title: Bone morphogenetic protein-2 and -6 heterodimer illustrates the nature of ligand-receptor assembly.
abstract: TGF-beta superfamily ligands are homo- or heterodimeric and recruit two type I and two type II Ser/Thr kinase receptors to initiate a transmembrane signaling cascade. Even with the known structure of the homodimer ligands in complex with extracellular domains of both receptor types, the sequential assembly of the signaling complex with its cognate receptors in the cell membrane remains elusive. We generated a bone morphogenetic protein-2/-6 heterodimer carrying two asymmetric interfaces for each receptor type. We demonstrate that the heterodimer possesses high affinity to both receptor types and increased Smad1-dependent signaling activity by both cell-based and chondrogenesis assays. Furthermore, we find that the minimal signaling complex consists of two type II receptors and one type I receptor per dimer. Our study reveals how the engineered heterodimers may use their independent binding interfaces to differentially recruit the different receptors for each receptor type to create new biological properties.
authors.affiliation: Structural Biology Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Isaacs
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kawakami
authors.forename: George P
authors.initials: GP
authors.lastname: Allendorph
authors.forename: Byung-Hak
authors.initials: BH
authors.lastname: Yoon
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Izpisua Belmonte
authors.forename: Senyon
authors.initials: S
authors.lastname: Choe
mesh_terms: D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism*; D055418:Bone Morphogenetic Protein 6 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D015202:Protein Engineering; D055503:Protein Multimerization / Q000235:genetics / Q000502:physiology; D020349:Surface Plasmon Resonance
chemical_list: C525816:BMP6 protein, human; D055396:Bone Morphogenetic Protein 2; D055418:Bone Morphogenetic Protein 6