ArticleThe Journal of biological chemistry2009
APH1 polar transmembrane residues regulate the assembly and activity of presenilin complexes.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 34 citations in OpenAlex.
- GPCR kinases generate an APH1A phosphorylation barcode to regulate amyloid-β generation.Cell reports · 2022Article
- Exploring the Role of PSEN Mutations in the Pathogenesis of Alzheimer's Disease.Neurotoxicity research · 2020Review
- The dark side of Alzheimer's disease: unstructured biology of proteins from the amyloid cascade signaling pathway.Cellular and molecular life sciences : CMLS · 2020Article
- Review
- Presenilins as Drug Targets for Alzheimer's Disease-Recent Insights from Cell Biology and Electrophysiology as Novel Opportunities in Drug Development.International journal of molecular sciences · 2018Review
- Structural and Chemical Biology of Presenilin Complexes.Cold Spring Harbor perspectives in medicine · 2017Review
- An atomic structure of human γ-secretase.Nature · 2015Article
- Structural biology of presenilin 1 complexes.Molecular neurodegeneration · 2014Review
- Pen-2 is essential for γ-secretase complex stability and trafficking but partially dispensable for endoproteolysis.Biochemistry · 2014Article
- The γ-secretase complex: from structure to function.Frontiers in cellular neuroscience · 2014Review
- The very many faces of presenilins and the γ-secretase complex.Protoplasma · 2013Review
- Cellular mechanisms of γ-secretase substrate selection, processing and toxicity.Progress in neurobiology · 2012Review
- Modification of γ-secretase by nitrosative stress links neuronal ageing to sporadic Alzheimer's disease.EMBO molecular medicine · 2012Article
- Specific domains in anterior pharynx-defective 1 determine its intramembrane interactions with nicastrin and presenilin.Neurobiology of aging · 2012Article
- Presenilins and γ-secretase: structure, function, and role in Alzheimer Disease.Cold Spring Harbor perspectives in medicine · 2012Review
- Phosphorylation of nicastrin by SGK1 leads to its degradation through lysosomal and proteasomal pathways.PloS one · 2012Article
- Polar transmembrane-based amino acids in presenilin 1 are involved in endoplasmic reticulum localization, Pen2 protein binding, and γ-secretase complex stabilization.The Journal of biological chemistry · 2011Article
- Aph-1 associates directly with full-length and C-terminal fragments of gamma-secretase substrates.The Journal of biological chemistry · 2010Article
Corrections and comments
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Authors and funding
13 authors at 7 institutions in 4 countries.
Funding
Abstract
Complexes involved in the gamma/epsilon-secretase-regulated intramembranous proteolysis of substrates such as the amyloid-beta precursor protein are composed primarily of presenilin (PS1 or PS2), nicastrin, anterior pharynx defective-1 (APH1), and PEN2. The presenilin aspartyl residues form the catalytic site, and similar potentially functional polar transmembrane residues in APH1 have been identified. Substitution of charged (E84A, R87A) or polar (Q83A) residues in TM3 had no effect on complex assembly or activity. In contrast, changes to either of two highly conserved histidines (H171A, H197A) located in TM5 and TM6 negatively affected PS1 cleavage and altered binding to other secretase components, resulting in decreased amyloid generating activity. Charge replacement with His-to-Lys substitutions rescued nicastrin maturation and PS1 endoproteolysis leading to assembly of the formation of structurally normal but proteolytically inactive gamma-secretase complexes. Substitution with a negatively charged side chain (His-to-Asp) or altering the structural location of the histidines also disrupted gamma-secretase binding and abolished functionality of APH1. These results suggest that the conserved transmembrane histidine residues contribute to APH1 function and can affect presenilin catalytic activity.
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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.