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Measuring TCR-pMHC Binding In Situ using a FRET-based Microscopy Assay
Published on: October 30, 2015
CD95/Fas stoichiometry in future precision medicine
Mauricio Sica1, Murielle Roussel2,3, Patrick Legembre4
1CONICET, Instituto Balseiro (UNCuyo), Departamento de Física Médica (GAANS-CNEA), Bariloche Atomic Center, Av. Bustillo 9500, Bariloche, Río Negro, Argentina. mp.sica@gmail.com.
Abstract:
CD95, also known as Fas, belongs to the tumor necrosis factor (TNF) receptor superfamily. The main biological function of this receptor is to orchestrate and control the immune response since mutations in CD95 or deregulation of its downstream signaling pathways lead to auto-immunity and inflammation. Interestingly, more than twenty years ago, pioneer studies highlighted that like TNFR1, TRAILR1 or CD40, CD95 pre-associates at the plasma membrane in a ligand-independent fashion. This self-association occurs through a domain designated pre-ligand assembly domain or PLAD. Although the disruption of this pre-association prevents CD95 signaling, no drugs targeting this region have been generated because many questions remain on the stoichiometry and conformation of this receptor. Despite more than 40.000 publications, no crystal structure of CD95 alone or in combination with its ligand, CD95L, exists. Based on other TNFR members, we herein discuss the predicted conformation of CD95 at the plasma membrane and how these putative structures might account for the induction of the cell signaling pathways.
Insights
CD95 (Fas) receptor pre-associates on the cell membrane. Understanding its structure is key to developing drugs for immune disorders, as mutations cause autoimmunity and inflammation.
Area of Science:
- Immunology
- Molecular Biology
- Structural Biology
Background:
- CD95 (Fas) is a TNF receptor superfamily member crucial for immune response regulation.
- Dysregulation of CD95 signaling is linked to autoimmune diseases and inflammation.
- CD95 undergoes ligand-independent pre-association via its pre-ligand assembly domain (PLAD).
Purpose of the Study:
- To explore the predicted conformation of CD95 at the plasma membrane.
- To understand how CD95's structure relates to cell signaling induction.
- To identify potential drug targets within the CD95 PLAD.
Main Methods:
- Comparative analysis of known TNF receptor structures.
- In silico modeling of CD95 conformation.
- Discussion of potential signaling mechanisms based on predicted structures.
Main Results:
- CD95 exhibits ligand-independent pre-association through its PLAD.
- The precise stoichiometry and conformation of CD95 remain undetermined.
- Predicted structures offer insights into CD95 signaling pathways.
Conclusions:
- Understanding CD95 conformation is critical for therapeutic development.
- Targeting the PLAD could offer novel strategies for treating immune-related disorders.
- Further structural studies are needed to elucidate CD95 function.
