PXD052540-1

PXD052540 is an original dataset announced via ProteomeXchange.

Title	Analysis of tauC3 PTMs following in vitro ubiquitination
Description	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 focused 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 revealed the mechanism of this clash and allowed 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.
HostingRepository	PRIDE
AnnounceDate	2025-01-18
AnnouncementXML	Submission_2025-01-17_19:32:08.862.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Matthew Callahan
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	ubiquitination signature dipeptidyl lysine; phosphorylated residue
Instrument	Orbitrap Fusion Lumos; Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2024-05-23 18:58:06	ID requested
⏵ 1	2025-01-17 19:32:09	announced

10.1038/s41467-024-52075-1;

Nadel CM, Pokhrel S, Wucherer K, Oehler A, Thwin AC, Basu K, Callahan MD, Southworth DR, Mordes DA, Craik CS, Gestwicki JE, Phosphorylation of tau at a single residue inhibits binding to the E3 ubiquitin ligase, CHIP. Nat Commun, 15(1):7972(2024) [pubmed]

submitter keyword: Ubiquitination,Tau, Phosphorylation

Jason Gestwicki
contact affiliation	UCSF IND
contact email	jason.gestwicki@ucsf.edu
lab head
Matthew Callahan
contact affiliation	UCSF
contact email	mattdcallahan@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD052540
     1. Label: PRIDE project
     2. Name: Analysis of tauC3 PTMs following in vitro ubiquitination