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

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

doi:10.1172/jci13890

Cited by 169 publications

(124 citation statements)

References 41 publications

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“…In the TNFR1-TNFβ or DR5-TRAIL complex, the hydrophobic interaction between Loop1 of the receptor and the DE loop of the ligand is the main force for binding, with the conserved tyrosine residue in the DE loop penetrating the hydrophobic groove formed by hydrophobic residues in Loop1 (23)(24)(25). However, Ile248 of eRANKL, which is equivalent to the Tyr residue in TNFR or DR5, is thought to be only marginal for receptor binding, because the I248D mutant maintained binding activity to RANK (28). This was corroborated in the structures presented here, because the electron densities of the Ile248 residues in the DE loop (residues 245-250) were very poor in both free (29) and ligand-bound forms (current study).…”

Section: Resultssupporting

confidence: 71%

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Structure-based development of a receptor activator of nuclear factor-κB ligand (RANKL) inhibitor peptide and molecular basis for osteopetrosis

Nguyen

Jin

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The receptor activator of nuclear factor-κB (RANK) and its ligand RANKL, which belong to the tumor necrosis factor (TNF) receptor-ligand family, mediate osteoclastogenesis. The crystal structure of the RANKL ectodomain (eRANKL) in complex with the RANK ectodomain (eRANK) combined with biochemical assays of RANK mutants indicated that three RANK loops (Loop1, Loop2, and Loop3) bind to the interface of a trimeric eRANKL. Loop3 is particularly notable in that it is structurally distinctive from other TNF-family receptors and forms extensive contacts with RANKL. The disulfide bond (C125-C127) at the tip of Loop3 is important for determining the unique topology of Loop3, and docking E126 close to RANKL, which was supported by the inability of C127A or E126A mutants of RANK to bind to RANKL. Inhibitory activity of RANK mutants, which contain loops of osteoprotegerin (OPG), a soluble decoy receptor to RANKL, confirmed that OPG shares the similar binding mode with RANK and OPG. Loop3 plays a key role in RANKL binding. Peptide inhibitors designed to mimic Loop3 blocked the RANKL-induced differentiation of osteoclast precursors, suggesting that they could be developed as therapeutic agents for the treatment of osteoporosis and bone-related diseases. Furthermore, some of the RANK mutations associated with autosomal recessive osteopetrosis (ARO) resulted in reduced RANKL-binding activity and failure to induce osteoclastogenesis. These results, together with structural interpretation of eRANK-eRANKL interaction, provided molecular understanding for pathogenesis of ARO.

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Section: Resultssupporting

confidence: 71%

“…However, the key structural features in the binding interface that control the biological specificity of a particular ligand-receptor pair have not been defined. For example, the binding mode between RANKL and RANK is not yet clearly understood, although the crystal structure of RANKL was extensively characterized (28,29).…”

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confidence: 99%

Structure-based development of a receptor activator of nuclear factor-κB ligand (RANKL) inhibitor peptide and molecular basis for osteopetrosis

Nguyen

Jin

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…These different isoforms are able to differentially regulate osteoclastogenesis [23][24][25]. In cells, RANKL forms homo-or hetero-trimer structures between the isoforms [26,27], and the trimeric combination of the isoforms is crucial for orientating the membranous localization, thereby controlling the osteoclast formation and differentiation process. Hence, the trimeric structure of RANKL1 alone or associated with RANKL2 is translated into a membranous localization.…”

Section: Introductionmentioning

confidence: 99%

Differential modulation of RANKL isoforms by human osteoarthritic subchondral bone osteoblasts: Influence of osteotropic factors

Tat

Pelletier

Lajeunesse

et al. 2008

Bone

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Background-Osteoarthritis (OA) is the most common human joint disease. Recent studies suggest that an abnormal subchondral bone metabolism is intimately involved in the genesis of this disease. Bone remodelling is tightly regulated by a molecular triad composed of OPG/RANK/ RANKL. RANKL exists as 3 isoforms: RANKL1, 2, and 3. RANKL1 and 2 enhance osteoclastogenesis whereas RANKL3 inhibits this phenomenon. We previously reported that human OA subchondral bone osteoblasts can be discriminated into two subgroups according to their level of PGE 2 [low (L) or high (H)]. Moreover, we also showed that L-OA osteoblasts express higher levels of total RANKL compared to H-OA osteoblasts. In this study, we investigated the level of membranous RANKL, comparing L-and H-OA subchondral bone osteoblasts, as well as its modulation by osteotropic factors. The impact of the modulation of RANKL1 and 3 on the membranous RANKL level was also studied.

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“…For sequence alignment, we incorporated known secondary structure from the following crystal structures: 1ALY of human CD40L (17), 1XU1 of murine APRIL bound to Taci (18); 1JTZ of human TNF-related activation-induced cytokine/RANKL (19); and 1D2Q of human TRAIL (20). For TWEAK, LIGHT, 4-1BBL, and FasL, ␤-sheet predictions from Bodmer et al (1) were used.…”

Section: Cloning and Sequencingmentioning

confidence: 99%

Early Diversification of the TNF Superfamily in Teleosts: Genomic Characterization and Expression Analysis

Glenney

Wiens

2007

The Journal of Immunology

109

121

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The TNF superfamily (TNFSF) of proteins are cytokines involved in diverse immunological and developmental pathways. Little is known about their evolution or expression in lower vertebrate species. Bioinformatic searches of Zebrafish, Tetraodon, and Fugu genome and other teleost expressed sequence tag databases identified 44 novel gene sequences containing a TNF homology domain. This work reveals the following: 1) teleosts possess orthologs of BAFF, APRIL, EDA, TWEAK, 4-1BBL, Fas ligand, LIGHT, CD40L, RANKL, and possibly TL1A; 2) the BAFF-APRIL subfamily is enriched by a third member, BALM, unique to fish; 3) orthologs of lymphotoxins ␣ and ␤ were not clearly identified in teleosts and are substituted by a related ligand, TNF-New; 4) as many as four TRAIL-like genes are present in teleosts, as compared with only one in mammals; and 5) T cell activation ligands OX40L, CD27L, CD30L, and GITRL were not identified in any fish species. Finally, we characterize mRNA expression of TNFSF members CD40L, LIGHT, BALM, APRIL, Fas ligand, RANKL, TRAIL-like, and TNF-New in rainbow trout, Oncorhynchus mykiss, immune and nonimmune tissues. In conclusion, we identified a total of 14 distinct TNFSF members in fishes, indicating expansion of this superfamily before the divergence of bony fish and tetrapods, ϳ360 -450 million years ago. Based on these findings, we extend a model of TNFSF evolution and the coemergence of the vertebrate adaptive immune system.

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

Cited by 169 publications

References 41 publications

Structure-based development of a receptor activator of nuclear factor-κB ligand (RANKL) inhibitor peptide and molecular basis for osteopetrosis

Structure-based development of a receptor activator of nuclear factor-κB ligand (RANKL) inhibitor peptide and molecular basis for osteopetrosis

Differential modulation of RANKL isoforms by human osteoarthritic subchondral bone osteoblasts: Influence of osteotropic factors

Early Diversification of the TNF Superfamily in Teleosts: Genomic Characterization and Expression Analysis

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