ArticleBiochemistry2014
Pen-2 is essential for γ-secretase complex stability and trafficking but partially dispensable for endoproteolysis.
Article in Biochemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 29 citations in OpenAlex.
- The γ-secretase complex: from discovery to a therapeutic target.RSC chemical biology · 2026Review
- Glycogen synthase kinase-3: the master switch driving neurodegeneration in Alzheimer's disease and Parkinson's disease.Archives of toxicology · 2025Review
- Empagliflozin Attenuates Pulmonary Arterial Remodeling Through Peroxisome Proliferator-Activated Receptor Gamma Activation.ACS pharmacology & translational science · 2024Article
- Metformin: update on mechanisms of action and repurposing potential.Nature reviews. Endocrinology · 2023Review
- Article
- Assembly of γ-secretase occurs through stable dimers after exit from the endoplasmic reticulum.The Journal of cell biology · 2021Article
- Exploring the Role of PSEN Mutations in the Pathogenesis of Alzheimer's Disease.Neurotoxicity research · 2020Review
- Review
- Structure and dynamics of γ-secretase with presenilin 2 compared to presenilin 1.RSC advances · 2019Article
- Structural and Chemical Biology of Presenilin Complexes.Cold Spring Harbor perspectives in medicine · 2017Review
- Amyloid precursor protein processing and bioenergetics.Brain research bulletin · 2017Review
- Effects and Mechanism of Huannao Yicong Decoction Extract on the Ethology of Transgenic APP/PS1 Mice.Evidence-based complementary and alternative medicine : eCAM · 2017Article
- Pen-2 and Presenilin are Sufficient to Catalyze Notch Processing.Journal of Alzheimer's disease : JAD · 2017Article
- Nicastrin is required for amyloid precursor protein (APP) but not Notch processing, while anterior pharynx-defective 1 is dispensable for processing of both APP and Notch.Journal of neurochemistry · 2016Article
- Structural biology of presenilin 1 complexes.Molecular neurodegeneration · 2014Review
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
The 19-transmembrane γ-secretase complex generates the amyloid β-peptide of Alzheimer's disease by intramembrane proteolysis of the β-amyloid precursor protein. This complex is comprised of presenilin, Aph1, nicastrin, and Pen-2. The exact function and mechanism of the highly conserved Pen-2 subunit remain poorly understood. Using systematic mutagenesis, we confirm and extend our understanding of which key regions and specific residues play roles in various aspects of γ-secretase function, including maturation, localization, and activity, but not processivity. In general, mutations (1) within the first half of transmembrane domain (TMD) 1 of Pen-2 decreased PS1 endoproteolysis and γ-secretase proteolytic activity, (2) within the second half of TMD1 increased proteolytic activity, (3) within the cytosolic loop region decreased proteolytic activity, (4) within TMD2 decreased PS1 endoproteolysis, (5) within the first half of TMD2 decreased proteolytic activity, and (6) within C-terminal residues decreased proteolytic activity. Specific mutational effects included N33A in TMD1 causing an increase in γ-secretase complexes at the cell surface and a modest decrease in stability and the previously unreported I53A mutation in the loop region reducing stability 10-fold and proteolytic activity by half. In addition, we confirm that minor PS1 endoproteolysis can occur in the complete absence of Pen-2. Together, these data suggest that rather than solely being a catalyst for γ-secretase endoproteolysis, Pen-2 may also stabilize the complex prior to PS1 endoproteolysis, allowing time for full assembly and proper trafficking.
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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.