Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, 94158, USA.
Institute for Neurodegenerative Diseases, University of California San Francisco, San Francisco, CA, 94158, USA.
Nat Commun. 2024 Sep 12;15(1):7972. doi: 10.1038/s41467-024-52075-1.
Microtubule-associated protein tau (MAPT/tau) accumulates in a family of neurodegenerative diseases, including Alzheimer's disease (AD). In disease, tau is aberrantly modified by post-translational modifications (PTMs), including hyper-phosphorylation. However, it is often unclear which of these PTMs contribute to tau's accumulation or what mechanisms might be involved. To explore these questions, we focus on a cleaved proteoform of tau (tauC3), which selectively accumulates in AD and was recently shown to be degraded by its direct binding to the E3 ubiquitin ligase, CHIP. Here, we find that phosphorylation of tauC3 at a single residue, pS416, is sufficient to weaken its interaction with CHIP. A co-crystal structure of CHIP bound to the C-terminus of tauC3 reveals the mechanism of this clash, allowing design of a mutation (CHIP) that partially restores binding and turnover of pS416 tauC3. We confirm that, in our models, pS416 is produced by the known AD-associated kinase, MARK2/Par-1b, providing a potential link to disease. In further support of this idea, an antibody against pS416 co-localizes with tauC3 in degenerative neurons within the hippocampus of AD patients. Together, these studies suggest a molecular mechanism for how phosphorylation at a discrete site contributes to accumulation of a tau proteoform.
微管相关蛋白 tau（MAPT/tau）在包括阿尔茨海默病（AD）在内的一系列神经退行性疾病中积累。在疾病中，tau 通过翻译后修饰（PTMs）异常修饰，包括过度磷酸化。然而，通常不清楚这些 PTMs 中哪些导致 tau 的积累，或者可能涉及哪些机制。为了探讨这些问题，我们专注于 tau 的一种切割蛋白形式（tauC3），它选择性地在 AD 中积累，并最近被证明可通过其与 E3 泛素连接酶 CHIP 的直接结合而降解。在这里，我们发现 tauC3 上单个残基的磷酸化（pS416）足以削弱其与 CHIP 的相互作用。CHIP 与 tauC3 C 端结合的共结晶结构揭示了这种冲突的机制，从而可以设计一种突变（CHIP），部分恢复 pS416 tauC3 的结合和周转。我们证实，在我们的模型中，pS416 是由已知的与 AD 相关的激酶 MARK2/Par-1b 产生的，这为疾病提供了一个潜在的联系。进一步支持这一观点的是，针对 pS416 的抗体与 AD 患者海马体中变性神经元中的 tauC3 共定位。总之，这些研究为特定位点磷酸化如何导致 tau 蛋白形式积累提供了一个分子机制。
