Title :
RANKL employs distinct binding modes to engage
RANK and the
osteopr otegerin decoy
receptor
Abstract :
- Osteoprotegerin ( OPG ) and receptor activator of nuclear factor κB ( RANK ) are members of the tumor necrosis fa ctor receptor (TNFR) superfamily that regulate osteoclast formation and function by competing for RANK ligand ( RANKL )
- RANKL promotes osteoclast development through RANK activation, while OPG inhibits this process by sequestering RANKL
- For comparison, we solved crystal structures of RANKL with RANK and RANKL with OPG
- Complementary biochemical and functional studies reveal that the monomeric cytokine-binding region of OPG binds RANKL with ∼500-fold higher affinity than RANK and inhibits RANKL-stimulated osteoclastogenesis ∼150 times more effectively, in part because the binding cleft of RANKL makes unique contacts with OPG
- Several side chains as well as the C-D and D-E loops of RANKL occupy different orientations when bound to OPG versus RANK
- High affinity OPG binding requires a 90s loop Phe residue that is mutated in juvenile Paget's disease
- These results suggest cytokine plasticity may help to fine-tune specific tumor ne crosis factor ( TNF )-family cytokine/ receptor pair selectivity