ArticleThe Journal of biological chemistry2012
The effects of transmembrane sequence and dimerization on cleavage of the p75 neurotrophin receptor by γ-secretase.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 47 citations in OpenAlex.
- Impaired migration and lung invasion of human melanoma by a novel small molecule targeting the transmembrane domain of death receptor p75EMBO molecular medicine · 2025Article
- Gamma secretase activity modulates BMP-7-induced dendritic growth in primary rat sympathetic neurons.Autonomic neuroscience : basic & clinical · 2023Article
- Article
- High-affinity TrkA and p75 neurotrophin receptor complexes: A twisted affair.The Journal of biological chemistry · 2022Review
- Does a rare mutation in PTPRA contribute to the development of Parkinson's disease in an Australian multi-incident family?PloS one · 2022Article
- c-Jun N-terminal Kinase Mediates Ligand-independent p75Neuroscience · 2021Article
- FLIM-FRET Analysis of Ras Nanoclustering and Membrane-Anchorage.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Revising the mechanism of p75NTR activation: intrinsically monomeric state of death domains invokes the "helper" hypothesis.Scientific reports · 2020Article
- Fast-diffusing p75Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Stoichiometry counts.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- The transmembrane domain of the p75 neurotrophin receptor stimulates phosphorylation of the TrkB tyrosine kinase receptor.The Journal of biological chemistry · 2017Article
- Piecing it together: Unraveling the elusive structure-function relationship in single-pass membrane receptors.Biochimica et biophysica acta. Biomembranes · 2017Review
- Transmembrane Interactions of Full-length Mammalian Bitopic Cytochrome-P450-Cytochrome-bScientific reports · 2017Article
- SPRED1 Interferes with K-ras but Not H-ras Membrane Anchorage and Signaling.Molecular and cellular biology · 2016Article
- Article
- Structural Basis of p75 Transmembrane Domain Dimerization.The Journal of biological chemistry · 2016Article
- Death Domain Signaling by Disulfide-Linked Dimers of the p75 Neurotrophin Receptor Mediates Neuronal Death in the CNS.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2016Article
- Recent advances in understanding neurotrophin signaling.F1000Research · 2016Review
- Detection of p75NTR Trimers: Implications for Receptor Stoichiometry and Activation.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2015Article
- Juxtamembrane contribution to transmembrane signaling.Biopolymers · 2015Review
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cleavage of transmembrane receptors by γ-secretase is the final step in the process of regulated intramembrane proteolysis (RIP) and has a significant impact on receptor function. Although relatively little is known about the molecular mechanism of γ-secretase enzymatic activity, it is becoming clear that substrate dimerization and/or the α-helical structure of the substrate can regulate the site and rate of γ-secretase activity. Here we show that the transmembrane domain of the pan-neurotrophin receptor p75(NTR), best known for regulating neuronal death, is sufficient for its homodimerization. Although the p75(NTR) ligands NGF and pro-NGF do not induce homerdimerization or RIP, homodimers of p75(NTR) are γ-secretase substrates. However, dimerization is not a requirement for p75(NTR) cleavage, suggesting that γ-secretase has the ability to recognize and cleave each receptor molecule independently. The transmembrane cysteine 257, which mediates covalent p75(NTR) interactions, is not crucial for homodimerization, but this residue is required for normal rates of γ-secretase cleavage. Similarly, mutation of the residues alanine 262 and glycine 266 of an AXXXG dimerization motif flanking the γ-secretase cleavage site within the p75(NTR) transmembrane domain alters the orientation of the domain and inhibits γ-secretase cleavage of p75(NTR). Nonetheless, heteromer interactions of p75(NTR) with TrkA increase full-length p75(NTR) homodimerization, which in turn potentiates the rate of γ-cleavage following TrkA activation independently of rates of α-cleavage. These results provide support for the idea that the helical structure of the p75(NTR) transmembrane domain, which may be affected by co-receptor interactions, is a key element in γ-secretase-catalyzed cleavage.
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