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

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.

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Predicting bacteriophage hosts based on sequences of annotated receptor-binding proteins

Scientific Reports ◽

10.1038/s41598-021-81063-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Dimitri Boeckaerts ◽

Michiel Stock ◽

Bjorn Criel ◽

Hans Gerstmans ◽

Bernard De Baets ◽

...

Keyword(s):

Machine Learning ◽

Predictive Model ◽

Receptor Binding ◽

Bacterial Infections ◽

Sequence Data ◽

Sequence Similarity ◽

Area Under The Curve ◽

Local Alignment ◽

Search Tool ◽

Different Levels

AbstractNowadays, bacteriophages are increasingly considered as an alternative treatment for a variety of bacterial infections in cases where classical antibiotics have become ineffective. However, characterizing the host specificity of phages remains a labor- and time-intensive process. In order to alleviate this burden, we have developed a new machine-learning-based pipeline to predict bacteriophage hosts based on annotated receptor-binding protein (RBP) sequence data. We focus on predicting bacterial hosts from the ESKAPE group, Escherichia coli, Salmonella enterica and Clostridium difficile. We compare the performance of our predictive model with that of the widely used Basic Local Alignment Search Tool (BLAST). Our best-performing predictive model reaches Precision-Recall Area Under the Curve (PR-AUC) scores between 73.6 and 93.8% for different levels of sequence similarity in the collected data. Our model reaches a performance comparable to that of BLASTp when sequence similarity in the data is high and starts outperforming BLASTp when sequence similarity drops below 75%. Therefore, our machine learning methods can be especially useful in settings in which sequence similarity to other known sequences is low. Predicting the hosts of novel metagenomic RBP sequences could extend our toolbox to tune the host spectrum of phages or phage tail-like bacteriocins by swapping RBPs.

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Decision letter: Structural basis of death domain signaling in the p75 neurotrophin receptor

10.7554/elife.11692.022 ◽

2015 ◽

Keyword(s):

Neurotrophin Receptor ◽

Structural Basis ◽

P75 Neurotrophin Receptor ◽

Death Domain

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

Journal of Neuroscience ◽

10.1523/jneurosci.4536-15.2016 ◽

2016 ◽

Vol 36 (20) ◽

pp. 5587-5595 ◽

Cited By ~ 16

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

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

Biomolecules ◽

10.3390/biom11010100 ◽

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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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.

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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

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Molecular Characterization of Post Harvest Fungus Associated with Spoilt Broccoli

Asian Journal of Biology ◽

10.9734/ajob/2021/v13i330189 ◽

2021 ◽

pp. 47-51

Author(s):

Ikechi – Nwogu, Chinyerum Gloria ◽

B. A. Odogwu ◽

O. G. Obiakoeze

Keyword(s):

Aspergillus Niger ◽

Fungal Pathogens ◽

Sequence Similarity ◽

Local Alignment ◽

Control Approach ◽

Post Harvest ◽

Morphological Studies ◽

Search Tool ◽

Fungal Organisms ◽

Post Harvest Deterioration

Broccoli (Brassica oleracea var. italica) is a nutritional vegetable that looks like a small tree. Despite the fact that it is extensively loaded with arrays of vitamins, minerals, fiber and antioxidants, it has been observed that it has a short lifespan of not more than 2-5 days due to post-harvest deterioration. A study was conducted to isolate and identify the common fungal pathogens causing post-harvest deterioration of broccoli crown. Diseased broccoli crowns were collected from Ogunabali Fruit Garden Market in D-Line, Port Harcourt Local Government Area of Rivers State. Fungal isolates were collected and morphologically identified. The DNA of the most common fungal isolate, BC-3B was molecularly characterized using Internal Transcribed Spacer 4 and 5 (ITS-4 and 5) molecular markers. The morphological studies revealed that the BC-3B isolate was an Aspergillus niger. The BC-3B isolate DNA sequence was aligned using Basic Local Alignment Search Tool for Nucleotide (BLASTN) 2.8.0 version of National Center for Biotechnology Information (NCBI) database. The molecular weight of the DNA of the isolates was over 600base pairs. Based on sequence similarity, it was observed that the broccoli isolate BC-3B was 93% identical to Aspergillus niger. From the above results, these findings showed that Aspergillus niger is the causal fungal pathogen of post-harvest rot of broccoli. Phylogenetic tree was constructed to access the relationship between the isolates obtained from this study. This study has provided information on some of the fungal organisms found in broccoli. It is anticipated that this result will provide information for disease control approach for alleviating the post-harvest losses of broccoli caused by Aspergillus niger and provide a foundation for further study of possible harm of consuming diseased broccoli.

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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.

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