CD95 Structure, Aggregation and Cell Signaling.

Nicolas Levoin,Patrick Legembre,Mickael Jean

doi:10.3389/fcell.2020.00314

Abstract

CD95 is a pre-ligand-associated transmembrane (TM) receptor. The interaction with its ligand CD95L brings to a next level its aggregation and triggers different signaling pathways, leading to cell motility, differentiation or cell death. This diversity of biological responses associated with a unique receptor devoid of enzymatic property raises the question of whether different ligands exist, or whether the fine-tuned control of CD95 aggregation and conformation, its distribution within certain plasma membrane sub-domains or the pattern of post-translational modifications account for this such broad-range of cell signaling. Herein, we review how the different domains of CD95 and their post-translational modifications or the different forms of CD95L can participate in the receptor aggregation and induction of cell signaling. Understanding how CD95 response goes from cell death to cell proliferation, differentiation and motility is a prerequisite to reveal novel therapeutic options to treat chronic inflammatory disorders and cancers.

Highlights

Many Tumor necrosis factor (TNF) receptor superfamily members display significant roles in the progression of human diseases, such as the death domain (DD)-containing receptors including CD95, TNF-related apoptosis-inducing ligand receptor (DR4 and DR5), TNFR1, DR3, DR6, nerve growth factor receptor (NGFR), and ectodysplasin receptor (EDAR, Figure 1A)
We found that the structure of CD40 extracellular domain (ECD) (PDB : 3QD6) was close to that of CD95, with good geometric superposition and extended sequence solved (PISA Qscore = 0.55, with RMSD = 1.4 Å for 87 amino acids)
The observed competition between c-Met and CD95L for CD95 interaction raises some questions because the YLGA-containing c-Met sequence (i) competes with CD95L for CD95 binding, despite the fact that the CD95/CD95L interface involves amino acid residues different from the CD95L YLGA sequence (Schneider et al, 1997) and (ii) seems to disrupt CD95 oligomerization even if the CD95/CD95 aggregation requires CRD1 (PLAD) and TM domains different from the CRD2 and CRD3 regions involved in CD95/CD95L interface

Summary

INTRODUCTION

Many Tumor necrosis factor (TNF) receptor superfamily members display significant roles in the progression of human diseases, such as the death domain (DD)-containing receptors including CD95, TNF-related apoptosis-inducing ligand receptor (DR4 and DR5), TNFR1, DR3, DR6, nerve growth factor receptor (NGFR), and ectodysplasin receptor (EDAR, Figure 1A). These receptors are characterized by the presence of an intracellular DD, which is required for their apoptosisinducing activity (Dostert et al, 2019). This review discusses how the CD95 stoichiometry is controlled by receptor-dependent and independent processes, and how stoichiometry can affect the implementation of apoptotic or non-apoptotic signals

A UNIQUE CD95 RECEPTOR BUT AT LEAST TWO FORMS OF THE LIGAND

DISCUSSION