Designer Nodal/BMP2 Chimeras Mimic Nodal Signaling, Promote Chondrogenesis, and Reveal a BMP2-like Structure
- Authors
- Esquivies, Luis; Blackler, Alissa; Peran, Macarena; Rodriguez-Esteban, Concepcion; Izpisua Belmonte, Juan Carlos; Booker, Evan; Gray, Peter C.; Ahn, Chihoon; Kwiatkowski, Witek; Choe, Senyon
- Issue Date
- 17-Jan-2014
- Publisher
- AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
- Keywords
- Bone Morphogenetic Protein (BMP); Cartilage Biology; Chondrogenesis; Protein Chimeras; Protein Structure; Nodal
- Citation
- JOURNAL OF BIOLOGICAL CHEMISTRY, v.289, no.3, pp.1788 - 1797
- Journal Title
- JOURNAL OF BIOLOGICAL CHEMISTRY
- Volume
- 289
- Number
- 3
- Start Page
- 1788
- End Page
- 1797
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/12902
- DOI
- 10.1074/jbc.M113.529180
- ISSN
- 1083-351X
- Abstract
- Background: Nodal is a TGF- superfamily member that plays important roles in development and diseases but is difficult to produce for biochemical studies. Results: Nodal promotes chondrogenesis, and Nodal/bone morphogenetic protein 2 chimeras function indistinguishably from Nodal but have BMP2-like structure. Conclusion: Nodal/BMP2 chimeras can substitute for Nodal in functional and structural studies. Significance: Nodal/BMP2 chimeras have therapeutic potential. Nodal, a member of the TGF- superfamily, plays an important role in vertebrate and invertebrate early development. The biochemical study of Nodal and its signaling pathway has been a challenge, mainly because of difficulties in producing the protein in sufficient quantities. We have developed a library of stable, chemically refoldable Nodal/BMP2 chimeric ligands (NB2 library). Three chimeras, named NB250, NB260, and NB264, show Nodal-like signaling properties including dependence on the co-receptor Cripto and activation of the Smad2 pathway. NB250, like Nodal, alters heart looping during the establishment of embryonic left-right asymmetry, and both NB250 and NB260, as well as Nodal, induce chondrogenic differentiation of human adipose-derived stem cells. This Nodal-induced differentiation is shown to be more efficient than BPM2-induced differentiation. Interestingly, the crystal structure of NB250 shows a backbone scaffold similar to that of BMP2. Our results show that these chimeric ligands may have therapeutic implications in cartilage injuries.
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