgen Kreienkamp
• 金额: --
• 依托单位: Institut für Humangenetik
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2011-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/45502901?language=en
• 关键词: Ubiquitylation; degradation; postsynaptic; scaffold; proteins

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.

一系列的多域蛋白构成了哺乳动物大脑兴奋性突触中的突触后密度（PSD）的支架，包括小腿和SAPAP家族的不同成员。 PSD分子组成的变化对于突触发育和可塑性是基本的。神经元活性可导致泛素/蛋白酶体系统（UPS）（包括柄和SAPAP亚型）降解几种选定的PSD成分。使用体内刺激方案，我们打算分析突触后位点UPS活性的动力学和底物特异性。在细胞和体外测定中，我们将研究有助于柄和SAPAP家族成员的泛素化和蛋白酶体靶向的分子机制。在这种情况下，我们将特别关注Sharpin，Sharpin是通过不同基序与柄和泛素相互作用的蛋白质。在细胞中，小腿/夏普蛋白的相互作用通过蛋白酶体抑制稳定，表明小腿/夏普蛋白络合物会迅速降解。我们将研究Sharpin作为突触后蛋白的E3连接酶复合物的一部分，还是它在将泛素化底物靶向蛋白酶体中起作用。概述的研究将有助于揭示UPS在活动引起的突触调制中的作用，这可能有助于学习和记忆。