Receptor activator of nuclear factor kappa-B—tumor necrosis factor receptor-associated factor 6 protein-protein interface (RANK–TRAF6 interface)

The **RANK–TRAF6 protein–protein interface** is the intracellular region where the receptor activator of nuclear factor kappa-B (RANK), a transmembrane member of the tumor necrosis factor (TNF) receptor superfamily, recruits the adaptor protein tumor necrosis factor receptor-associated factor 6 (TRAF6) upon binding its ligand, RANKL (receptor activator of nuclear factor kappa-B ligand). This interaction is essential for the activation of TRAF6’s E3 ubiquitin ligase activity and the downstream propagation of the NF-kβ and JNK signaling pathways, which are crucial for osteoclast differentiation, bone resorption, and immune responses. Disruption of RANK–TRAF6 interaction abrogates osteoclast functional activity and is an established therapeutic target for metabolic bone diseases and certain cancers with bone involvement. While no approved drugs currently target the interface itself, inhibitors of RANKL (such as denosumab) block upstream activation, preventing RANK–TRAF6 complex formation[1][2][3][4][6].

Other names

RANK–TRAF6 binding interfaceRANK–TRAF6 interactionRANK cytoplasmic domain–TRAF6 interface

Inhibition of RANK ligand binding blocks RANK–TRAF6 recruitment, suppressing osteoclast activation Blocking interface prevents downstream NF-kβ pathway activation