ArticleThe EMBO journal2004
The presenilin C-terminus is required for ER-retention, nicastrin-binding and gamma-secretase activity.
Article in The EMBO journal, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 98 citations in OpenAlex.
- The manipulator behind "Scissors": γ -secretase and its modulators in Alzheimer's disease.Frontiers in aging neuroscience · 2025Review
- Visualization of PS/γ-Secretase Activity in Living Cells.iScience · 2020Article
- Presenilin 1 and Presenilin 2 Target γ-Secretase Complexes to Distinct Cellular Compartments.The Journal of biological chemistry · 2016Article
- Suppressor Mutations for Presenilin 1 Familial Alzheimer Disease Mutants Modulate γ-Secretase Activities.The Journal of biological chemistry · 2016Article
- G206D Mutation of Presenilin-1 Reduces Pen2 Interaction, Increases Aβ42/Aβ40 Ratio and Elevates ER Ca(2+) Accumulation.Molecular neurobiology · 2015Article
- The topology of pen-2, a γ-secretase subunit, revisited: evidence for a reentrant loop and a single pass transmembrane domain.Molecular neurodegeneration · 2015Article
- Structural basis of human γ-secretase assembly.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- Cooperative roles of hydrophilic loop 1 and the C-terminus of presenilin 1 in the substrate-gating mechanism of γ-secretase.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2015Article
- Three-dimensional structure of human γ-secretase.Nature · 2014Article
- Gamma-secretase subunits associate in intracellular membrane compartments in Arabidopsis thaliana.Journal of experimental botany · 2014Article
- The γ-secretase complex: from structure to function.Frontiers in cellular neuroscience · 2014Review
- Toward the structure of presenilin/γ-secretase and presenilin homologs.Biochimica et biophysica acta · 2013Review
- The very many faces of presenilins and the γ-secretase complex.Protoplasma · 2013Review
- Biological function of Presenilin and its role in AD pathogenesis.Translational neurodegeneration · 2013Article
- Structural biology of presenilins and signal peptide peptidases.The Journal of biological chemistry · 2013Review
- Auxiliary KChIP4a suppresses A-type K+ current through endoplasmic reticulum (ER) retention and promoting closed-state inactivation of Kv4 channels.The Journal of biological chemistry · 2013Article
- Protein quality control by Rer1p in the early secretory pathway: from mechanism to implication in Alzheimer's disease.Alzheimer's research & therapy · 2013Review
- Functional and genetic analysis of haplotypic sequence variation at the nicastrin genomic locus.Neurobiology of aging · 2012Article
- Contribution of the γ-secretase subunits to the formation of catalytic pore of presenilin 1 protein.The Journal of biological chemistry · 2012Article
- The α-helical content of the transmembrane domain of the British dementia protein-2 (Bri2) determines its processing by signal peptide peptidase-like 2b (SPPL2b).The Journal of biological chemistry · 2012Article
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
gamma-Secretase is an intramembrane cleaving protease involved in Alzheimer's disease. gamma-Secretase occurs as a high molecular weight complex composed of presenilin (PS1/2), nicastrin (NCT), anterior pharynx-defective phenotype 1 and PS enhancer 2. Little is known about the cellular mechanisms of gamma-secretase assembly. Here we demonstrate that the cytoplasmic tail of PS1 fulfills several functions required for complex formation, retention of unincorporated PS1 and gamma-secretase activity. The very C-terminus interacts with the transmembrane domain of NCT and may penetrate into the membrane. Deletion of the last amino acid is sufficient to completely block gamma-secretase assembly and release of PS1 from the endoplasmic reticulum (ER). This suggests that unincorporated PS1 is actively retained within the ER. We identified a hydrophobic stretch of amino acids within the cytoplasmic tail of PS1 distinct from the NCT-binding site, which is required to retain unincorporated PS1 within the ER. Deletion of the retention signal results in the release of PS1 from the ER and the assembly of a nonfunctional gamma-secretase complex, suggesting that at least a part of the retention motif may also be required for the function of PS1.
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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.