The RANKL cytokine at 2.6 Å

September 26, 2001

The tumor necrosis factor (TNF) superfamily represents a large, loosely related, and versatile group of homotrimeric cytokines. There has been considerable interest in the structure of these proteins, and X-ray analyses are available for several of them, both in isolated form and as co-crystals with their corresponding receptors. Still, the substantial divergence in primary sequence within this family has made it difficult to predict the structure of other members with confidence. Here, Lamn et al. report a high-resolution crystal structure of the RANK ligand (RANKL), a TNF relative that acts through its receptor (RANK) to promote the differentiation and bone-resorptive activity of osteoclasts and to block apoptosis by several other cell types. As with other members of this superfamily, RANKL monomers trimerize only with each other, even when they are coexpressed with other related cytokines. Likewise, the mature trimeric protein binds specifically to RANK and not to other members of the TNF receptor family. The present crystal structure goes far toward explaining these biochemical observations. While the protein folds to form a characteristic structure that has been seen in related cytokines, there are also several solvent-exposed loops with sequences not found in other family members. Based on the well defined quaternary structure of receptors of this family, Lamm et al. predicted that one of these loops binds directly to RANK. To confirm this hypothesis, the authors mutated RANKL so that it either entirely lacks the loop in question or bears in its place a sequence from TNF. As expected, the resulting proteins form trimers normally but are incapable of interacting with RANK. This loop sequence would therefore be expected to antagonize RANK signaling and might prove useful in controlling ostoeporosis by blocking osteoclast-mediated bone resorption.
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