Transmembrane Domain Oligomerization and Intracellular Domain-Lipid Interaction Oppositely Modulates OX40 Receptor Activation Unveiled by 19F NMR
Related Experiment Video
Updated: May 31, 2026
Transmembrane Domain Oligomerization Propensity determined by ToxR Assay
Published on: May 26, 2011
Wenge Dong1, Wanqi Wang1, Yin Yang1
1State Key Laboratory of Elemento-Organic Chemistry and Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, Tianjin 300071, China.
Abstract:
The OX40 (CD134) receptor is an important drug target for antitumor and autoimmune therapies, yet its signaling mechanisms remain poorly understood. Here, we present the first investigation of the OX40 transmembrane domain (TMD) and intracellular domain (ICD), as well as their association with downstream TRAF2, within near-native membrane environments using a combination of chemical and biophysical methods. Using fluorine nuclear magnetic resonance (19F NMR), double electron-electron resonance (DEER), and isothermal titration calorimetry (ITC), we demonstrate that the association of downstream TRAF2 with the acid-rich sequence (ARS) signaling motif of OX40 is oppositely modulated by the TMD oligomerization and ICD-lipid interaction. Specifically, receptor clustering mediated by TMD oligomerization enhances TRAF2 association, whereas ICD-lipid interaction inhibits it. This work reveals a novel regulatory mechanism for OX40, suggesting that its signal transduction and activation are governed by a dynamic tug-of-war between lipid-ICD interaction-mediated inhibition and TMD oligomerization-driven activation.
Insights
The OX40 receptor
Area of Science:
- Immunology and Molecular Biology
- Biophysics and Chemical Biology
Background:
- The OX40 (CD134) receptor is a key target for antitumor and autoimmune treatments.
- Its precise signaling pathways are not fully understood, hindering therapeutic development.
Purpose of the Study:
- To investigate the role of the OX40 transmembrane domain (TMD) and intracellular domain (ICD) in receptor signaling.
- To elucidate the association mechanisms between OX40 and downstream TRAF2 in a near-native membrane environment.
Main Methods:
- Utilized a combination of fluorine nuclear magnetic resonance (19F NMR), double electron-electron resonance (DEER), and isothermal titration calorimetry (ITC).
- Studied the OX40 receptor within simulated near-native membrane environments.
Main Results:
- Demonstrated that OX40 transmembrane domain oligomerization enhances TRAF2 association.
- Showed that intracellular domain-lipid interactions inhibit TRAF2 association.
- Revealed opposing modulatory effects of TMD oligomerization and ICD-lipid interactions on TRAF2 binding to the acid-rich sequence (ARS) motif.
Conclusions:
- Uncovered a novel regulatory mechanism for OX40 signaling involving a balance between activation and inhibition.
- OX40 signal transduction is dynamically controlled by a tug-of-war between lipid-ICD inhibition and TMD oligomerization-driven activation.
Related Concept Videos
01:18Membrane Domains
Protein Domains
The membrane comprises a group of distinct proteins responsible for carrying out a cell's specific function. For example, the plasma membrane of the human sperm, or a single germ cell, contains a unique set of proteins in the anterior...
00:59Mechanisms of Membrane Domain Formation
Another mechanism for membrane domain formation involves membrane proteins interacting with cytoskeletal...
01:26Signal Transduction: Overview
Typically, signal transduction involves three...
01:38Receptor-mediated Endocytosis
01:09Multi-pass Transmembrane Proteins and β-barrels
α-Helix containing multi-pass transmembrane proteins
Multi-pass transmembrane proteins such as G-protein-linked receptors (GPCRs) and...
01:26Membrane Fluidity
Mosaic nature of the membrane
The mosaic characteristic of the membrane helps the plasma membrane remain fluid. The integral proteins and lipids exist as separate but loosely-attached molecules in the membrane. The membrane is a relatively...