The E3 Ubiquitin Ligase, CHIP/STUB1, Inhibits Aggregation of Phosphorylated Proteoforms of Microtubule-associated Protein Tau (MAPT).
The E3 Ubiquitin Ligase, CHIP/STUB1, Inhibits Aggregation of Phosphorylated Proteoforms of Microtubule-associated Protein Tau (MAPT).
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DOI：
10.1016/j.jmb.2023.168026
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发表时间：
2023-06-01
影响因子：
5.6
通讯作者：
Gestwicki, Jason E.
中科院分区：
文献类型：
--
作者：
Nadel, Cory M.;Thwin, Aye C.;Callahan, Matthew;Lee, Kanghyun;Connelly, Emily;Craik, Charles S.;Southworth, Daniel R.;Gestwicki, Jason E.
关键词：
在阿尔茨海默病(AD)和相关的痴呆症中，过度磷酸化的tau以不溶性纤维的形式积累。磷酸化的tau与疾病之间的强烈相关性引起了人们对了解细胞因素如何将其与正常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，以确定那些可能与磷酸化tau选择性相互作用的蛋白。我们发现，E3泛素连接酶CHIP/STUB1与磷酸化的tau的结合强度是未经修饰的tau的10倍。甚至亚化学计量浓度的CHIP的存在强烈地抑制了磷酸化tau的聚集和播种。我们还发现，在体外，CHIP促进了磷酸化的tau的快速泛素化，但不能促进未修饰的tau的泛素化。与磷酸化tau的结合需要CHIP的TPR结构域，但结合模式与典型模式部分不同。在细胞中，CHIP通过磷酸化tau来限制播种，这表明它可能是细胞间传播的重要障碍。综上所述，这些发现表明，CHIP识别tau上的磷酸化依赖的降解，建立了一条调节这种病理性蛋白形式的溶解和周转的途径。
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.
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影响因子：
16.6
作者：
Moll, Antonia;Ramirez, Lisa Marie;Ninov, Momchil;Schwarz, Juliane;Urlaub, Henning;Zweckstetter, Markus
通讯作者：
Zweckstetter, Markus
影响因子：
3.5
作者：
Fontaine, Sarah N.;Martin, Mackenzie D.;Dickey, Chad A.
通讯作者：
Dickey, Chad A.
影响因子：
16.2
作者：
BRAMBLETT, GT;GOEDERT, M;LEE, VMY
通讯作者：
LEE, VMY
影响因子：
5.8
作者：
Omasits, Ulrich;Ahrens, Christian H.;Wollscheid, Bernd
通讯作者：
Wollscheid, Bernd
影响因子：
3.5
作者：
Petrucelli, L;Dickson, D;Hutton, M
通讯作者：
Hutton, M