Higher-Order Clustering of the Transmembrane Anchor of DR5 Drives Signaling

• Published in: Cell Vol. 176; no. 6; pp. 1477 - 1489.e14
• Main Authors: Pan, Liqiang, Fu, Tian-Min, Zhao, Wenbin, Zhao, Linlin, Chen, Wen, Qiu, Chixiao, Liu, Wenhui, Liu, Zhijun, Piai, Alessandro, Fu, Qingshan, Chen, Shuqing, Wu, Hao, Chou, James J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.03.2019
• Subjects: Apoptosis; Cell Line, Tumor; Cell Membrane - metabolism; HEK293 Cells; Humans; Ligands; Models, Molecular; Mutagenesis, Site-Directed - methods; Protein Binding; Proteolysis; Receptors, Cytoplasmic and Nuclear - metabolism; Receptors, TNF-Related Apoptosis-Inducing Ligand - chemistry; Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism; Receptors, TNF-Related Apoptosis-Inducing Ligand - ultrastructure; Signal Transduction
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2019.02.001

Receptor clustering on the cell membrane is critical in the signaling of many immunoreceptors, and this mechanism has previously been attributed to the extracellular and/or the intracellular interactions. Here, we report an unexpected finding that for death receptor 5 (DR5), a receptor in the tumor necrosis factor receptor superfamily, the transmembrane helix (TMH) alone in the receptor directly assembles a higher-order structure to drive signaling and that this structure is inhibited by the unliganded ectodomain. Nuclear magnetic resonance structure of the TMH in bicelles shows distinct trimerization and dimerization faces, allowing formation of dimer-trimer interaction networks. Single-TMH mutations that disrupt either trimerization or dimerization abolish ligand-induced receptor activation. Surprisingly, proteolytic removal of the DR5 ectodomain can fully activate downstream signaling in the absence of ligand. Our data suggest a receptor activation mechanism in which binding of ligand or antibodies to overcome the pre-ligand autoinhibition allows TMH clustering and thus signaling. [Display omitted] •Transmembrane helix of death receptor 5 oligomerizes to drive downstream signaling•The transmembrane helix in lipid bilayer forms dimer-trimer interaction network•Receptor ectodomain in pre-ligand state inhibits receptor clustering and activation•Ligand binding overcomes the pre-ligand autoinhibition Unlike traditional receptor clustering mediated by intracellular and extracellular domain oligomerization, the transmembrane domain alone of some TNF family receptors can form higher-order structures competent to drive signaling, basally inhibited by the unliganded ectodomain.