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

Abstract

Receptor clustering on cell membrane plays important roles 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 Type‐1 receptor in the tumor necrosis factor receptor (TNFR) superfamily, the single‐pass transmembrane helix (TMH) alone in the receptor directly assembles a defined higher‐order structure to drive signaling, and that this higher‐order structure is in turn inhibited by the unliganded extracellular domain. Nuclear magnetic resonance structure of the DR5 TMH in bicelles shows distinct faces of the TMH that mediate trimeric and dimeric interactions, allowing formation of dimer‐trimer interaction networks on membrane. Single TMH mutations that disrupt either trimerization or dimerization, as well as double mutations that disrupt both all abolish ligand‐induced receptor activation. Surprisingly, proteolytic removal of the DR5 extracellular domain, which releases the TMH from physical restraints of the pre‐ligand receptor association, can fully activate downstream signaling in the absence of ligand binding. A dimer‐disruptive, but not trimer‐disruptive mutant, decreases DR5 pre‐ligand association, demonstrating dimerization of DR5 before ligand engagement. Collectively, our data suggest a novel model of receptor signaling in which TMH clustering alone can drive DR5 signal transduction, and binding of ligands or agonistic antibodies at the extracellular domain helps to overcome the pre‐ligand autoinhibition.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.