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RANK Interaction and Signaling − RANKL Structural and Functional Structural and Functional Insights of RANKL −RANK Interaction and Signaling Changzhen Liu, Thomas S. Walter, Peng Huang, Shiqian Zhang, Xuekai Zhu, Ying Wu, Lucy R. Wedderburn, Peifu This information is current as Tang, Raymond J. Owens, David I. Stuart, Jingshan Ren and of October 1, 2021. Bin Gao J Immunol published online 14 May 2010 http://www.jimmunol.org/content/early/2010/05/14/jimmun ol.0904033 Downloaded from Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: by guest on October 1, 2021 http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published May 14, 2010, doi:10.4049/jimmunol.0904033 The Journal of Immunology Structural and Functional Insights of RANKL–RANK Interaction and Signaling Changzhen Liu,*,†,1 Thomas S. Walter,‡,1 Peng Huang,x Shiqian Zhang,{ Xuekai Zhu,*,† Ying Wu,*,† Lucy R. Wedderburn,‖ Peifu Tang,x Raymond J. Owens,‡ David I. Stuart,‡ Jingshan Ren,‡ and Bin Gao*,†,‖ Bone remodeling involves bone resorption by osteoclasts and synthesis by osteoblasts and is tightly regulated by the receptor activator of the NF-kB ligand (RANKL)/receptor activator of the NF-kB (RANK)/osteoprotegerin molecular triad. RANKL, a member of the TNF superfamily, induces osteoclast differentiation, activation and survival upon interaction with its receptor RANK. The decoy receptor osteoprotegerin inhibits osteoclast formation by binding to RANKL. Imbalance in this molecular triad can result in diseases, including osteoporosis and rheumatoid arthritis. In this study, we report the crystal structures of unliganded RANK and its complex with RANKL and elucidation of critical residues for the function of the receptor pair. RANK represents the longest Downloaded from TNFR with four full cysteine-rich domains (CRDs) in which the CRD4 is stabilized by a sodium ion and a rigid linkage with CRD3. On association, RANK moves via a hinge region between the CRD2 and CRD3 to make close contact with RANKL; a significant structural change previously unseen in the engagement of TNFR superfamily 1A with its ligand. The high-affinity interaction between RANK and RANKL, maintained by continuous contact between the pair rather than the patched interaction commonly observed, is necessary for the function because a slightly reduced affinity induced by mutation produces significant disruption of osteoclast formation. The structures of RANK and RANKL–RANK complex and the biological data presented in the paper are http://www.jimmunol.org/ essential for not only our understanding of the specific nature of the signaling mechanism and of disease-related mutations found in patients but also structure based drug design. The Journal of Immunology, 2010, 184: 000–000. he receptor activator of the NF-kB (RANK; TNFR super- cytokines and hormones (1–5). Recently the pair was also found family [TNFRSF] 11A), and its cognate ligand, RANKL, to be important for thermoregulation (6), demonstrating them to T play a pivotal role in bone remodeling, immune function be one of the most versatile physiological modulators in the body. and mammary gland development in conjunction with various RANK is a type I transmembrane protein, consisting of around 620 aas with ∼85% homology between mouse and human by guest on October 1, 2021 *The Center for Molecular Immunology and †China-Japan Joint Laboratory for homologs (7). The extracellular region (residues 30–194) is Molecular Immunology and Virology, Key Laboratory of Pathogenic Microbiology comprised of four tandem cysteine-rich pseudo-repeat domains and Immunology, Institute of Microbiology, Chinese Academy of Sciences; xDepart- ment of Orthopaedics, Chinese People’s Liberation Army General Hospital, Beijing; (CRDs) that are characteristic of the TNFRSF (8). The C- {Department of Orthopaedics, the First Clinical College of Harbin Medical Univer- terminal 383 residues form one of the largest cytoplasmic domains ‡ sity, Harbin, China Division of Structural Biology, Oxford Protein Production Fa- in the TNFRSF. Like other members of the family this region of cility, The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford; and ‖Unit of Rheumatology, University College London Institute of Child the protein lacks intrinsic enzymatic activity, therefore it trans- Health, London, United Kingdom duces intracellular signals by the recruitment of various adaptor 1C.L. and T.S.W. contributed equally to this work. proteins, including TNFR-associated factors (TRAFs), leading to Received for publication December 15, 2009. Accepted for publication April 1, 2010. the activation of JNK, ERK, p38, NFATc1, AKT, and NF-kB This work was supported by the 973 Scheme of Ministry of Science and Technology signaling pathways (9–13). RANKL (TNF superfamily [TNFSF] (Grant 2006CB504306), the National Natural Science Foundation of China (Grant 11), the only ligand binding to the extracellular portion of RANK 30700749 and 30600623), the National S and T Major Project (Grant 2009ZX09503- 007), the Ministry of Science and Technology Science Exchange Program (Grant (14) was cloned respectively by four different groups (7, 15–17) 2007DFC30240), the Beijing Municipal Natural Science Foundation (Grant and identified as a member of the TNFSF. It is a type II trans- 7072072), and the United Kingdom Medical Research Council and Biotechnology membrane protein, primarily expressed on the surface of activated Biological Sciences Research Council. T-cells, bone marrow stromal cells, and osteoblasts. Soluble forms The coordinates and structure factors presented in this article for the mouse RANK and RANKL–RANK complex have been deposited in the Protein Data Bank with of RANKL that arise from either proteolytic processing or alter- access code 3ME4 and 3ME2, respectively, (www.rcsb.org/pdb/) for immediate re- native mRNA splicing have also been observed (18). Both the lease on publication. membrane-spanning and soluble forms of RANKL are assembled Address correspondence and reprint requests to Prof. Bin Gao and Prof. Jingshan Ren, into functional homotrimers like other members of the TNFSF. Institute of Microbiology, Chinese Academy of Sciences, 1 Beichn Xilu Road, Beijing 100101, China, or Division of Structural Bioloy, Oxford Protein Production Facility, The The binding of RANKL to RANK causes trimerisation of the Wellcome Trust Centre for Human Genetics, The Henry Wellcome Building for Genomic receptor, which activates the signaling pathway and results in Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, U.K.. E-mail ad- osteoclastogenesis from progenitor cells and the activation of ma- dresses: [email protected] and [email protected] ture osteoclasts (19–21). Abbreviations used in this paper: CRD, cysteine-rich domain; GST, glutathione S- transferase; M-CSF, macrophage-CSF; OPG, osteoprotegerin; RANK, receptor Osteoprotegerin (OPG, TNFRSF11B), a soluble homolog of activator of the NF-kB; RANKL, RANK ligand; rmsd, root mean square deviation; RANK primarily secreted by bone marrow stromal cells and TRAF, TNFR-associated factor; TNFRSF, TNFR superfamily; TNFSF, TNF super- osteoblasts, acts as a decoy receptor of RANKL to block the family; TRAP, tartrate-resistant acid phosphatase. binding of RANKL to RANK (22). The RANKL/OPG ratio is Copyright Ó 2010 by The American Association of Immunologists, Inc. 0022-1767/10/$16.00 differently regulated between physiological and pathological www.jimmunol.org/cgi/doi/10.4049/jimmunol.0904033 2 STRUCTURAL INSIGHTS OF RANKL–RANK COMPLEX conditions. Various pathological conditions characterized as Materials and Methods deregulated bone remodeling are associated with an imbalance Cloning, protein expression, and purification between OPG and RANKL. Thus, RANKL, RANK, and OPG Oligonucleotides were prepared by Sangon Biotech (Shanghai, China). provide a ligand/receptor/receptor antagonist system for control- Restriction enzymes, T4 DNA ligase, and First Strand cDNA Synthesis kit ling bone homeostasis and other related biological processes. were purchased from Fermentas (Burlington, Ontario, Canada). Pfu DNA OPG-deficient mice exhibit a decrease in total bone density and polymerase was purchased from Tiangen Biotech (Beijing, China). Glu- develop osteoporosis (23). Mice with a genetic mutation of rank, tathione (reduced and oxidized) was purchased from Sigma-Aldrich phenotypically exactly like rankl2/2 knock-out mice (24), have (St. Louis, MO). The cDNA coding for the extracellular domain of murine RANK severely defective osteoclast development (25), which can be re- (residues 26–210) was obtained by RT-PCR from the mRNA of mouse stored by the reintroduction of rank cDNA into bone marrow RAW264.7 cells and cloned into pET28a vector (Novagen, Madison, WI). progenitor cells (26). In humans, mutations in the genes encoding The expression plasmid for GST–RANKL (encoding residues 159–361 of RANKL and RANK have
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