ArticleThe Journal of biological chemistry2009
Glu-333 of nicastrin directly participates in gamma-secretase activity.
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 37 papers.
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Who cites it
37 citing papers in PubMed, 65 citations in OpenAlex.
- The manipulator behind "Scissors": γ -secretase and its modulators in Alzheimer's disease.Frontiers in aging neuroscience · 2025Review
- Notch signaling without the APH-2/nicastrin subunit of gamma secretase in Caenorhabditis elegans germline stem cells.Genetics · 2024Article
- The critical role of γ-secretase and its inhibitors in cancer and cancer therapeutics.International journal of biological sciences · 2023Review
- The Genomic Architecture of Hidradenitis Suppurativa-A Systematic Review.Frontiers in genetics · 2022Review
- Nicastrin-Like, a Novel Transmembrane Protein fromMicroorganisms · 2021Article
- Review
- Allosteric Modulation of Intact γ-Secretase Structural Dynamics.Biophysical journal · 2017Article
- High-efficient production and biophysical characterisation of nicastrin and its interaction with APPC100.Scientific reports · 2017Article
- Physiological and pathological roles of the γ-secretase complex.Brain research bulletin · 2016Review
- Substrate recruitment of γ-secretase and mechanism of clinical presenilin mutations revealed by photoaffinity mapping.The EMBO journal · 2016Article
- Loss of Nicastrin from Oligodendrocytes Results in Hypomyelination and Schizophrenia with Compulsive Behavior.The Journal of biological chemistry · 2016Article
- Evidence That the "Lid" Domain of Nicastrin Is Not Essential for Regulating γ-Secretase Activity.The Journal of biological chemistry · 2016Article
- Nicastrin functions to sterically hinder γ-secretase-substrate interactions driven by substrate transmembrane domain.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- An atomic structure of human γ-secretase.Nature · 2015Article
- Structural basis of human γ-secretase assembly.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- Cleavage of amyloid precursor protein by an archaeal presenilin homologue PSH.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- Structure of nicastrin unveils secrets of γ-secretase.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Crystal structure of the γ-secretase component nicastrin.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Three-dimensional structure of human γ-secretase.Nature · 2014Article
- Pen-2 is essential for γ-secretase complex stability and trafficking but partially dispensable for endoproteolysis.Biochemistry · 2014Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
gamma-Secretase is a proteolytic membrane complex that processes a variety of substrates including the amyloid precursor protein and the Notch receptor. Earlier we showed that one of the components of this complex, nicastrin (NCT), functions as a receptor for gamma-secretase substrates. A recent report challenged this, arguing instead that the Glu-333 residue of NCT predicted to participate in substrate recognition only participates in gamma-secretase complex maturation and not in activity per se. Here, we present evidence that Glu-333 directly participates in gamma-secretase activity. By normalizing to the active pool of gamma-secretase with two separate methods, we establish that gamma-secretase complexes containing NCT-E333A are indeed deficient in intrinsic activity. We also demonstrate that the NCT-E333A mutant is deficient in its binding to substrates. Moreover, we find that the cleavage of substrates by gamma-secretase activity requires a free N-terminal amine but no minimal length of the extracellular N-terminal stub. Taken together, these studies provide further evidence supporting the role of NCT in substrate recognition. Finally, because gamma-secretase cleaves itself during its maturation and because NCT-E333A also shows defects in gamma-secretase complex maturation, we present a model whereby Glu-333 can serve a dual role via similar mechanisms in the recruitment of both Type 1 membrane proteins for activity and the presenilin intracellular loop during complex maturation.
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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.