Structural analysis of the interaction between human cytokine BMP-2 and the antagonist Noggin reveals molecular details of cell chondrogenesis inhibition.
Noggin; X-ray crystallography; bone morphogenetic protein (BMP); cell differentiation; chondrogenesis; protein folding; protein structure; protein-protein interaction; recombinant protein expression; site-directed mutagenesis; Cell Biology; Molecular Biology; Biochemistry
Abstract :
[en] Bone morphogenetic proteins (BMPs) are secreted cytokines belonging to the transforming growth factor-β (TGF-β) superfamily. New therapeutic approaches based on BMP activity, particularly for cartilage and bone repair, have sparked considerable interest; however, a lack of understanding of their interaction pathways and the side effects associated with their use as biopharmaceuticals have dampened initial enthusiasm. Here, we used BMP-2 as a model system to gain further insight into both the relationship between structure and function in BMPs, and the principles that govern affinity for their cognate antagonist Noggin. We produced BMP- 2 and Noggin as inclusion bodies in Escherichia coli and developed simple and efficient protocols for preparing pure and homogeneous (in terms of size distribution) solutions of the native dimeric forms of the two proteins. The identity and integrity of the proteins were confirmed using mass spectrometry. Additionally, several in vitro cell-based assays, including enzymatic measurements, RT-qPCR and matrix staining, demonstrated their biological activity during cell chondrogenic and hypertrophic differentiation. Furthermore, we characterized the simple 1:1 non-covalent interaction between the two ligands (KDca. 0.4 nM) using bio-layer interferometry and solved the crystal structure of the complex using X-ray diffraction methods. We identified the residues and binding forces involved in the interaction between the two proteins. Finally, results obtained with the BMP-2 N102D mutant suggest that Noggin is remarkably flexible and able to accommodate major structural changes at the BMP-2 level. Altogether, our findings provide insights into BMP-2 activity and reveal the molecular details of its interaction with Noggin.
Filée, Patrice; Laboratory of immuno-biology, CER Groupe, Novalis Science Park, Rue de la Science 8, 6900 Aye, Belgium
Matagne, André ; Université de Liège - ULiège > Département des sciences de la vie > Enzymologie et repliement des protéines
Language :
English
Title :
Structural analysis of the interaction between human cytokine BMP-2 and the antagonist Noggin reveals molecular details of cell chondrogenesis inhibition.
scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.
Bibliography
Uris, M.R., Bone: formation by autoinduction. Science 150 (1965), 893–899.
Katagiri, T., Watabe, T., Bone morphogenetic proteins. Cold Spring Harb. Perspect. Biol., 8, 2016, a021899.
Brazil, D.P., Church, R.H., Surae, S., Godson, C., Martin, F., BMP signalling: agony and antagony in the family. Trends Cell Biol. 25 (2015), 249–264.
Sanchez-Duffhues, G., Williams, E., Goumans, M.J., Heldin, C.H., ten Dijke, P., Bone morphogenetic protein receptors: structure, function and targeting by selective small molecule kinase inhibitors. Bone, 138, 2020, 115472.
Morikawa, M., Derynck, R., Miyazono, K., TGF- β and the TGF-β family: context-dependent roles in cell and tissue physiology. Cold Spring Harb. Perspect. Biol., 8, 2016, a021873.
Ricard, N., Ciais, D., Levet, S., Subileau, M., Mallet, C., Zimmers, T.A., et al. BMP9 and BMP10 are critical for postnatal retinal vascular remodeling. Blood 119 (2012), 6162–6171.
Hart, C.G., Karimi-Abdolrezaee, S., Bone morphogenetic proteins: new insights into their roles and mechanisms in CNS development, pathology and repair. Exp. Neurol., 334, 2020, 113455.
Salazar, V.S., Gamer, L.W., Rosen, V., BMP signalling in skeletal development, disease and repair. Nat. Rev. Endocrinol. 12 (2016), 203–221.
Shu, D.Y., Lovicu, F.J., Insights into bone morphogenetic protein—(BMP-) signaling in ocular lens biology and pathology. Cells, 10, 2021, 2604.
Scheufler, C., Sebald, W., Hülsmeyer, M., Crystal structure of human bone morphogenetic protein-2 at 2.7 Å resolution. J. Mol. Biol. 287 (1999), 103–115.
Griffith, D.L., Keck, P.C., Sampath, T.K., Rueger, D.C., Carlson, W.D., Three-dimensional structure of recombinant human osteogenic protein 1: structural paradigm for the transforming growth factor β superfamily. Proc. Natl. Acad. Sci. U. S. A. 93 (1996), 878–883.
Weber, D., Kotzsch, A., Nickel, J., Harth, S., Seher, A., Mueller, U., et al. A silent H-bond can be mutationally activated for high-affinity interaction of BMP-2 and activin type IIB receptor. BMC Struct. Biol., 7, 2007, 6.
Simic, P., Vukicevic, S., Bone morphogenetic proteins: from developmental signals to tissue regeneration. Conference on Bone Morphogenetic Proteins. EMBO Rep. 8 (2007), 327–331.
Miyazono, K., Kamiya, Y., Morikawa, M., Bone morphogenetic protein receptors and signal transduction. J. Biochem. 147 (2010), 35–51.
Hill, C.S., Transcriptional control by the SMADs. Cold Spring Harb. Perspect. Biol., 8, 2016, a022079.
Yilmaz, A., Kattamuri, C., Ozdeslik, R.N., Schmiedel, C., Mentzer, S., Schorl, C., et al. MuSK is a BMP co-receptor that shapes BMP responses and calcium signaling in muscle cells. Sci. Signal., 9, 2016, ra87.
Villar, A.V., García, R., Llano, M., Cobo, M., Merino, D., Lantero, A., et al. BAMBI (BMP and activin membrane-bound inhibitor) protects the murine heart from pressure-overload biomechanical stress by restraining TGF-β signaling. Biochim. Biophys. Acta - Mol. Basis Dis. 1832 (2013), 323–335.
Sedlmeier, G., Sleeman, J.P., Extracellular regulation of BMP signaling: welcome to the matrix. Biochem. Soc. Trans. 45 (2017), 173–181.
Nickel, J., Ten Dijke, P., Mueller, T.D., TGF-β family co-receptor function and signaling. Acta Biochim. Biophys. Sin. (Shanghai). 50 (2018), 12–36.
Kišonaite, M., Wang, X., Hyvönen, M., Structure of Gremlin-1 and analysis of its interaction with BMP-2. Biochem. J. 473 (2016), 1593–1604.
Groppe, J., Greenwald, J., Wiater, E., Rodriguez-Leon, J., Economides, A.N., Kwiatkowski, W., et al. Structural basis of BMP signalling inhibition by the cystine knot protein Noggin. Nature 420 (2002), 636–642.
Vukicevic, S., Sampath, K., Luyten, F., The role of bone morphogenetic proteins in musculoskeletal system biology. Bone, 141, 2020, 115622.
Van der Kraan, P.M., Van den Berg, W.B., Chondrocyte hypertrophy and osteoarthritis: role in initiation and progression of cartilage degeneration?. Osteoarthr. Cartil. 20 (2012), 223–232.
Yu, X., Kawakami, H., Tahara, N., Olmer, M., Hayashi, S., Akiyama, R., et al. Expression of Noggin and Gremlin1 and its implications in fine-tuning BMP activities in mouse cartilage tissues. J. Orthop. Res. 35 (2017), 1671–1682.
Bobick, B.E., Cobb, J., Shox2 regulates progression through chondrogenesis in the mouse proximal limb. J. Cell Sci. 125 (2012), 6071–6083.
Lian, C., Wang, X., Qiu, X., Wu, Z., Gao, B., Liu, L., et al. Collagen type II suppresses articular chondrocyte hypertrophy and osteoarthritis progression by promoting integrin β1−SMAD1 interaction. Bone Res., 7, 2019, 8.
Dreier, R., Hypertrophic differentiation of chondrocytes in osteoarthritis: the developmental aspect of degenerative joint disorders. Arthritis Res. Ther., 12, 2010, 216.
Gillman, C.E., Jayasuriya, A.C., FDA-approved bone grafts and bone graft substitute devices in bone regeneration. Mater. Sci. Eng. C Mater. Biol., 130, 2021, 112466.
Seeherman, H.J., Berasi, S.P., Brown, C.T., Martinez, R.X., Sean Juo, Z., Jelinsky, S., et al. A BMP/activin A chimera is superior to native BMPs and induces bone repair in nonhuman primates when delivered in a composite matrix. Sci. Transl. Med., 11, 2019, eaar4953.
Wozney, J.M., Overview of bone morphogenetic proteins. Spine (Phila. Pa. 1976) 27 (2002), S2–S8.
James, A.W., LaChaud, G., Shen, J., Asatrian, G., Nguyen, V., Zhang, X., et al. A review of the clinical side effects of bone morphogenetic protein-2. Tissue Eng. - Part B Rev. 22 (2016), 284–297.
Poon, B., Kha, T., Tran, S., Dass, C.R., Bone morphogenetic protein-2 and bone therapy: successes and pitfalls. J. Pharm. Pharmacol. 68 (2016), 139–147.
Berrow, N., de Marco, A., Lebendiker, M., Garcia-Alai, M., Knauer, S.H., Lopez-Mendez, B., et al. Quality control of purified proteins to improve data quality and reproducibility: results from a large-scale survey. Eur. Biophys. J. 50 (2021), 453–460.
de Marco, A., Berrow, N., Lebendiker, M., Garcia-Alai, M., Knauer, S.H., Lopez-Mendez, B., et al. Quality control of protein reagents for the improvement of research data reproducibility. Nat. Commun., 12, 2021, 2795.
Economides, A., Stahl, N.E., Harland, R.M., Modified Noggin Polypetide and Compositions. 2000, University of California Regeneron Pharmaceuticals Inc, United States.
Zhang, W., He, H., Tian, Y., Gan, Q., Zhang, J., Yuan, Y., et al. Calcium ion-induced formation of β-sheet/-turn structure leading to alteration of osteogenic activity of bone morphogenetic protein-2. Sci. Rep., 5, 2015, 12694.
Morrow, J.A., Segall, M.L., Lund-Katz, S., Phillips, M.C., Knapp, M., Rupp, B., et al. Differences in stability among the human apolipoprotein E isoforms determined by the amino-terminal domain. Biochemistry 39 (2000), 11657–11666.
Song, K., Krause, C., Shi, S., Patterson, M., Suto, R., Grgurevic, L., et al. Identification of a key residue mediating bone morphogenetic protein (BMP)-6 resistance to noggin inhibition allows for engineered BMPs with superior agonist activity. J. Biol. Chem. 285 (2010), 12169–12180.
McDonald, N.Q., Hendrickson, W.A., A structural superfamily of growth factors containing a cystine knot motif. Cell 73 (1993), 421–424.
Murray-Rust, J., McDonald, N.Q., Blundell, T.L., Hosang, M., Oefner, C., Winkler, F., et al. Topological similarities in TGF-β2, PDGF-BB and NGF define a superfamily of polypeptide growth factors. Structure 1 (1993), 153–159.
Nolan, K., Kattamuri, C., Rankin, S.A., Read, R.J., Zorn, A.M., Thompson, T.B., Structure of gremlin-2 in complex with GDF5 gives insight into DAN-family-mediated BMP antagonism. Cell Rep 16 (2016), 2077–2086.
Cash, J.N., Rejon, C.A., McPherron, A.C., Bernard, D.J., Thompson, T.B., The structure of myostatin:follistatin 288: insights into receptor utilization and heparin binding. EMBO J. 28 (2009), 2662–2676.
Zhang, J. li, Qiu, L.Y., Kotzsch, A., Weidauer, S., Patterson, L., Hammerschmidt, M., et al. Crystal structure analysis reveals how the chordin family member crossveinless 2 blocks BMP-2 receptor binding. Dev. Cell 14 (2008), 739–750.
Kirsch, T., Sebald, W., Dreyer, M.K., Crystal structure of the BMP-2-BRIA ectodomain complex. Nat. Struct. Biol. 6 (2000), 492–496.
Yao, Y., Wang, Y., ATDC5: an excellent in vitro model cell line for skeletal development. J. Cell. Biochem. 114 (2013), 1223–1229.
Sophia Fox, A.J., Bedi, A., Rodeo, S.A., The basic science of articular cartilage: structure, composition, and function. Sports Health 1 (2009), 461–468.
Caron, M.M.J., Emans, P.J., Cremers, A., Surtel, D.A.M., Coolsen, M.M.E., van Rhijn, L.W., et al. Hypertrophic differentiation during chondrogenic differentiation of progenitor cells is stimulated by BMP-2 but suppressed by BMP-7. Osteoarthr. Cartil. 21 (2013), 604–613.
Steinbusch, M.M.F., Caron, M.M.J., Surtel, D.A.M., Friedrich, F., Lausch, E., Pruijn, G.J.M., et al. Expression of RMRP RNA is regulated in chondrocyte hypertrophy and determines chondrogenic differentiation. Sci. Rep., 7, 2017, 6440.
Nasrabadi, D., Rezaeiani, S., Sayadmanesh, A., Eslaminejad, M.B., Shabani, A., Inclusion body expression and refolding of recombinant bone morphogenetic Protein-2. Avicenna J. Med. Biotechnol. 10 (2018), 202–207.
Vallejo, L.F., Brokelmann, M., Marten, S., Trappe, S., Cabrera-Crespo, J., Hoffmann, A., et al. Renaturation and purification of bone morphogenetic protein-2 produced as inclusion bodies in high-cell-density cultures of recombinant Escherichia coli. J. Biotechnol. 94 (2002), 185–194.
Gieseler, G., Pepelanova, I., Stuckenberg, L., Villain, L., Nölle, V., Odenthal, U., et al. Purification of bone morphogenetic protein-2 from refolding mixtures using mixed-mode membrane chromatography. Appl. Microbiol. Biotechnol. 101 (2017), 123–130.
Guo, W., Zhu, X., Cai, J., Huang, L., Cen, P., Xu, Z., Refolding and two-step purification by hydrophobic interaction chromatography of recombinant human bone morphogenetic protein-2 from Escherichia coli. Process. Biochem. 47 (2012), 960–967.
Von Einem, S., Schwarz, E., Rudolph, R., A novel TWO-STEP renaturation procedure for efficient production of recombinant BMP-2. Protein Expr. Purif. 73 (2010), 65–69.
Hillger, F., Herr, G., Rudolph, R., Schwarz, E., Biophysical comparison of BMP-2, ProBMP-2, and the free pro-peptide reveals stabilization of the pro-peptide by the mature growth factor. J. Biol. Chem. 280 (2005), 14974–14980.
Venyaminov, S.Y., Yang, J.T., Determination of protein secondary structure. Fasman, G.D., (eds.) Circular Dichroism and the Conformational Analysis of Biomolecules, 1996, Plenum, NY, 69–107.
Woody, R.W., Dunker, A.K., Aromatic and cystine side-chain circular dichroism in proteins. Fasman, G.D., (eds.) Circular Dichroism and the Conformational Analysis of Biomolecules, 1996, Plenum, New York, 109–157.
Chen, H., Tan, X.N., Hu, S., Liu, R.Q., Peng, L.H., Li, Y.M., et al. Molecular mechanisms of chondrocyte proliferation and differentiation. Front. Cell Dev. Biol., 9, 2021, 664168.
Yoon, B.S., Pogue, R., Ovchinnikov, D.A., Yoshii, I., Mishina, Y., Behringer, R.R., et al. BMPs regulate multiple aspects of growth-plate chondrogenesis through opposing actions on FGF pathways. Development 133 (2006), 4667–4678.
Allendorph, G.P., Vale, W.W., Choe, S., Structure of the ternary signaling complex of a TGF-β superfamily member. Proc. Natl. Acad. Sci. U. S. A. 103 (2006), 7643–7648.
Hinck, A.P., Mueller, T.D., Springer, T.A., Structural biology and evolution of the TGF-β family. Cold Spring Harb. Perspect. Biol., 8, 2016, a022103.
Yoon, B.H., Esquivies, L., Ahn, C., Gray, P.C., Ye, S.K., Kwiatkowski, W., et al. An activin A/BMP2 chimera, AB204, displays bone-healing properties superior to those of BMP2. J. Bone Miner. Res. 29 (2014), 1950–1959.
Harrington, A.E., Morris-Triggs, S.A., Ruotolo, B.T., Robinson, C.V., Ohnuma, S.I., Hyvönen, M., Structural basis for the inhibition of activin signalling by follistatin. EMBO J. 25 (2006), 1035–1045.
Magalhães, P.O., Lopes, A.M., Mazzola, P.G., Rangel-yagui, C., Penna, T.C.V., Pessoa, A.J., Methods of endotoxin removal from biological preparations: a review. J. Pharm. Sci. 10 (2007), 388–404.
Pace, C.N., Vajdos, F., Fee, L., Grimsley, G., Gray, T., How to measure and predict the molar absorption coefficient of a protein. Protein Sci. 4 (1995), 2411–2423.
Johnson, W.C., Analyzing protein circular dichroism spectra for accurate secondary structures. Proteins Struct. Funct. Genet. 35 (1999), 307–312.
Sreerama, N., Woody, R.W., Estimation of protein secondary structure from circular dichroism spectra: comparison of CONTIN, SELCON, and CDSSTR methods with an expanded reference set. Anal. Biochem. 287 (2000), 252–260.
Provencher, S.W., Glöckner, J., Estimation of globular protein secondary structure from circular dichroism. Biochemistry 20 (1981), 33–37.
van Stokkum, I.H.M., Spoelder, H.J.W., Bloemendal, M., van Grondelle, R., Groen, F.C.A., Estimation of protein secondary structure and error analysis from circular dichroism spectra. Anal. Biochem. 191 (1990), 110–118.
Kabsch, W., Xds. Acta Crystallogr. Sect. D Biol. Crystallogr. 66 (2010), 125–132.
This website uses cookies to improve user experience. Read more
Save & Close
Accept all
Decline all
Show detailsHide details
Cookie declaration
About cookies
Strictly necessary
Performance
Strictly necessary cookies allow core website functionality such as user login and account management. The website cannot be used properly without strictly necessary cookies.
This cookie is used by Cookie-Script.com service to remember visitor cookie consent preferences. It is necessary for Cookie-Script.com cookie banner to work properly.
Performance cookies are used to see how visitors use the website, eg. analytics cookies. Those cookies cannot be used to directly identify a certain visitor.
Used to store the attribution information, the referrer initially used to visit the website
Cookies are small text files that are placed on your computer by websites that you visit. Websites use cookies to help users navigate efficiently and perform certain functions. Cookies that are required for the website to operate properly are allowed to be set without your permission. All other cookies need to be approved before they can be set in the browser.
You can change your consent to cookie usage at any time on our Privacy Policy page.