8FYU

Crystal structure of the human CHIP-TPR domain in complex with a 10mer acetylated tau peptide

8FYU の概要

• エントリーDOI: 10.2210/pdb8fyu/pdb
• 分子名称: E3 ubiquitin-protein ligase CHIP, ACE-SER-SER-THR-GLY-SER-ILE-ASP-MET-VAL-ASP (3 entities in total)
• 機能のキーワード: e3 ligase, ligand, tpr domain, ligase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 31353.56

構造登録者

Wucherer, K.,Bohn, M.F.,Basu, K.,Nadel, C.M.,Gestwicki, J.E.,Craik, C.S. (登録日: 2023-01-26, 公開日: 2023-08-30, 最終更新日: 2024-10-16)

主引用文献

Nadel, C.M.,Pokhrel, S.,Wucherer, K.,Oehler, A.,Thwin, A.C.,Basu, K.,Callahan, M.D.,Southworth, D.R.,Mordes, D.A.,Craik, C.S.,Gestwicki, J.E.
Phosphorylation of tau at a single residue inhibits binding to the E3 ubiquitin ligase, CHIP.
Nat Commun, 15:7972-7972, 2024

PubMed Abstract: 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.

PubMed: 39266525
DOI: 10.1038/s41467-024-52075-1

実験手法

X-RAY DIFFRACTION (1.84839139202 Å)