Designer Nodal/BMP2 chimeras mimic Nodal signaling, promote chondrogenesis, and reveal a BMP2-like structure [Protein Structure and Folding]

December 5th, 2013 by Esquivies, L., Blackler, A., Peran, M., Rodriguez-Esteban, C., Izpisua Belmonte, J. C., Booker, E., Gray, P. C., Ahn, C., Kwiatkowski, W., Choe, S.

Nodal, a member of the Transforming Growth Factor-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 due to 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.