E3 泛素连接酶 CHIP/STUB1 抑制微管相关蛋白 Tau（MAPT）磷酸化蛋白构象的聚集。

The E3 Ubiquitin Ligase, CHIP/STUB1, Inhibits Aggregation of Phosphorylated Proteoforms of Microtubule-associated Protein Tau (MAPT).

机构信息

Departments of Pharmaceutical Chemistry and University of California San Francisco, San Francisco, CA 94508, USA; Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, CA 94508, USA.

Biochemistry & Biophysics and the University of California San Francisco, San Francisco, CA 94508, USA; Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, CA 94508, USA.

出版信息

J Mol Biol. 2023 Jun 1;435(11):168026. doi: 10.1016/j.jmb.2023.168026. Epub 2023 Jun 16.

DOI:10.1016/j.jmb.2023.168026

PMID:37330289

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10491737/

Abstract

Hyper-phosphorylated tau accumulates as insoluble fibrils in Alzheimer's disease (AD) and related dementias. The strong correlation between phosphorylated tau and disease has led to an interest in understanding how cellular factors discriminate it from normal tau. Here, we screen a panel of chaperones containing tetratricopeptide repeat (TPR) domains to identify those that might selectively interact with phosphorylated tau. We find that the E3 ubiquitin ligase, CHIP/STUB1, binds 10-fold more strongly to phosphorylated tau than unmodified tau. The presence of even sub-stoichiometric concentrations of CHIP strongly suppresses aggregation and seeding of phosphorylated tau. We also find that CHIP promotes rapid ubiquitination of phosphorylated tau, but not unmodified tau, in vitro. Binding to phosphorylated tau requires CHIP's TPR domain, but the binding mode is partially distinct from the canonical one. In cells, CHIP restricts seeding by phosphorylated tau, suggesting that it could be an important barrier in cell-to-cell spreading. Together, these findings show that CHIP recognizes a phosphorylation-dependent degron on tau, establishing a pathway for regulating the solubility and turnover of this pathological proteoform.

摘要

过度磷酸化的 tau 蛋白在阿尔茨海默病（AD）和相关痴呆症中积累为不溶性纤维。磷酸化 tau 与疾病之间的强相关性促使人们产生了理解细胞因子如何将其与正常 tau 区分开来的兴趣。在这里，我们筛选了一组包含四肽重复（TPR）结构域的伴侣蛋白，以鉴定那些可能与磷酸化 tau 选择性相互作用的伴侣蛋白。我们发现，E3 泛素连接酶 CHIP/STUB1 与磷酸化 tau 的结合强度比未修饰的 tau 强 10 倍。即使存在亚化学计量浓度的 CHIP，也能强烈抑制磷酸化 tau 的聚集和种子形成。我们还发现，CHIP 在体外能促进磷酸化 tau 的快速泛素化，但不能促进未修饰 tau 的泛素化。与磷酸化 tau 的结合需要 CHIP 的 TPR 结构域，但结合模式与经典模式部分不同。在细胞中，CHIP 限制了磷酸化 tau 的种子形成，这表明它可能是细胞间传播的重要障碍。总之，这些发现表明 CHIP 识别 tau 上依赖于磷酸化的降解基序，为调节这种病理蛋白形式的可溶性和周转率建立了一种途径。