The tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a multifunctional cytokine playing a key role in tissue regeneration and remodeling. Dysregulation of TWEAK signaling is involved in various pathological processes like autoimmune diseases and cancer. The unique interaction with its cognate receptor Fn14 makes both ligand and receptor promising targets for novel therapeutics. To gain insights into this important signaling pathway, we determined the structure of soluble human TWEAK in complex with the Fab fragment of an antibody selected for inhibition of receptor binding. In the crystallized complex TWEAK is bound by three Fab fragments of the neutralizing antibody. Homology modeling shows that Fab binding overlaps with the putative Fn14 binding site of TWEAK. Docking of the Fn14 cysteine rich domain (CRD) to that site generates a highly complementary interface with perfectly opposing charged and hydrophobic residues. Taken together the presented structure provides new insights into the biology of TWEAK and the TWEAK/Fn14 pathway, which will help to optimize the therapeutic strategy for treatment of related cancer types and autoimmune diseases.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3648529 | PMC |
| http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0062697 | PLOS |
Publication Analysis
Top Keywords
Similar Publications
To Tweak or Not to Tweak. How Exploiting Flexibilities in Gene Set Analysis Leads to Overoptimism.
Biom J
February 2025
Institute for Medical Information Processing, Biometry, and Epidemiology, Faculty of Medicine, LMU Munich, Munich, Germany.
Gene set analysis, a popular approach for analyzing high-throughput gene expression data, aims to identify sets of genes that show enriched expression patterns between two conditions. In addition to the multitude of methods available for this task, users are typically left with many options when creating the required input and specifying the internal parameters of the chosen method. This flexibility can lead to uncertainty about the "right" choice, further reinforced by a lack of evidence-based guidance.
View Article and Find Full Text PDFEvaluative conditioning as a source gut feelings and its potential for behavioral nudging.
Curr Opin Psychol
February 2025
Department of Psychology, Florida State University, 1107 W. Call St., Tallahassee, FL, 32306, USA.
The theme of limited resources pervades the mental health landscape. Practitioners often lack adequate resources to provide interventions for all who could benefit from them, and potential beneficiaries often lack adequate cognitive, financial, and temporal resources to make use of them. Even under rare conditions of bounty, many intensive interventions show small, fleeting effects.
View Article and Find Full Text PDFSelf-supervised learning on dual-sequence magnetic resonance imaging for automatic segmentation of nasopharyngeal carcinoma.
Comput Med Imaging Graph
December 2024
Shenzhen-Hong Kong Institute of Brain Science-Shenzhen Fundamental Research Institutions, Shenzhen, China; Shenzhen University Medical School, Shenzhen University, Shenzhen, 518055, Guangdong, China. Electronic address:
Article Synopsis
- Automating the segmentation of nasopharyngeal carcinoma (NPC) improves treatment processes, but challenges arise from the lack of large annotated datasets.
- The study leverages self-supervised learning combined with a saliency transformation module using unlabeled dual-sequence MRI to enhance segmentation accuracy, achieving a Dice similarity coefficient of 0.77 with a limited number of labeled cases.
- This method not only reduces the annotation workload for oncologists, making the process more efficient and objective, but also ensures reliable identification of NPC.
Expression of TWEAK/Fn14 axis in the context of metabolic dysfunction associated-fatty liver disease: an approach in liver regeneration.
Rev Gastroenterol Peru
November 2024
Department of Biochemistry, Faculty of Medicine, University of Cartagena, Cartagena de Indias, Colombia.
Background: One of the pathways involved in liver regeneration processes is TWEAK/Fn14 (tumor necrosis factor-related weak inducer of apoptosis/fibroblast growth factor-inducible 14), which has been proposed to act directly and selectively on hepatic progenitor cells; however, its role in the regeneration of steatotic liver metabolic dysfunction associated fatty liver disease has not been fully elucidated.
Objective: To evaluate the behavior of Fn14 and its ligand TWEAK, as well as cellular stress signals as biochemical cues for possible liver regeneration in MAFLD.
Materials And Methods: A prospective study was carried out where the behavior of Fn14 and its ligand TWEAK, as well as cellular stress signals were observed as biochemical indications of a possible liver regeneration in a condition of tissue damage caused by excessive lipid accumulation.
Co-Stimulation with TWEAK and TGF-β1 Induces Steroid-Insensitive TSLP and CCL5 Production in BEAS-2B Human Bronchial Epithelial Cells.
Int J Mol Sci
October 2024
Department of Respiratory Medicine, Juntendo University Faculty of Medicine and Graduate School of Medicine, Tokyo 113-8421, Japan.
Steroid-resistant asthma is a common cause of refractory asthma. Type 2 inflammation is the main inflammatory response in asthma, and the mechanism underlying the steroid-resistance of type 2 inflammation has not been completely elucidated. Tumor-necrosis-factor-like apoptosis-inducing factor (TWEAK) and transforming growth factor (TGF)-β1 are involved in epithelial-mesenchymal transition (EMT) and the production of thymic stromal lymphopoietin (TSLP) and C-C motif chemokine ligand 5 (CCL5).
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!