scholarly journals Structural and functional elucidation of NF-κB signaling by the p75 neurotrophin receptor through recruitment of TRADD

2021 ◽  
Author(s):  
Ning Zhang ◽  
Lilian Kisiswa ◽  
Ajeena Ramanujan ◽  
Zhen Li ◽  
Eunice Weiling Sim ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Adaptor Protein ◽  
Adaptor Proteins ◽  
Neurotrophin Receptor ◽  
Structural Basis ◽  
P75 Neurotrophin Receptor ◽  
Death Domain ◽  
Structural Mechanism ◽  
Downstream Signaling ◽  
Developing Neurons

Abstractp75 neurotrophin receptor (p75NTR) is a critical mediator of neuronal death and tissue remodeling and has been implicated in various neurodegenerative diseases. The death domain (DD) of p75NTR is an intracellular signaling hub and has been shown to interact with diverse adaptor proteins. However, the structural mechanism and physiological relevance of the adaptor protein TRADD in neuronal p75NTR signaling remain poorly understood. Here we report an NMR structure of the complex between p75NTR-DD and TRADD-DD and elucidate the structural basis of specific DD recognition in the p75NTR/TRADD signaling pathway. Furthermore, we identify spatiotemporal overlap of p75NTR and TRADD expression in developing cerebellar granule neurons (CGNs) at early postnatal stages and reveal the functional role of TRADD recruitment to p75NTR in the regulation of canonical NF-κB signaling and cell survival in CGNs. Our results provide a new structural framework for understanding how the recruitment of TRADD to p75NTR through DD interactions creates a membrane-proximal platform to propagate downstream signaling in developing neurons.

scholarly journals Structural basis of death domain signaling in the p75 neurotrophin receptor

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Zhi Lin ◽  
Jason Y Tann ◽  
Eddy TH Goh ◽  
Claire Kelly ◽  
Kim Buay Lim ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Binding Sites ◽  
Receptor Activation ◽  
Neurotrophin Receptor ◽  
Structural Basis ◽  
P75 Neurotrophin Receptor ◽  
Death Domain ◽  
Protein Protein Interactions ◽  
Dimer Interface ◽  
Downstream Signaling

Death domains (DDs) mediate assembly of oligomeric complexes for activation of downstream signaling pathways through incompletely understood mechanisms. Here we report structures of complexes formed by the DD of p75 neurotrophin receptor (p75NTR) with RhoGDI, for activation of the RhoA pathway, with caspase recruitment domain (CARD) of RIP2 kinase, for activation of the NF-kB pathway, and with itself, revealing how DD dimerization controls access of intracellular effectors to the receptor. RIP2 CARD and RhoGDI bind to p75NTR DD at partially overlapping epitopes with over 100-fold difference in affinity, revealing the mechanism by which RIP2 recruitment displaces RhoGDI upon ligand binding. The p75NTR DD forms non-covalent, low-affinity symmetric dimers in solution. The dimer interface overlaps with RIP2 CARD but not RhoGDI binding sites, supporting a model of receptor activation triggered by separation of DDs. These structures reveal how competitive protein-protein interactions orchestrate the hierarchical activation of downstream pathways in non-catalytic receptors.

scholarly journals Author response: Structural basis of death domain signaling in the p75 neurotrophin receptor

2015 ◽  
Author(s):  
Zhi Lin ◽  
Jason Y Tann ◽  
Eddy TH Goh ◽  
Claire Kelly ◽  
Kim Buay Lim ◽  
...  
Keyword(s):  
Author Response ◽  
Neurotrophin Receptor ◽  
Structural Basis ◽  
P75 Neurotrophin Receptor ◽  
Death Domain

scholarly journals Isoflurane Neurotoxicity Is Mediated by p75NTR-RhoA Activation and Actin Depolymerization

2011 ◽  
Vol 114 (1) ◽  
pp. 49-57 ◽  
Author(s):  
Brian P. Lemkuil ◽  
Brian P. Head ◽  
Matthew L. Pearn ◽  
Hemal H. Patel ◽  
John C. Drummond ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Hippocampal Slice ◽  
Hippocampal Slices ◽  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor ◽  
Actin Depolymerization ◽  
Rhoa Activation ◽  
Hippocampal Slice Cultures ◽  
Developing Neurons

Background The mechanisms by which isoflurane injured the developing brain are not clear. Recent work has demonstrated that it is mediated in part by activation of p75 neurotrophin receptor. This receptor activates RhoA, a small guanosine triphosphatase that can depolymerize actin. It is therefore conceivable that inhibition of RhoA or prevention of cytoskeletal depolymerization might attenuate isoflurane neurotoxicity. This study was conducted to test these hypotheses using primary cultured neurons and hippocampal slice cultures from neonatal mouse pups. Methods Primary neuron cultures (days in vitro, 4-7) and hippocampal slice cultures from postnatal day 4-7 mice were exposed to 1.4% isoflurane (4 h). Neurons were pretreated with TAT-Pep5, an intracellular inhibitor of p75 neurotrophin receptor, the cytoskeletal stabilizer jasplakinolide, or their corresponding vehicles. Hippocampal slice cultures were pretreated with TAT-Pep5 before isoflurane exposure. RhoA activation was evaluated by immunoblot. Cytoskeletal depolymerization and apoptosis were evaluated with immunofluorescence microscopy using drebrin and cleaved caspase-3 staining, respectively. Results RhoA activation was increased after 30 and 120 min of isoflurane exposure in neurons; TAT-Pep5 (10 μm) decreased isoflurane-mediated RhoA activation at both time intervals. Isoflurane decreased drebrin immunofluorescence and enhanced cleaved caspase-3 in neurons, effects that were attenuated by pretreatment with either jasplakinolide (1 μm) or TAT-Pep5. TAT-Pep5 attenuated the isoflurane-mediated decrease in phalloidin immunofluorescence. TAT-Pep5 significantly attenuated isoflurane-mediated loss of drebrin immunofluorescence in hippocampal slices. Conclusions Isoflurane results in RhoA activation, cytoskeletal depolymerization, and apoptosis. Inhibition of RhoA activation or prevention of downstream actin depolymerization significantly attenuated isoflurane-mediated neurotoxicity in developing neurons.

scholarly journals Fibronectin-stimulated signaling from a focal adhesion kinase-c-Src complex: involvement of the Grb2, p130cas, and Nck adaptor proteins.

1997 ◽  
Vol 17 (3) ◽  
pp. 1702-1713 ◽  
Author(s):  
D D Schlaepfer ◽  
M A Broome ◽  
T Hunter
Keyword(s):  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Intracellular Signaling ◽  
Protein Tyrosine Kinase ◽  
Adaptor Protein ◽  
Adaptor Proteins ◽  
Sh2 Domain ◽  
Mitogen Activated Protein Kinase

The focal adhesion kinase (FAK), a protein-tyrosine kinase (PTK), associates with integrin receptors and is activated by cell binding to extracellular matrix proteins, such as fibronectin (FN). FAK autophosphorylation at Tyr-397 promotes Src homology 2 (SH2) domain binding of Src family PTKs, and c-Src phosphorylation of FAK at Tyr-925 creates an SH2 binding site for the Grb2 SH2-SH3 adaptor protein. FN-stimulated Grb2 binding to FAK may facilitate intracellular signaling to targets such as ERK2-mitogen-activated protein kinase. We examined FN-stimulated signaling to ERK2 and found that ERK2 activation was reduced 10-fold in Src- fibroblasts, compared to that of Src- fibroblasts stably reexpressing wild-type c-Src. FN-stimulated FAK phosphotyrosine (P.Tyr) and Grb2 binding to FAK were reduced, whereas the tyrosine phosphorylation of another signaling protein, p130cas, was not detected in the Src- cells. Stable expression of residues 1 to 298 of Src (Src 1-298, which encompass the SH3 and SH2 domains of c-Src) in the Src- cells blocked Grb2 binding to FAK; but surprisingly, Src 1-298 expression also resulted in elevated p130cas P.Tyr levels and a two- to threefold increase in FN-stimulated ERK2 activity compared to levels in Src- cells. Src 1-298 bound to both FAK and p130cas and promoted FAK association with p130cas in vivo. FAK was observed to phosphorylate p130cas in vitro and could thus phosphorylate p130cas upon FN stimulation of the Src 1-298-expressing cells. FAK-induced phosphorylation of p130cas in the Src 1-298 cells promoted the SH2 domain-dependent binding of the Nck adaptor protein to p130cas, which may facilitate signaling to ERK2. These results show that there are additional FN-stimulated pathways to ERK2 that do not involve Grb2 binding to FAK.

scholarly journals Small molecule modulation of the p75 neurotrophin receptor inhibits multiple amyloid beta-induced tau pathologies

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Tao Yang ◽  
Kevin C. Tran ◽  
Anne Y. Zeng ◽  
Stephen M. Massa ◽  
Frank M. Longo
Keyword(s):  
Small Molecule ◽  
Intracellular Signaling ◽  
Rho Kinase ◽  
Tau Phosphorylation ◽  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor ◽  
Fyn Kinase ◽  
Synapse Degeneration ◽  
Preclinical And Clinical Studies

AbstractLongitudinal preclinical and clinical studies suggest that Aβ drives neurite and synapse degeneration through an array of tau-dependent and independent mechanisms. The intracellular signaling networks regulated by the p75 neurotrophin receptor (p75NTR) substantially overlap with those linked to Aβ and to tau. Here we examine the hypothesis that modulation of p75NTR will suppress the generation of multiple potentially pathogenic tau species and related signaling to protect dendritic spines and processes from Aβ-induced injury. In neurons exposed to oligomeric Aβ in vitro and APP mutant mouse models, modulation of p75NTR signaling using the small-molecule LM11A-31 was found to inhibit Aβ-associated degeneration of neurites and spines; and tau phosphorylation, cleavage, oligomerization and missorting. In line with these effects on tau, LM11A-31 inhibited excess activation of Fyn kinase and its targets, tau and NMDA-NR2B, and decreased Rho kinase signaling changes and downstream aberrant cofilin phosphorylation. In vitro studies with pseudohyperphosphorylated tau and constitutively active RhoA revealed that LM11A-31 likely acts principally upstream of tau phosphorylation, and has effects preventing spine loss both up and downstream of RhoA activation. These findings support the hypothesis that modulation of p75NTR signaling inhibits a broad spectrum of Aβ-triggered, tau-related molecular pathology thereby contributing to synaptic resilience.

scholarly journals Death Domain Signaling by Disulfide-Linked Dimers of the p75 Neurotrophin Receptor Mediates Neuronal Death in the CNS

2016 ◽  
Vol 36 (20) ◽  
pp. 5587-5595 ◽  
Author(s):  
K. Tanaka ◽  
C. E. Kelly ◽  
K. Y. Goh ◽  
K. B. Lim ◽  
C. F. Ibanez
Keyword(s):  
Neuronal Death ◽  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor ◽  
Death Domain

scholarly journals Nradd Acts as a Negative Feedback Regulator of Wnt/β-Catenin Signaling and Promotes Apoptosis

Biomolecules ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 100
Author(s):  
Ozgun Ozalp ◽  
Ozge Cark ◽  
Yagmur Azbazdar ◽  
Betul Haykir ◽  
Gokhan Cucun ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Mammalian Cells ◽  
Genetic Disorders ◽  
Negative Regulator ◽  
Neurotrophin Receptor ◽  
P75 Neurotrophin Receptor ◽  
Death Domain ◽  
C Terminus ◽  
And Function ◽  
Functional Analyses

Wnt/β-catenin signaling controls many biological processes for the generation and sustainability of proper tissue size, organization and function during development and homeostasis. Consequently, mutations in the Wnt pathway components and modulators cause diseases, including genetic disorders and cancers. Targeted treatment of pathway-associated diseases entails detailed understanding of the regulatory mechanisms that fine-tune Wnt signaling. Here, we identify the neurotrophin receptor-associated death domain (Nradd), a homolog of p75 neurotrophin receptor (p75NTR), as a negative regulator of Wnt/β-catenin signaling in zebrafish embryos and in mammalian cells. Nradd significantly suppresses Wnt8-mediated patterning of the mesoderm and neuroectoderm during zebrafish gastrulation. Nradd is localized at the plasma membrane, physically interacts with the Wnt receptor complex and enhances apoptosis in cooperation with Wnt/β-catenin signaling. Our functional analyses indicate that the N-glycosylated N-terminus and the death domain-containing C-terminus regions are necessary for both the inhibition of Wnt signaling and apoptosis. Finally, Nradd can induce apoptosis in mammalian cells. Thus, Nradd regulates cell death as a modifier of Wnt/β-catenin signaling during development.

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