ArticleThe Journal of biological chemistry2016
Amyloid Precursor Protein (APP) May Act as a Substrate and a Recognition Unit for CRL4CRBN and Stub1 E3 Ligases Facilitating Ubiquitination of Proteins Involved in Presynaptic Functions and Neurodegeneration.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 81 citations in OpenAlex.
- Safety considerations for cereblon-recruiting targeted protein degraders.Nature reviews. Drug discovery · 2026Review
- Amyloid Precursor Protein Processing Links Female Urgency Urinary Incontinence with Alzheimer's Disease: Implications for Treatment.International journal of molecular sciences · 2026Article
- PCMT1 generates the C-terminal cyclic imide degron on CRBN substrates.Nature chemical biology · 2026Article
- E3 ubiquitin ligases in neurodegenerative diseases.Military Medical Research · 2026Review
- Methylomic signatures of tau and amyloid-beta in transgenic mouse models of Alzheimer's disease neuropathology.NPJ dementia · 2026Article
- Mining Alzheimer's Interactomes, Macromolecular Complexes and Pathways for Drug Discovery.Proteomics · 2025Review
- Amyloid-β protein precursor modulates mitophagy and mitochondrial function through its cellular localization.Journal of Alzheimer's disease : JAD · 2025Article
- Negative interplay between HIV-1 Gag and amyloid precursor protein centers around competition for VPS4A and TSG101.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Unraveling the Roles of UBE3A in Neurodevelopment and Neurodegeneration.International journal of molecular sciences · 2025Review
- The reciprocal relationship between amyloid precursor protein and mitochondrial function.Journal of neurochemistry · 2024Review
- Pirh2 modulates the mitochondrial function and cytochrome c-mediated neuronal death during Alzheimer's disease.Cell death & disease · 2024Article
- The Involvement of Post-Translational Modifications in Regulating the Development and Progression of Alzheimer's Disease.Molecular neurobiology · 2023Review
- Interactions between amyloid, amyloid precursor protein, and mitochondria.Biochemical Society transactions · 2023Article
- Amyloid precursor protein and mitochondria.Current opinion in neurobiology · 2023Review
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- Arc Regulates Transcription of Genes for Plasticity, Excitability and Alzheimer's Disease.Biomedicines · 2022Article
- SimPLIT: Simplified Sample Preparation for Large-Scale Isobaric Tagging Proteomics.Journal of proteome research · 2022Article
- The amyloid precursor protein: a converging point in Alzheimer's disease.Molecular neurobiology · 2022Review
- Review
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
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 CRL4(CRBN), 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 CRL4(CRBN), 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 Lys(649/650/651/676/688) Deletion of Crbn reduces ubiquitination of Lys(676) suggesting that Lys(676) is physiologically ubiquitinated by CRL4(CRBN) 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.
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