Crystal structure of the TRANCE/RANKL cytokine reveals determinants of receptor-ligand specificity.
RANK, the receptor activator of NF-kappaB, 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 A. 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.
Lam
J
J
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Nelson
C A
CA
Ross
F P
FP
Teitelbaum
S L
SL
Fremont
D H
DH
D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics; D018360:Crystallography, X-Ray; D008024:Ligands; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000235:genetics; D051379:Mice; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry* / Q000235:genetics
D002352:Carrier Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D011993:Recombinant Fusion Proteins; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha