Structural and functional insights of RANKL-RANK interaction and signaling.
Bone remodeling involves bone resorption by osteoclasts and synthesis by osteoblasts and is tightly regulated by the receptor activator of the NF-kappaB ligand (RANKL)/receptor activator of the NF-kappaB (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 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 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.
Liu
Changzhen
C
The Center for Molecular Immunology, Institute of Microbiology, Chinese Academy of Sciences, Department of Orthopaedics, Chinese People's Liberation Army General Hospital, Beijing, China.
Walter
Thomas S
TS
Huang
Peng
P
Zhang
Shiqian
S
Zhu
Xuekai
X
Wu
Ying
Y
Wedderburn
Lucy R
LR
Tang
Peifu
P
Owens
Raymond J
RJ
Stuart
David I
DI
Ren
Jingshan
J
Gao
Bin
B
D000595:Amino Acid Sequence; D000818:Animals; D003460:Crystallization; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D020836:Protein Structure, Quaternary; D053245:RANK Ligand / Q000737:chemistry* / Q000378:metabolism*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000737:chemistry* / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000276:immunology*; D014961:X-Ray Diffraction
D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B