The amyloid precursor protein (APP) and its neurotoxic cleavage product Aβ are key players in the development of Alzheimer's disease and appear essential for neuronal development and cell homeostasis in mammals. Proteolytic processing of APP is influenced by metal ions, protein ligands and its oligomerization state. However, the structural basis and functional mechanism of APP regulation are hitherto largely unknown. Here we identified a metal-dependent molecular switch located within the E2 domain of APP containing four evolutionary highly conserved histidine residues. Three X-ray structures of the metal-bound molecule were solved at 2.6-2.0 Å resolution. Using protein crystallographic and biochemical methods, we characterized this novel high-affinity binding site within the E2 domain that binds competitively to copper and zinc at physiological concentrations. Metal-specific coordination spheres induce large conformational changes and enforce distinct structural states, most likely regulating the physiological function of APP and its processing in Alzheimer's disease.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.jmb.2011.12.057 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Glycation-induced oxidative stress underlies the numerous metabolic ravages of Alzheimer's disease (AD). Reduced glutathione levels in AD lead to increased oxidative stress, including glycation-induced pathology. Previously, we showed that the accumulation of reactive 1,2-dicarbonyls such as methylglyoxal, the major precursor of non-enzymatic glycation products, was reduced by the increased function of GSH-dependent glyoxalase-1 enzyme in the brain.
View Article and Find Full Text PDFAn approach to predict and inhibit Amyloid Beta dimerization pattern in Alzheimer's disease.
Toxicol Rep
June 2025
Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata, West Bengal 700054, India.
Alzheimer's Disease (AD) is one of the leading neurodegenerative diseases that affect the human population. Several hypotheses are in the pipeline to establish the commencement of this disease; however, the amyloid hypothesis is one of the most widely accepted ones. Amyloid plaques are rich in Amyloid Beta (Aβ) proteins, which are found in the brains of Alzheimer's patients.
View Article and Find Full Text PDFDiverse 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.
Int J Mol Sci
January 2025
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, 117997 Moscow, Russia.
Alzheimer's disease (AD) pathogenesis is correlated with the membrane content of various lipid species, including cholesterol, whose interactions with amyloid precursor protein (APP) have been extensively explored. Amyloid-β peptides triggering AD are products of APP cleavage by secretases, which differ depending on the APP and secretase location relative to ordered or disordered membrane microdomains. We used high-resolution NMR to probe the interactions of the cholesterol analog with APP transmembrane domain in two membrane-mimicking systems resembling ordered or perturbed lipid environments (bicelles/micelles).
View Article and Find Full Text PDFProduction of Amyloid-β in the Aβ-Protein-Precursor Proteolytic Pathway Is Discontinued or Severely Suppressed in Alzheimer's Disease-Affected Neurons: Contesting the 'Obvious'.
Genes (Basel)
January 2025
Division of Molecular Medicine, Children's Hospital, Boston, MA 02115, USA.
A notion of the continuous production of amyloid-β (Aβ) via the proteolysis of Aβ-protein-precursor (AβPP) in Alzheimer's disease (AD)-affected neurons constitutes both a cornerstone and an article of faith in the Alzheimer's research field. The present Perspective challenges this assumption. It analyses the relevant empirical data and reaches an unexpected conclusion, namely that in AD-afflicted neurons, the production of AβPP-derived Aβ is either discontinued or severely suppressed, a concept that, if proven, would fundamentally change our understanding of the disease.
View Article and Find Full Text PDFBeclin 1-Mediated Autophagy Is Potentiated by an Interaction with the Neuronal Adaptor FE65.
Biology (Basel)
January 2025
School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Hong Kong, China.
Autophagy is a vital cellular pathway in eukaryotic cells, including neurons, where it plays significant roles in neurodevelopment and maintenance. A crucial step in autophagy is the formation of the class III phosphatidylinositol 3-kinase complex 1 (PI3KC3-C1), which is essential for initiating autophagosome biogenesis. Beclin 1 is the key component of PI3KC3-C1, and its interactors have been reported to affect autophagy.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!