Dimerization interface of osteoprotegerin revealed by hydrogen–deuterium exchange mass spectrometry

Xiao, Yiming; Li, Miaomiao; Larocque, Rinzhi; Zhang, Fuming; Malhotra, Anju; Chen, Jianle; Linhardt, Robert J.; Konermann, Lars; Xu, Ding

doi:10.1074/jbc.ra118.004489

Cited by 6 publications

(7 citation statements)

References 38 publications

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“…A PSI-BLAST search across TNFSFR sequences, to identify other family members with hydrophobic C-terminal motifs at this location only finds OPG, a soluble decoy receptor for RANKL, which interestingly also has a bent shape curved away from the ligand. The hydrophobic motif in this OPG CRD domain has been hypothesized to interact intramolecularly with the flanking death domain 1 32 , but has not been tested for CRD–CRD interactions.…”

Section: Resultsmentioning

confidence: 99%

“…If CRD3-CRD3 interactions are responsible for bringing together neighboring receptor trimers to form an intracellular TRAF network, it would be consistent with the diminished intracellular signaling we see in the IL-2 assay from mutations that reduce those interactions. These C-terminal interactions would also allow TMDs from neighboring GITR molecules to interact, the importance of which has been shown for other TNFR members, such as FAS, which forms trimers 32 , or DR5, which forms both dimers and trimers 36,37 . If GITR has dimeric TMD interactions, it might explain the residual clustering seen with the AA mutant.…”

Section: Discussionmentioning

confidence: 99%

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Structures of mouse and human GITR–GITRL complexes reveal unique TNF superfamily interactions

et al. 2021

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Glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) and GITR ligand (GITRL) are members of the tumor necrosis superfamily that play a role in immune cell signaling, activation, and survival. GITR is a therapeutic target for directly activating effector CD4 and CD8 T cells, or depleting GITR-expressing regulatory T cells (Tregs), thereby promoting anti-tumor immune responses. GITR activation through its native ligand is important for understanding immune signaling, but GITR structure has not been reported. Here we present structures of human and mouse GITR receptors bound to their cognate ligands. Both species share a receptor–ligand interface and receptor–receptor interface; the unique C-terminal receptor–receptor enables higher order structures on the membrane. Human GITR–GITRL has potential to form a hexameric network of membrane complexes, while murine GITR–GITRL complex forms a linear chain due to dimeric interactions. Mutations at the receptor–receptor interface in human GITR reduce cell signaling with in vitro ligand binding assays and minimize higher order membrane structures when bound by fluorescently labeled ligand in cell imaging experiments.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Structures of mouse and human GITR–GITRL complexes reveal unique TNF superfamily interactions

et al. 2021

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“…1A). We and others have previously determined that the CRDs are responsible for RANKL binding, while the D2 and tail domain are responsible for binding to HS (7,(15)(16)(17)(18). Eight basic amino acid residues have been identified to mediate HS binding in OPG (Fig.…”

Section: Resultsmentioning

confidence: 99%

Antiresorptive activity of osteoprotegerin requires an intact heparan sulfate-binding site

2020

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

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Osteoprotegerin (OPG), a secreted decoy receptor for receptor activator of nuclear factor B ligand (RANKL), plays an essential role in regulating bone resorption. While much is known about the function of the N-terminal domains of OPG, which is responsible for binding to RANKL, the exact biological functions of the three C-terminal domains of OPG remain uncertain. We have previously shown that one likely function of the C-terminal domains of OPG is to bind cell surface heparan sulfate (HS), but the in vivo evidence was lacking. To investigate the biological significance of OPG–HS interaction in bone remodeling, we created OPG knock-in mice (opgAAA). The mutated OPG is incapable of binding to HS but binds RANKL normally. Surprisingly, opgAAA/AAA mice displayed a severe osteoporotic phenotype that is very similar to opg-null mice, suggesting that the antiresorption activity of OPG requires HS. Mechanistically, we propose that the HS immobilizes secreted OPG at the surface of osteoblasts lineage cells, which facilitates binding of OPG to membrane-anchored RANKL. To further support this model, we altered the structure of osteoblast HS genetically to make it incapable of binding to OPG. Interestingly, osteocalcin-Cre;Hs2stf/f mice also displayed osteoporotic phenotype with similar severity to opgAAA/AAA mice. Combined, our data provide strong genetic evidence that OPG–HS interaction is indispensable for normal bone homeostasis.

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“…OPG is also a TNFR family member, the only one to be produced as a soluble monomer or homodimer within the cells. The two forms of the protein are both released and active, however, the disulfide-linked dimer has a higher binding affinity for RANKL exerting more potent biological activity [38].…”

Section: Discussionmentioning

confidence: 99%

Rank-Rankl-Opg Axis in Multiple Sclerosis: The Contribution of Placenta

Passaponti

Ermini

Acconci

et al. 2022

Cells

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Women with multiple sclerosis (MS) can safely become pregnant and give birth, with no side effects or impediments. Pregnancy is generally accepted as a period of well-being in which relapses have a softer evolution, particularly in the third trimester. Herein, we hypothesized that the placenta, via its “secretome”, could contribute to the recognized beneficial effects of pregnancy on MS activity. We focused on a well-known receptor/ligand/decoy receptor system, such as the one composed by the receptor activator of nuclear factor-kB (RANK), its ligand (RANKL), and the decoy receptor osteoprotegerin (OPG), which have never been investigated in an integrated way in MS, pregnancy, and placenta. We reported that pregnancy at the term of gestation influences the balance between circulating RANKL and its endogenous inhibitor OPG in MS women. We demonstrated that the placenta at term is an invaluable source of homodimeric OPG. By functional studies on astrocytes, we showed that placental OPG suppresses the mRNA expression of the CCL20, a chemokine responsible for Th17 cell recruitment. We propose placental OPG as a crucial molecule for the recognized beneficial effect of late pregnancy on MS and its potential utility for the development of new and more effective therapeutic approaches.

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Dimerization interface of osteoprotegerin revealed by hydrogen–deuterium exchange mass spectrometry

Cited by 6 publications

References 38 publications

Structures of mouse and human GITR–GITRL complexes reveal unique TNF superfamily interactions

Structures of mouse and human GITR–GITRL complexes reveal unique TNF superfamily interactions

Antiresorptive activity of osteoprotegerin requires an intact heparan sulfate-binding site

Rank-Rankl-Opg Axis in Multiple Sclerosis: The Contribution of Placenta

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