ArticleProceedings of the National Academy of Sciences of the United States of America2012
Identification of a tetratricopeptide repeat-like domain in the nicastrin subunit of γ-secretase using synthetic antibodies.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 35 citations in OpenAlex.
- An interactive network of elastase, secretases, and PAR-2 protein regulates CXCR1 receptor surface expression on neutrophils.The Journal of biological chemistry · 2014Trial
- Nicastrin-Like, a Novel Transmembrane Protein fromMicroorganisms · 2021Article
- The Effect of Mutations in the TPR and Ankyrin Families of Alpha Solenoid Repeat Proteins.Frontiers in bioinformatics · 2021Review
- Curcumin Derivative GT863 Inhibits Amyloid-Beta Production via Inhibition of Protein N-Glycosylation.Cells · 2020Article
- Review
- Article
- High-efficient production and biophysical characterisation of nicastrin and its interaction with APPC100.Scientific reports · 2017Article
- Aromatic claw: A new fold with high aromatic content that evades structural prediction.Protein science : a publication of the Protein Society · 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
- Evidence That the "Lid" Domain of Nicastrin Is Not Essential for Regulating γ-Secretase Activity.The Journal of biological chemistry · 2016Article
- Analysis of nicastrin gene phylogeny and expression in zebrafish.Development genes and evolution · 2015Article
- The dynamic conformational landscape of gamma-secretase.Journal of cell science · 2015Article
- Structural biology of presenilin 1 complexes.Molecular neurodegeneration · 2014Review
- A synthetic antibody fragment targeting nicastrin affects assembly and trafficking of γ-secretase.The Journal of biological chemistry · 2014Article
- Anti-nicastrin monoclonal antibodies elicit pleiotropic anti-tumour pharmacological effects in invasive breast cancer cells.Breast cancer research and treatment · 2014Article
- Complex regulation of γ-secretase: from obligatory to modulatory subunits.Frontiers in aging neuroscience · 2014Review
- Recombinant antibodies to histone post-translational modifications.Nature methods · 2013Article
- Conformational states and recognition of amyloidogenic peptides of human insulin-degrading enzyme.Proceedings of the National Academy of Sciences of the United States of America · 2013Article
- Structural biology of presenilins and signal peptide peptidases.The Journal of biological chemistry · 2013Review
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Authors and funding
13 authors at 5 institutions in 2 countries.
Funding
Abstract
The γ-secretase complex, composed of presenilin, anterior-pharynx-defective 1, nicastrin, and presenilin enhancer 2, catalyzes the intramembranous processing of a wide variety of type I membrane proteins, including amyloid precursor protein (APP) and Notch. Earlier studies have revealed that nicastrin, a type I membrane-anchored glycoprotein, plays a role in γ-secretase assembly and trafficking and has been proposed to bind substrates. To gain more insights regarding nicastrin structure and function, we generated a conformation-specific synthetic antibody and used it as a molecular probe to map functional domains within nicastrin ectodomain. The antibody bound to a conformational epitope within a nicastrin segment encompassing residues 245-630 and inhibited the processing of APP and Notch substrates in in vitro γ-secretase activity assays, suggesting that a functional domain pertinent to γ-secretase activity resides within this region. Epitope mapping and database searches revealed the presence of a structured segment, located downstream of the previously identified DAP domain (DYIGS and peptidase; residues 261-502), that is homologous to a tetratricopeptide repeat (TPR) domain commonly involved in peptide recognition. Mutagenesis analyses within the predicted TPR-like domain showed that disruption of the signature helical structure resulted in the loss of γ-secretase activity but not the assembly of the γ-secretase and that Leu571 within the TPR-like domain plays an important role in mediating substrate binding. Taken together, these studies offer provocative insights pertaining to the structural basis for nicastrin function as a "substrate receptor" within the γ-secretase complex.
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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.