Abstract
Nodal, a member of the TGF-β 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.
Keywords:
Bone Morphogenetic Protein (BMP); Cartilage Biology; Chondrogenesis; Nodal; Protein Chimeras; Protein Structure.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adipose Tissue / metabolism*
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Adipose Tissue / pathology
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Adult
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Bone Morphogenetic Protein 2* / chemistry
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Bone Morphogenetic Protein 2* / genetics
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Bone Morphogenetic Protein 2* / pharmacology
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Cartilage / injuries
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Cartilage / metabolism
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Cartilage / pathology
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Cell Line
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Chondrogenesis / drug effects*
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Female
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GPI-Linked Proteins / genetics
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GPI-Linked Proteins / metabolism
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Humans
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Intercellular Signaling Peptides and Proteins / genetics
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Intercellular Signaling Peptides and Proteins / metabolism
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Nodal Protein* / chemistry
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Nodal Protein* / genetics
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Nodal Protein* / pharmacology
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Recombinant Fusion Proteins* / chemistry
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Recombinant Fusion Proteins* / genetics
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Recombinant Fusion Proteins* / pharmacology
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Signal Transduction / drug effects*
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Signal Transduction / genetics
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Smad2 Protein / genetics
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Smad2 Protein / metabolism
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Stem Cells / metabolism*
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Stem Cells / pathology
Substances
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BMP2 protein, human
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Bone Morphogenetic Protein 2
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GPI-Linked Proteins
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Intercellular Signaling Peptides and Proteins
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NODAL protein, human
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Neoplasm Proteins
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Nodal Protein
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Recombinant Fusion Proteins
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Smad2 Protein
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TDGF1 protein, human