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Crystal Structure of the TRANCE/RANKL Cytokine Reveals Determinants of Receptor-Ligand Specificity

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Crystal Structure of the TRANCE/RANKL Cytokine Reveals Determinants of Receptor-Ligand Specificity Crystal structure of the TRANCE/RANKL cytokine reveals determinants of receptor-ligand specificity Jonathan Lam, … , Steven L. Teitelbaum, Daved H. Fremont J Clin Invest. 2001;108(7):971-979. https://doi.org/10.1172/JCI13890. Article 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. Find the latest version: https://jci.me/13890/pdf Crystal structure of the Online first publication TRANCE/RANKL cytokine reveals determinants of receptor-ligand specificity Jonathan Lam,1 Christopher A. Nelson,1 F. Patrick Ross,1 Steven L. Teitelbaum,1 and Daved H. Fremont1,2 1Department of Pathology and Immunology, and 2Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, Missouri, USA Address correspondence to: Daved H. Fremont, Department of Pathology and Immunology, Washington University School of Medicine, Campus Box 8118, 660 South Euclid Avenue, St. Louis, Missouri 63110, USA. Phone: (314) 747-6547; Fax: (314) 362-8888; E-mail: [email protected]. Jonathan Lam and Christopher A. Nelson contributed equally to this work. Received for publication August 2, 2001, and accepted in revised form August 27, 2001. 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 superfami- ly, the means by which these molecules achieve specificity cannot be completely understood with- out 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, there- by establishing their necessity in mediating the biological activities of RANKL. Such structural deter- minants of RANKL-RANK specificity may be of relevance in the pharmacologic design of com- pounds to ameliorate osteopenic disorders of bone. This article was published online in advance of the print edition. The date of publication is available from the JCI website, http://www.jci.org. J. Clin. Invest. 108:971–979 (2001). DOI:10.1172/JCI200113890. Introduction clasts (5, 6). Mice deficient in RANKL, or its receptor RANKL is a member of the TNF superfamily of RANK, exhibit a complete lack of osteoclasts, result- cytokines. The protein was initially identified as a ing in severe osteopetrosis and hypocalcemia. Clini- cytokine with an ability to stimulate T cell and den- cally, RANKL has been implicated in the pathogenesis dritic cell function and was termed TRANCE–TNF- of postmenopausal osteoporosis. In this disorder, related activation-induced cytokine (1), or alternative- estrogen deficiency leads to enhanced expression of ly as RANKL (2). Cloned independently by two groups TNF and RANKL, as well as decreased production of for its ability to stimulate osteoclast differentiation, osteoprotegerin (OPG, a soluble TNF receptor [TNFR] activity, and survival, it was given the names ODF, family decoy receptor for RANKL) (7, 8). Together, osteoclast differentiation factor (3), and OPGL, osteo- these alterations in cytokine expression induce bone protegerin ligand (4). TNF family members mediate a loss by stimulating osteoclast formation. We have panoply of biological phenomena, modulating essen- demonstrated recently that TNF synergizes with tial aspects of inflammation, organogenesis, host RANKL both in vitro and in vivo to drive cells of the defense, autoimmunity, and apoptosis. In general, TNF monocyte-macrophage lineage to differentiate along family cytokines demonstrate pleiotropic capabilities the osteoclastogenic pathway (9). This synergism is in coordinating the development and function of many achieved at the level of AP-1 and NF-κB activation, two disparate tissues and cell lineages. RANKL, in particu- downstream transcriptional pathways activated by lar, assumes prominent roles in bone, the immune sys- both TNFR and RANK. tem, and mammary epithelium. RANKL also plays an essential role in immunobiolo- RANKL is an essential cytokine in osteobiology. It gy. Expressed on T cells, dendritic cells, and their pre- mediates the differentiation of bone-resorbing osteo- cursors, RANKL mediates the differentiation of T and clasts from monocyte-macrophage precursors and B lymphocytes, as well as the survival of dendritic cells modulates the survival and function of mature osteo- in the immune system. Hematopoietic CD4+ precur- The Journal of Clinical Investigation | October 2001 | Volume 108 | Number 7 971 sors require autocrine RANKL-RANK signaling for sur- The emerging complexity of the TNF superfamily vival and differentiation while migrating from the mar- and the essential role that RANKL plays in immunolo- row to primitive lymphoid tissue anlagen. Mice lacking gy and osteobiology raise functional questions that can RANKL or its receptor RANK exhibit defective periph- be determined only by structural analysis. For instance, eral and mesenteric lymph node organogenesis (10–12). recognition between TNF family cytokines and their Clinically, the expression of RANKL by CD4+ T cells receptors is highly specific, with typical dissociation mediates bone loss and joint destruction in animal mod- constants in the nanomolar to picomolar range. A els of arthritis and inflammatory osteolysis (13, 14). number of crystal structures for TNF family cytokines, In addition to its regulatory roles in bone and the either alone or in complex with their receptors, have been immune system, RANKL-RANK signaling also governs reported: TNF-α (18, 20), TNF-β (21), TNF-β–TNFR the differentiation of mammary epithelium (15). Preg- complex (22), CD40L (23), ACRP30 (adipocyte comple- nant mice lacking RANKL fail to form lactating breast ment–related protein) (24), TRAIL (25), and the TRAIL- tissue, with a complete absence of competent lobulo- DR5 complex (26–28). From these analyses, it is evident alveolar glands. Mammary epithelial precursors lacking that the amino acid conservation among TNF cytokines RANK undergo accelerated apoptosis due to a defect in is largely confined to internal hydrophobic residues Akt activation. Furthermore, the osteoclast deficit in involved in monomer folding or trimer assembly. In con- these animals obviates mobilization of calcium from trast, the unique regions form surface loops of varying bone to the milk. Collectively, these observations illus- composition and length that connect the core β-strands. trate the prominent role of RANKL-RANK in coordi- Importantly, however, the overall lack of sequence con- nating the normal development and function of lym- servation among both ligands and receptors has hindered phoid and mammary tissue, as well as the homeostatic meaningful structural prediction. regulation of calcium metabolism and bone mass. In order to identify the elements of RANKL that gov- Structurally, TNF family cytokines are expressed as type ern interaction with its receptor RANK, we have deter- II transmembrane proteins, each containing a mem- mined the crystal structure of murine RANKL to a res- brane-anchoring domain, a connecting stalk, and a recep- olution of 2.6 Å. We find that RANKL adopts the tor-binding ectodomain. All TNF cytokines share a com- characteristic structural fold of a TNF family cytokine. mon structural core (reviewed in refs. 16, 17)—a scaffold Comparison of the RANKL structure with the available of ten hydrogen-bonded strands, in two sheets, that structures of other TNF family cytokines and receptors assume a characteristic jellyroll β-sandwich fold. Individ- has identified elements of RANKL that it may use to ual TNF family cytokines differ primarily in the length interact with its receptors. Structure-based mutagene- and composition of the surface loops that connect these sis of these regions confirms their
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