2. Academic Validation
  3. 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)

  • J Mol Biol. 2023 Jun 1;435(11):168026. doi: 10.1016/j.jmb.2023.168026.
Cory M Nadel 1,  Aye C Thwin 2,  Matthew Callahan 1,  Kanghyun Lee 2,  Emily Connelly 3,  Charles S Craik 3,  Daniel R Southworth 4,  Jason E Gestwicki 5
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Departments of Pharmaceutical Chemistry and University of California San Francisco, San Francisco, CA 94508, USA.
  • 4 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. Electronic address: daniel.southworth@ucsf.edu.
  • 5 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. Electronic address: jason.gestwicki@ucsf.edu.
PMID: 37330289 DOI: 10.1016/j.jmb.2023.168026
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.

Keywords

intrinsically disordered protein; phospho-degrons; protein aggregation; protein–protein interactions; tauopathy.

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