ArticleBiochemistry2008
Structural studies of the transmembrane C-terminal domain of the amyloid precursor protein (APP): does APP function as a cholesterol sensor?
Article in Biochemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 104 papers.
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Who cites it
104 citing papers in PubMed, 175 citations in OpenAlex.
- Accurate determination of the preferred aggregation number of a micelle-encapsulated membrane protein dimer.Biophysical journal · 2026Article
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- Accurate determination of the preferred aggregation number of a micelle-encapsulated membrane protein dimer.bioRxiv : the preprint server for biology · 2025Article
- Transient cholesterol interactions with the amyloid precursor protein involved in Alzheimer's disease pathogenesis.Biophysical reviews · 2025Review
- Detergent-free isolation and characterization of amyloid precursor protein C99 in E. coli native lipid-nanodiscs using non-ionic polymer.Protein science : a publication of the Protein Society · 2025Article
- The complex web of membrane contact sites in brain aging and neurodegeneration.Cellular and molecular life sciences : CMLS · 2025Review
- The Lassa Virus Stable Signal Peptide Undergoes a Conformational Change to Aid Viral Fusion.Chemistry (Weinheim an der Bergstrasse, Germany) · 2025Article
- Diverse Interactions of Sterols with Amyloid Precursor Protein Transmembrane Domain Can Shift Distribution Between Alternative Amyloid-β Production Cascades in Manner Dependent on Local Lipid Environment.International journal of molecular sciences · 2025Article
- Cholesterol and Lipid Rafts in the Biogenesis of Amyloid-β Protein and Alzheimer's Disease.Annual review of biophysics · 2024Review
- Towards a Unitary Hypothesis of Alzheimer's Disease Pathogenesis.Journal of Alzheimer's disease : JAD · 2024Article
- Cholesterol-dependent amyloid β production: space for multifarious interactions between amyloid precursor protein, secretases, and cholesterol.Cell & bioscience · 2023Review
- Amyloid Precursor Protein Changes Arrangement in a Membrane and Its Structure Depending on the Cholesterol Content.Membranes · 2023Article
- Sulfotransferase 2B1b, Sterol Sulfonation, and Disease.Pharmacological reviews · 2023Review
- The Binding of Different Substrate Molecules at the Docking Site and the Active Site of γ-Secretase Can Trigger Toxic Events in Sporadic and Familial Alzheimer's Disease.International journal of molecular sciences · 2023Article
- Flavonoids and fibrate modulate apoE4-induced processing of amyloid precursor protein in neuroblastoma cells.Frontiers in neuroscience · 2023Article
- Formation of extramembraneProceedings of the National Academy of Sciences of the United States of America · 2022Article
- Specific Mutations in the Cholesterol-Binding Site of APP Alter Its Processing and Favor the Production of Shorter, Less Toxic Aβ Peptides.Molecular neurobiology · 2022Article
- Structural Determinant of β-Amyloid Formation: From Transmembrane Protein Dimerization to β-Amyloid Aggregates.Biomedicines · 2022Review
- Transient lipid-bound states of spike protein heptad repeats provide insights into SARS-CoV-2 membrane fusion.Science advances · 2021Article
- APOE4-carrying human astrocytes oversupply cholesterol to promote neuronal lipid raft expansion and Aβ generation.Stem cell reports · 2021Article
44 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
The amyloid precursor protein (APP) is subject to alternative pathways of proteolytic processing, leading either to production of the amyloid-beta (Abeta) peptides or to non-amyloidogenic fragments. Here, we report the first structural study of C99, the 99-residue transmembrane C-terminal domain of APP liberated by beta-secretase cleavage. We also show that cholesterol, an agent that promotes the amyloidogenic pathway, specifically binds to this protein. C99 was purified into model membranes where it was observed to homodimerize. NMR data show that the transmembrane domain of C99 is an alpha-helix that is flanked on both sides by mostly disordered extramembrane domains, with two exceptions. First, there is a short extracellular surface-associated helix located just after the site of alpha-secretase cleavage that helps to organize the connecting loop to the transmembrane domain, which is known to be essential for Abeta production. Second, there is a surface-associated helix located at the cytosolic C-terminus, adjacent to the YENPTY motif that plays critical roles in APP trafficking and protein-protein interactions. Cholesterol was seen to participate in saturable interactions with C99 that are centered at the critical loop connecting the extracellular helix to the transmembrane domain. Binding of cholesterol to C99 and, most likely, to APP may be critical for the trafficking of these proteins to cholesterol-rich membrane domains, which leads to cleavage by beta- and gamma-secretase and resulting amyloid-beta production. It is proposed that APP may serve as a cellular cholesterol sensor that is linked to mechanisms for suppressing cellular cholesterol uptake.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.