Death domain of p75 neurotrophin receptor: a structural perspective on an intracellular signalling hub

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.

Download Full-text

Inactive variants of death receptor p75NTR reduce Alzheimer’s neuropathology by interfering with APP internalization

10.1101/2020.01.10.901926 ◽

2020 ◽

Author(s):

Chenju Yi ◽

Ket Yin Goh ◽

Lik-Wei Wong ◽

Kazuhiro Tanaka ◽

Sreedharan Sajikumar ◽

...

Keyword(s):

Hippocampal Neurons ◽

Transmembrane Domain ◽

Death Receptor ◽

Amyloid Plaque ◽

Neurotrophin Receptor ◽

Plaque Burden ◽

P75 Neurotrophin Receptor ◽

Death Domain ◽

Model Of Alzheimer’S Disease ◽

5Xfad Mice

AbstractA prevalent model of Alzheimer’s disease (AD) pathogenesis postulates the generation of neurotoxic fragments derived from the amyloid precursor protein (APP) after its internalization to endocytic compartments. However, the molecular pathways that regulate APP internalization and intracellular trafficking in neurons are unknown. Here we report that 5xFAD mice, an animal model of AD, expressing signaling-deficient variants of the p75 neurotrophin receptor (p75NTR) show greater neuroprotection from AD neuropathology than animals lacking this receptor. p75NTR knock-in mice lacking the death domain or transmembrane Cys259 showed lower levels of Aβ species, amyloid plaque burden, gliosis, mitochondrial stress and neurite dystrophy than global knock-outs. Strikingly, long-term synaptic plasticity and memory, which are completely disrupted in 5xFAD mice, were fully recovered in the knock-in mice. Mechanistically, we found that p75NTR interacts with APP and regulates its internalization in hippocampal neurons. Inactive p75NTR variants internalized much slower and to lower levels than wild type p75NTR, favoring non-amyloidogenic APP cleavage by reducing APP internalization and colocalization with BACE1, the critical protease for generation of neurotoxic APP fragments. These results reveal a novel pathway that directly and specifically regulates APP internalization, amyloidogenic processing and disease progression, and suggest that inhibitors targeting the p75NTR transmembrane domain may be an effective therapeutic strategy in AD.

Download Full-text

Faculty Opinions recommendation of Death Domain Signaling by Disulfide-Linked Dimers of the p75 Neurotrophin Receptor Mediates Neuronal Death in the CNS.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726359783.793520820 ◽

2016 ◽

Author(s):

Mark Bothwell

Keyword(s):

Neuronal Death ◽

Neurotrophin Receptor ◽

P75 Neurotrophin Receptor ◽

Death Domain

Download Full-text

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

10.1101/2021.02.07.430167 ◽

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.

Download Full-text

PLAIDD,a Type II Death Domain Protein that Interacts with p75 Neurotrophin Receptor

NeuroMolecular Medicine ◽

10.1385/nmm:1:3:153 ◽

2002 ◽

Vol 1 (3) ◽

pp. 153-170 ◽

Cited By ~ 23

Author(s):

Dale E. Bredesen ◽

Harald Frankowski ◽

Susana Castro-Obregon ◽

Gabriel del Rio ◽

Rammohan V. Rao

Keyword(s):

Neurotrophin Receptor ◽

P75 Neurotrophin Receptor ◽

Type Ii ◽

Death Domain ◽

Domain Protein

Download Full-text

NMR structure of the death domain of the p75 neurotrophin receptor

The EMBO Journal ◽

10.1093/emboj/16.16.4999 ◽

1997 ◽

Vol 16 (16) ◽

pp. 4999-5005 ◽

Cited By ~ 198

Author(s):

E. Liepinsh

Keyword(s):

Nmr Structure ◽

Neurotrophin Receptor ◽

P75 Neurotrophin Receptor ◽

Death Domain

Download Full-text

Structural basis of death domain signaling in the p75 neurotrophin receptor

eLife ◽

10.7554/elife.11692 ◽

2015 ◽

Vol 4 ◽

Cited By ~ 30

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.

Download Full-text

PITA, a pre-bilaterian p75NTR, is the evolutionary ancestor of TNF receptors

10.1101/2021.12.26.474206 ◽

2021 ◽

Author(s):

Mark J Cumming ◽

Julien Gibon ◽

Wayne S Sossin ◽

Philip A Barker

Keyword(s):

Large Scale ◽

Sequence Similarity ◽

Evolutionary Model ◽

Neurotrophin Receptor ◽

Local Alignment ◽

P75 Neurotrophin Receptor ◽

Death Domain ◽

Search Tool ◽

Health And Disease ◽

Tnfr Superfamily

Tumor necrosis factor receptors (TNFRs) regulate a diverse array of biological functions, including adaptive immunity, neurodevelopment, and many others. Although TNFRs are expressed in all metazoan phyla, a coherent model of the molecular origins of mammalian TNFRs—and how they relate to TNFRs in other phyla—has remained elusive. To address this, we executed a large-scale, systematic Basic Local Alignment Search Tool (BLAST)-based approach to trace the evolutionary ancestry of all 29 human TNFRs. We discovered that all human TNFRs are descendants of a single pre-bilaterian TNFR with strong sequence similarity to the p75 neurotrophin receptor (p75NTR), which we designate as PITA for ‘ p75NTR is the TNFR Ancestor’ . A distinct subset of human TNFRs—including EDAR, XEDAR and TROY—share a unique history as descendants of EDAR-XEDAR-TROY (EXT), which diverged from PITA in a bilaterian ancestor. Most PITA descendants possess a death domain (DD) within their intracellular domain (ICD) but EXTs do not. PITA descendants are expressed in all bilaterian phyla and Cnidaria, but not in non-planulozoan ParaHoxozoa, suggesting that PITA originated in an ancestral planulozoan. Drosophila melanogaster TNFRs (Wengen (Wgn) and Grindelwald (Grnd)) were identified as divergent PITA descendants, providing the first evolutionary link between this model TNFR system and the mammalian TNFR superfamily. This study reveals PITA as the ancestor to human and Drosophila TNFR systems and describes an evolutionary model that will facilitate deciphering TNF-TNFR functions in health and disease.

Download Full-text