title: Designer nodal/BMP2 chimeras mimic nodal signaling, promote chondrogenesis, and reveal a BMP2-like structure.
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.
authors: From the Structural Biology Laboratory.
authors: Luis
authors: L
authors: Esquivies
authors: Alissa
authors: A
authors: Blackler
authors: Macarena
authors: M
authors: Peran
authors: Concepcion
authors: C
authors: Rodriguez-Esteban
authors: Juan Carlos
authors: JC
authors: Izpisua Belmonte
authors: Evan
authors: E
authors: Booker
authors: Peter C
authors: PC
authors: Gray
authors: Chihoon
authors: C
authors: Ahn
authors: Witek
authors: W
authors: Kwiatkowski
authors: Senyon
authors: S
authors: Choe
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D055396:Bone Morphogenetic Protein 2 / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D002356:Cartilage / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D020219:Chondrogenesis / Q000187:drug effects*; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D055457:Nodal Protein / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D058851:GPI-Linked Proteins; D036341:Intercellular Signaling Peptides and Proteins; C526007:NODAL protein, human; D009363:Neoplasm Proteins; D055457:Nodal Protein; D011993:Recombinant Fusion Proteins; D051899:Smad2 Protein; C070636:TDGF1 protein, human
keywords: Bone Morphogenetic Protein (BMP); Cartilage Biology; Chondrogenesis; Nodal; Protein Chimeras; Protein Structure