Characterization of the Ligand Binding Functionality of the Extracellular Domain of Activin Receptor Type IIB
Open accessAbstract
The single transmembrane domain serine/threonine kinase activin receptor type IIB (ActRIIB) has been proposed to bind key regulators of skeletal muscle mass development, including the ligands GDF-8 (myostatin) and GDF-11 (BMP-11). Here we provide a detailed kinetic characterization of ActRIIB binding to several low and high affinity ligands using a soluble activin receptor type IIB-Fc chimera (ActRIIB.Fc). We show that both GDF-8 and GDF-11 bind the extracellular domain of ActRIIB with affinities comparable with those of activin A, a known high affinity ActRIIB ligand, whereas BMP-2 and BMP-7 affinities for ActRIIB are at least 100-fold lower. Using site-directed mutagenesis, we demonstrate that ActRIIB binds GDF-11 and activin A in different ways such as, for example, substitutions in ActRIIB Leu(79) effectively abolish ActRIIB binding to activin A yet not to GDF-11. Native ActRIIB has four isoforms that differ in the length of the C-terminal portion of their extracellular domains. We demonstrate that the C terminus of the ActRIIB extracellular domain is crucial for maintaining biological activity of the ActRIIB.Fc receptor chimera. In addition, we show that glycosylation of ActRIIB is not required for binding to activin A or GDF-11. Together, our findings reveal binding specificity and activity determinants of the ActRIIB receptor that combine to effect specificity in the activation of distinct signaling pathways.
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BMP-4, BMP-6, BMP-7, and TGFβ1 are not known to be capable of binding ACVR2B.
“none of which are known to be capable of binding ACVR2B (32).”
From Targeting myostatin/activin A protects against skeletal muscle and bone loss during spaceflight (2020) · cites this paper as [32]
The Results report that BMP-7 binds the extracellular domain of ActRIIB.Fc, and Table 1 gives a measured binding affinity of 418 pM. This directly contradicts the claim that BMP-7 is not known to bind ACVR2B. The passages do not establish whether BMP-4, BMP-6, or TGFβ1 bind it; no page numbers are available in our copy. (LLM, conf=0.91)
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References 42 · Cited by 152
Research works printed but not linked: 4
- Lee, S. J., Reed, L. A., Davies, M. V., Girgenrath, S., Goad, M. E., Tomkin- son, K. N., Wright, J. F., Barker, C., Ehrmantraut, G., Holmstrom, J., Trow- ell, B., Gertz, B., Jiang, M. S., Sebald, S. M., Matzuk, M., Li, E., Liang, L. F., Quattlebaum, E., Stotish, R. L., and Wolfman, N. M. (2005) Proc. Natl. Acad. Sci. U.S.A. 102, 18117-18122
- Pearsall, R. S., Canalis, E., Cornwall-Brady, M., Underwood, K. W., Haigis, B., Ucran, J., Kumar, R., Pobre, E., Grinberg, A., Werner, E. D., Glatt, V., Stadmeyer, L., Smith, D., Seehra, J., and Bouxsein, M. L. (2008) Proc. Natl. Acad. Sci. U.S.A. 105, 7082-7087
- Wolfman, N. M., McPherron, A. C., Pappano, W. N., Davies, M. V., Song, K., Tomkinson, K. N., Wright, J. F., Zhao, L., Sebald, S. M., Greenspan, D. S., and Lee, S. J. (2003) Proc. Natl. Acad. Sci. U.S.A. 100, 15842-15846
- McPherron, A. C., and Lee, S. J. (1997) Proc. Natl. Acad. Sci. U.S.A. 94, 12457-12461
- Authors
- Sako, D., Grinberg, A. V., Liu, J., Davies, M. V., Castonguay, R., Maniatis, S., Andreucci, A. J., Pobre, E. G., Tomkinson, K. N., Monnell, T. E., Ucran, J. A., Martinez-Hackert, E., Pearsall, R. S., Underwood, K. W., Seehra, J., & Kumar, R.
- Affiliations
- Acceleron Pharma (United States) (US)
- Harvard University (US)
- Corresponding author
- Kumar, Ravindra
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2010-07
- Volume
- 285
- Issue
- 27
- Pages
- 21037-21048
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2898293
- OpenAlex
- W2122484354
- Cited by
- 152
- References
- 42
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 9 · 2023: 5 · 2022: 7 · 2021: 17 · 2020: 16 · 2019: 14 · 2018: 5 · 2017: 9 · 2016: 9 · 2015: 12 · 2014: 9 · 2013: 9 · 2012: 10
- FWCI
- 3.65
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Acceleron
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- ActRIIB, ligand specificity, myostatin, GDF11, activin A, BMP-2, BMP-7, extracellular domain, receptor isoforms, C-terminal domain, glycosylation, binding kinetics, skeletal muscle mass, receptor chimeras
- MeSH terms
- Animals, Binding Sites, Chlorocebus aethiops, Humans, Ligands, Plasmids, Plasminogen Activators, Protein Binding, Recombinant Fusion Proteins, Mutagenesis, Genes, Reporter, DNA, Complementary, COS Cells, Activin Receptors, Type II, Mutant Chimeric Proteins, Myostatin
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