Crystal structure of the TRANCE/RANKL cytokine reveals determinants of receptor-ligand specificity
Jonathan Lam, … , Steven L. Teitelbaum, Daved H. Fremont
Jonathan Lam, … , Steven L. Teitelbaum, Daved H. Fremont
Published October 1, 2001
Citation Information: J Clin Invest. 2001;108(7):971-979. https://doi.org/10.1172/JCI13890.
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Article

Crystal structure of the TRANCE/RANKL cytokine reveals determinants of receptor-ligand specificity

Abstract

RANK, the receptor activator of NF-κB, and its ligand RANKL (initially termed TRANCE, also termed ODF and OPGL), are a TNF superfamily receptor-ligand pair that govern the development and function of osteoclasts, lymphoid tissue, and mammary epithelium. While TNF family cytokines share a common structural scaffold, individual receptor-ligand pairs associate with high specificity. Given the low level of amino acid conservation among members of the TNF superfamily, the means by which these molecules achieve specificity cannot be completely understood without knowledge of their three-dimensional structures. To determine the elements of RANKL that mediate RANK activation, we have crystallized the ectodomain of murine RANKL and solved its structure to a resolution of 2.6 Å. RANKL self-associates as a homotrimer with four unique surface loops that distinguish it from other TNF family cytokines. Mutagenesis of selected residues in these loops significantly modulates RANK activation, as evidenced by in vitro osteoclastogenesis, thereby establishing their necessity in mediating the biological activities of RANKL. Such structural determinants of RANKL-RANK specificity may be of relevance in the pharmacologic design of compounds to ameliorate osteopenic disorders of bone.

Authors

Jonathan Lam, Christopher A. Nelson, F. Patrick Ross, Steven L. Teitelbaum, Daved H. Fremont

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Receptor contact regions of RANKL. (a) Schematic depiction of a RANKL tr...
Receptor contact regions of RANKL. (a) Schematic depiction of a RANKL trimer (green, cyan, and magenta monomers) docked with its receptor RANK (drawn here as four CRDs, yellow). (b) Surface representation of a RANKL trimer, oriented as in a, docked with a monomer of DR5, the TRAIL receptor (yellow Cα backbone worm). Areas on the surface of RANKL calculated to engage DR5 are shaded green, as is the sequence in Figure 2. (c) Surface representation of a RANKL trimer docked with a monomer of the TNFR (yellow Cα backbone worm). Areas on the surface of RANKL calculated to engage the TNFR are shaded magenta. (d) Comparison of DR5 (green shading) and TNFR (magenta shading) contact sites on the surface of RANKL. Overlapping areas that contact both receptors are shown in yellow. (e) Surface representation of a RANKL trimer with degrees of conservation mapped to the surface. The degree of conservation is directly proportional to intensity of colorization (white, no conservation; brown, conserved). Areas that contact both receptors show little to no sequence conservation across this family of cytokines (light tan to white shading). These unique regions provide specificity for receptor-ligand recognition, underlying the lack of cross-reactivity among receptors and ligands in this cytokine family. (f) Potential receptor contact areas of RANKL that were targeted for structure-based mutagenesis are shown in red.