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.

一系列多结构域蛋白质构成了哺乳动物脑兴奋性突触中突触后密度（postsynaptic density，PSD）的骨架，包括Shank和SAPAP家族的不同成员。PSD分子组成的变化是突触发育和可塑性的基础。神经元活性通过泛素/蛋白酶体系统（UPS）诱导几种选定的PSD组分降解，包括Shank和SAPAP亚型。使用在体内的刺激协议，我们打算分析的动力学和底物特异性的UPS活动在突触后的网站。在细胞和体外试验中，我们将研究促进Shank和SAPAP家族成员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，一种通过不同基序与Shank和泛素相互作用的蛋白质。在细胞中，通过蛋白酶体抑制稳定Shank/sharpin相互作用，表明Shank/sharpin复合物易于快速降解。我们将研究sharpin是否作为突触后蛋白的E3连接酶复合物的一部分，或者它是否在靶向蛋白酶体的泛素化底物中起作用。概述的研究将有助于揭示UPS在活动诱导的突触调制中的作用，这可能有助于学习和记忆。