High-order clustering of the transmembrane anchor of DR5 drives signaling, ZJU and Harvard scientists suggest

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 intracellular interactions.

CHEN Shuqing, a professor from ZJU's College of Pharmaceutical Sciences teamed up with Prof. James J. Chou and Prof. WU Hao from the Blavatnik Institute at Harvard Medical School to conduct research into the structure and function of the transmembrane helix (TMH) of death receptor 5 (DR5), a receptor in the tumor necrosis factor receptor superfamily (TNFRSF), as well as the roles of TMH in receptor signaling.

In this study, researchers report an unexpected finding that the single-pass TMH of DR5 displays distinct trimerization and dimerization interfaces to allow the formation of higher-order structures in membrane,and that the TMH alone is sufficient to drive signaling in the absence of the ECD. They surmise that the primary consequence of ligand binding is to overcome the inhibitory restraint that the ECD places on the TMH by altering the pre-ligand conformation. This autoinhibition hypothesis provides an explanation for the long-standing enigma on how dimeric agonistic antibodies or dimeric ligand NGF activate TNFRSF family members as trimeric TNF family ligands do. Many different ECD interactions may overcome a specific autoinhibition state, while ECD clustering with an optimal geometry to position the TMH is unlikely to achieve in the different dimer-trimer, trimertrimer, or dimer-dimer networks that these different activating agents may assume with the receptors.

Researchers also discover that the extraordinary function of a single TMH of DR5 to mediate both ligand-receptor complex assembly and higher-order receptor clustering may be partly attributable to the GXXXG motif. Notably, two other members of the TNFRSF, OX40 and TNFR2, also have TMHs that contain GXXXG, and they are expected to cluster similarly as that of DR5. TNFR2 and OX40 could be efficiently activated by proteolytic removal of the receptor ECD in the absence of their respective ligands, suggesting that their TMHs drive downstream signaling in a manner similar to that of DR5. Thus, the role of GXXXG in mediating receptor clustering may represent a more general concept in receptor biology.

The study, published in the March 7 issue of Cell, opens up a novel dimension to modulating the signal transduction of these receptors for disease treatment including cancer immunotherapy. It also offers theoretical backup for monoclonal antibodies, activation of bispecific and multi-specific antibodies and modulation of immunoreceptors, thus holding great promise for promoting antibody-based immunotherapy.