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Structure analysis of bone morphogenetic protein-2 type I receptor complexes reveals a mechanism of receptor inactivation in juvenile polyposis syndrome.

Kotzsch A, Nickel J, Seher A, Heinecke K, van Geersdaele L, Herrmann T, Sebald W, Mueller TD
J Biol Chem 283 5876-87 (2008)
Related entries: 2qja, 2qjb

Cited: 37 times
EuropePMC logo PMID: 18160401

Abstract

Bone morphogenetic proteins regulate many developmental processes during embryogenesis as well as tissue homeostasis in the adult. Signaling of bone morphogenetic proteins (BMPs) is accomplished by binding to two types of serine/threonine kinase transmembrane receptors termed type I and type II. Because a large number of ligands signal through a limited number of receptors, ligand-receptor interaction in the BMP superfamily is highly promiscuous, with a ligand binding to various receptors and a receptor binding many different BMP ligands. In this study we investigate the interaction of BMP-2 with its two high affinity type I receptors, BMP receptors IA (BMPR-IA) and BMPR-IB. Interestingly, 50% of the residues in the BMP-2 binding epitope of the BMPR-IA receptor are exchanged in BMPR-IB without a decrease in binding affinity or specificity for BMP-2. Our structural and functional analyses show that promiscuous binding of BMP-2 to both type I receptors is achieved by inherent backbone and side-chain flexibility as well as by variable hydration of the ligand-receptor interface enabling the BMP-2 surface to adapt to different receptor geometries. Despite the high degree of amino acid variability found in BMPR-IA and BMPR-IB binding equally to BMP-2, three single point missense mutations in the ectodomain of BMPR-IA cannot be tolerated. In juvenile polyposis syndrome these mutations have been shown to inactivate BMPR-IA. On the basis of our biochemical and biophysical analyses, we can show that the mutations, which are located outside the ligand binding epitope, alter the local or global fold of the receptor, thereby inactivating BMPR-IA and causing a loss of the BMP-2 tumor suppressor function in colon epithelial cells.

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Reviews citing this publication (8)

  1. Signaling Receptors for TGF-β Family Members. Heldin CH, Moustakas A. Cold Spring Harb Perspect Biol 8 a022053 (2016)
  2. Structural Biology and Evolution of the TGF-β Family. Hinck AP, Mueller TD, Springer TA. Cold Spring Harb Perspect Biol 8 a022103 (2016)
  3. Bone morphogenetic protein and growth differentiation factor cytokine families and their protein antagonists. Rider CC, Mulloy B. Biochem J 429 1-12 (2010)
  4. Intricacies of BMP receptor assembly. Nickel J, Sebald W, Groppe JC, Mueller TD. Cytokine Growth Factor Rev 20 367-377 (2009)
  5. Grading the commercial optical biosensor literature-Class of 2008: 'The Mighty Binders'. Rich RL, Myszka DG. J Mol Recognit 23 1-64 (2010)
  6. Signaling pathways involved in osteogenesis and their application for bone regenerative medicine. Hayrapetyan A, Jansen JA, van den Beucken JJ. Tissue Eng Part B Rev 21 75-87 (2015)
  7. Structural biology of the TGFβ family. Goebel EJ, Hart KN, McCoy JC, Thompson TB. Exp Biol Med (Maywood) 244 1530-1546 (2019)
  8. Structural perspective of BMP ligands and signaling. Gipson GR, Goebel EJ, Hart KN, Kappes EC, Kattamuri C, McCoy JC, Thompson TB. Bone 140 115549 (2020)

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  1. SKEMPI: a Structural Kinetic and Energetic database of Mutant Protein Interactions and its use in empirical models. Moal IH, Fernández-Recio J. Bioinformatics 28 2600-2607 (2012)
  2. Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2. Dathe K, Kjaer KW, Brehm A, Meinecke P, Nürnberg P, Neto JC, Brunoni D, Tommerup N, Ott CE, Klopocki E, Seemann P, Mundlos S. Am J Hum Genet 84 483-492 (2009)
  3. Receptor oligomerization and beyond: a case study in bone morphogenetic proteins. Heinecke K, Seher A, Schmitz W, Mueller TD, Sebald W, Nickel J. BMC Biol 7 59 (2009)
  4. Enrichment map profiling of the cancer invasion front suggests regulation of colorectal cancer progression by the bone morphogenetic protein antagonist, gremlin-1. Karagiannis GS, Berk A, Dimitromanolakis A, Diamandis EP. Mol Oncol 7 826-839 (2013)
  5. Discovery of fully human anti-MET monoclonal antibodies with antitumor activity against colon cancer tumor models in vivo. van der Horst EH, Chinn L, Wang M, Velilla T, Tran H, Madrona Y, Lam A, Ji M, Hoey TC, Sato AK. Neoplasia 11 355-364 (2009)
  6. GDF-5 can act as a context-dependent BMP-2 antagonist. Klammert U, Mueller TD, Hellmann TV, Wuerzler KK, Kotzsch A, Schliermann A, Schmitz W, Kuebler AC, Sebald W, Nickel J. BMC Biol 13 77 (2015)
  7. New insights into the molecular mechanism of multiple synostoses syndrome (SYNS): mutation within the GDF5 knuckle epitope causes noggin-resistance. Schwaerzer GK, Hiepen C, Schrewe H, Nickel J, Ploeger F, Sebald W, Mueller T, Knaus P. J Bone Miner Res 27 429-442 (2012)
  8. BMP-2 and bFGF release and in vitro effect on human osteoblasts after adsorption to bone grafts and biomaterials. Draenert FG, Nonnenmacher AL, Kämmerer PW, Goldschmitt J, Wagner W. Clin Oral Implants Res 24 750-757 (2013)
  9. Expression patterns of bone morphogenetic protein antagonists in colorectal cancer desmoplastic invasion fronts. Karagiannis GS, Treacy A, Messenger D, Grin A, Kirsch R, Riddell RH, Diamandis EP. Mol Oncol 8 1240-1252 (2014)
  10. BmpR1A is a major type 1 BMP receptor for BMP-Smad signaling during skull development. Pan H, Zhang H, Abraham P, Komatsu Y, Lyons K, Kaartinen V, Mishina Y. Dev Biol 429 260-270 (2017)
  11. Production, Isolation, and Structural Analysis of Ligands and Receptors of the TGF-β Superfamily. Huang T, Hinck AP. Methods Mol Biol 1344 63-92 (2016)
  12. An evolutionary and structural characterization of mammalian protein complex organization. Wong P, Althammer S, Hildebrand A, Kirschner A, Pagel P, Geissler B, Smialowski P, Blöchl F, Oesterheld M, Schmidt T, Strack N, Theis FJ, Ruepp A, Frishman D. BMC Genomics 9 629 (2008)
  13. Optimal effector functions in human natural killer cells rely upon autocrine bone morphogenetic protein signaling. Robson NC, Hidalgo L, Mc Alpine T, Wei H, Martínez VG, Entrena A, Melen GJ, MacDonald AS, Phythian-Adams A, Sacedón R, Maraskovsky E, Cebon J, Ramírez M, Vicente A, Varas A. Cancer Res 74 5019-5031 (2014)
  14. Secreted phosphoprotein 24 kD (Spp24) and Spp14 affect TGF-β induced bone formation differently. Tian H, Bi X, Li CS, Zhao KW, Brochmann EJ, Montgomery SR, Aghdasi B, Chen D, Daubs MD, Wang JC, Murray SS. PLoS One 8 e72645 (2013)
  15. BMP pathway suppression is an early event in inflammation-driven colon neoplasmatogenesis of uPA-deficient mice. Karagiannis GS, Afaloniati H, Karamanavi E, Poutahidis T, Angelopoulou K. Tumour Biol 37 2243-2255 (2016)
  16. Modifications of human growth differentiation factor 9 to improve the generation of embryos from low competence oocytes. Li JJ, Sugimura S, Mueller TD, White MA, Martin GA, Ritter LJ, Liang XY, Gilchrist RB, Mottershead DG. Mol Endocrinol 29 40-52 (2015)
  17. N-linked glycosylation of the bone morphogenetic protein receptor type 2 (BMPR2) enhances ligand binding. Lowery JW, Amich JM, Andonian A, Rosen V. Cell Mol Life Sci 71 3165-3172 (2014)
  18. A selection fit mechanism in BMP receptor IA as a possible source for BMP ligand-receptor promiscuity. Harth S, Kotzsch A, Hu J, Sebald W, Mueller TD. PLoS One 5 e13049 (2010)
  19. A host-guest relationship in bone morphogenetic protein receptor-II defines specificity in ligand-receptor recognition. Yeh LC, Falcon WE, Garces A, Lee JC, Lee JC. Biochemistry 51 6968-6980 (2012)
  20. Heterodimer-heterotetramer formation mediates enhanced sensor activity in a biophysical model for BMP signaling. Karim MS, Madamanchi A, Dutko JA, Mullins MC, Umulis DM. PLoS Comput Biol 17 e1009422 (2021)
  21. BMPR1A mutations in juvenile polyposis affect cellular localization. Howe JR, Dahdaleh FS, Carr JC, Wang D, Sherman SK, Howe JR. J Surg Res 184 739-745 (2013)
  22. High-throughput measurements of bone morphogenetic protein/bone morphogenetic protein receptor interactions using biolayer interferometry. Khodr V, Machillot P, Migliorini E, Reiser JB, Picart C. Biointerphases 16 031001 (2021)
  23. Crystallization of BMP receptor type IA bound to the antibody Fab fragment AbD1556. Harth S, Kotzsch A, Sebald W, Mueller TD. Acta Crystallogr Sect F Struct Biol Cryst Commun 66 964-968 (2010)
  24. The anti-myeloma activity of bone morphogenetic protein 2 predominantly relies on the induction of growth arrest and is apoptosis-independent. Lagler C, El-Mesery M, Kübler AC, Müller-Richter UDA, Stühmer T, Nickel J, Müller TD, Wajant H, Seher A. PLoS One 12 e0185720 (2017)
  25. Familial juvenile polyposis syndrome with a de novo germline missense variant in BMPR1A gene: a case report. Liu Q, Liu M, Liu T, Yu Y. BMC Med Genet 21 196 (2020)
  26. Moderate-Affinity Affibodies Modulate the Delivery and Bioactivity of Bone Morphogenetic Protein-2. Dorogin J, Hochstatter HB, Shepherd SO, Svendsen JE, Benz MA, Powers AC, Fear KM, Townsend JM, Prell JS, Hosseinzadeh P, Hettiaratchi MH. Adv Healthc Mater 12 e2300793 (2023)


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