Phosphorylation of tau at a single residue inhibits binding to the E3 ubiquitin ligase, CHIP
Year: 2024
Type: article
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.
Source: Nature Communications
Institution: University of California, San Francisco
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,790
Awards: Frontotemporal Dementia: Genes, Images and Emotions, G1888650583, Probing the Role of Chaperone-TPR Complexes in Tau Proteostasis, G2648772700, New Approaches to Dementia Heterogeneity, G4770108118, G5298385048, Decoding the molecular logic of TPR cochaperones, G603598372, G6598791355, G6856438935, G7341112949, G7510529155, G8198605733, G8342502279, G898313041, G9000018678, G9000029343, G9000036492, G9000052518, G9000107808
OpenAlex ID: W4402496537