Amyloid precursor protein (APP) may act as a substrate and a recognition unit for CRL4CRBNand stub1 E3 ligases facilitating ubiquitination of proteins involved in presynaptic functions and neurodegeneration

Dolores Del Prete, Richard C. Rice, Anjali M. Rajadhyaksha, Luciano D'Adamio

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

The amyloid precursor protein (APP), whose mutations cause Alzheimer disease, plays an important in vivo role and facilitates transmitter release. Because the APP cytosolic region (ACR) is essential for these functions, we have characterized its brain interactome. We found that the ACR interacts with proteins that regulate the ubiquitin-proteasome system, predominantly with the E3 ubiquitin-protein ligases Stub1, which binds the NH2 terminus of the ACR, and CRL4CRBN , which is formed by Cul4a/b, Ddb1, and Crbn, and interacts with the COOH terminus of the ACR via Crbn. APP shares essential functions with APP-like protein-2 (APLP2) but not APP-like protein-1 (APLP1). Noteworthy, APLP2, but not APLP1, interacts with Stub1 and CRL4CRBN , pointing to a functional pathway shared only by APP and APLP2. In vitro ubiquitination/ubiquitome analysis indicates that these E3 ligases are enzymatically active and ubiquitinate the ACR residues Lys649/650/651/676/688 . Deletion of Crbn reduces ubiquitination of Lys676 suggesting that Lys676 is physiologically ubiquitinated by CRL4CRBN . The ACR facilitated in vitro ubiquitination of presynaptic proteins that regulate exocytosis, suggesting a mechanism by which APP tunes transmitter release. Other dementia-related proteins, namely Tau and apoE, interact with and are ubiquitinated via the ACR in vitro. This, and the evidence that CRBN and CUL4B are linked to intellectual disability, prompts us to hypothesize a pathogenic mechanism, in which APP acts as a modulator of E3 ubiquitin-protein ligase(s), shared by distinct neuronal disorders. The well described accumulation of ubiquitinated protein inclusions in neurodegenerative diseases and the link between the ubiquitin-proteasome system and neurodegeneration make this concept plausible.

Original languageEnglish (US)
Pages (from-to)17209-17227
Number of pages19
JournalJournal of Biological Chemistry
Volume291
Issue number33
DOIs
StatePublished - Aug 12 2016

ASJC Scopus subject areas

  • Biochemistry
  • Medicine(all)
  • Molecular Biology
  • Cell Biology

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