title: The prodomain of BMP4 is necessary and sufficient to generate stable BMP4/7 heterodimers with enhanced bioactivity in vivo.
abstract: Bone morphogenetic proteins 4 and 7 (BMP4 and BMP7) are morphogens that signal as either homodimers or heterodimers to regulate embryonic development and adult homeostasis. BMP4/7 heterodimers exhibit markedly higher signaling activity than either homodimer, but the mechanism underlying the enhanced activity is unknown. BMPs are synthesized as inactive precursors that dimerize and are then cleaved to generate both the bioactive ligand and prodomain fragments, which lack signaling activity. Our study reveals a previously unknown requirement for the BMP4 prodomain in promoting heterodimer activity. We show that BMP4 and BMP7 precursor proteins preferentially or exclusively form heterodimers when coexpressed in vivo. In addition, we show that the BMP4 prodomain is both necessary and sufficient for generation of stable heterodimeric ligands with enhanced activity and can enable homodimers to signal in a context in which they normally lack activity. Our results suggest that intrinsic properties of the BMP4 prodomain contribute to the relative bioactivities of homodimers versus heterodimers in vivo. These findings have clinical implications for the use of BMPs as regenerative agents for the treatment of bone injury and disease.
authors.affiliation: Departments of Neurobiology and Anatomy and.
authors.forename: Judith M
authors.initials: JM
authors.lastname: Neugebauer
authors.affiliation: Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University School of Medicine, Portland, OR 97239-3098.
authors.forename: Sunjong
authors.initials: S
authors.lastname: Kwon
authors.affiliation: Departments of Neurobiology and Anatomy and.
authors.forename: Hyung-Seok
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University School of Medicine, Portland, OR 97239-3098.
authors.forename: Nathan
authors.initials: N
authors.lastname: Donley
authors.affiliation: Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University School of Medicine, Portland, OR 97239-3098.
authors.forename: Anup
authors.initials: A
authors.lastname: Tilak
authors.affiliation: Department of Cell, Developmental and Cancer Biology, Oregon Health & Science University School of Medicine, Portland, OR 97239-3098.
authors.forename: Shailaja
authors.initials: S
authors.lastname: Sopory
authors.affiliation: Departments of Neurobiology and Anatomy and Internal Medicine, Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, UT 84132-3401; and jan.christian@neuro.utah.edu.
authors.forename: Jan L
authors.initials: JL
authors.lastname: Christian
mesh_terms: D000818:Animals; D055415:Bone Morphogenetic Protein 4 / Q000737:chemistry*; D055419:Bone Morphogenetic Protein 7 / Q000737:chemistry*; D000939:Epitopes / Q000737:chemistry; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D051379:Mice; D011485:Protein Binding; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry; D015398:Signal Transduction; D014981:Xenopus
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D055419:Bone Morphogenetic Protein 7; D000939:Epitopes; D008024:Ligands; D011994:Recombinant Proteins; C525820:bmp7 protein, mouse
keywords: BMP4; BMP7; bone morphogenetic protein; heterodimer; prodomain