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Phosphorylation of tau at a single residue inhibits binding to the E3 ubiquitin ligase, CHIP

Author

Listed:
  • Cory M. Nadel

    (University of California San Francisco
    University of California San Francisco)

  • Saugat Pokhrel

    (University of California San Francisco
    University of California San Francisco)

  • Kristin Wucherer

    (University of California San Francisco)

  • Abby Oehler

    (University of California San Francisco)

  • Aye C. Thwin

    (University of California San Francisco
    University of California San Francisco)

  • Koli Basu

    (University of California San Francisco)

  • Matthew D. Callahan

    (University of California San Francisco
    University of California San Francisco)

  • Daniel R. Southworth

    (University of California San Francisco
    University of California San Francisco)

  • Daniel A. Mordes

    (University of California San Francisco
    University of California San Francisco)

  • Charles S. Craik

    (University of California San Francisco)

  • Jason E. Gestwicki

    (University of California San Francisco
    University of California San Francisco)

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 (CHIPD134A) 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.

Suggested Citation

  • Cory M. Nadel & Saugat Pokhrel & Kristin Wucherer & Abby Oehler & Aye C. Thwin & Koli Basu & Matthew D. Callahan & Daniel R. Southworth & Daniel A. Mordes & Charles S. Craik & Jason E. Gestwicki, 2024. "Phosphorylation of tau at a single residue inhibits binding to the E3 ubiquitin ligase, CHIP," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52075-1
    DOI: 10.1038/s41467-024-52075-1
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    References listed on IDEAS

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    1. Antonia Moll & Lisa Marie Ramirez & Momchil Ninov & Juliane Schwarz & Henning Urlaub & Markus Zweckstetter, 2022. "Hsp multichaperone complex buffers pathologically modified Tau," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Susmitha Ambadipudi & Jacek Biernat & Dietmar Riedel & Eckhard Mandelkow & Markus Zweckstetter, 2017. "Liquid–liquid phase separation of the microtubule-binding repeats of the Alzheimer-related protein Tau," Nature Communications, Nature, vol. 8(1), pages 1-13, December.
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