title: Structure of protein related to Dan and Cerberus: insights into the mechanism of bone morphogenetic protein antagonism.
abstract: The bone morphogenetic proteins (BMPs) are secreted ligands largely known for their functional roles in embryogenesis and tissue development. A number of structurally diverse extracellular antagonists inhibit BMP ligands to regulate signaling. The differential screening-selected gene aberrative in neuroblastoma (DAN) family of antagonists represents the largest group of BMP inhibitors; however, little is known of how they mechanistically inhibit BMP ligands. Here, we present the structure of the DAN family member, protein related to Dan and Cerberus (PRDC), solved by X-ray crystallography. The structure reveals a growth factor-like appearance with an unexpected dimerization mechanism that is formed through extensive β strand contacts. Using site-directed mutagenesis coupled with in vitro and in vivo activity assays, we identified a BMP-binding epitope on PRDC. We also determined that PRDC binds heparin with high affinity and that heparin binding to PRDC interferes with BMP antagonism. These results offer insight for how DAN family antagonists functionally inhibit BMP ligands.
authors.affiliation: Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati, Medical Sciences Building, Cincinnati, OH 45267, USA.
authors.forename: Kristof
authors.initials: K
authors.lastname: Nolan
authors.forename: Chandramohan
authors.initials: C
authors.lastname: Kattamuri
authors.forename: David M
authors.initials: DM
authors.lastname: Luedeke
authors.forename: Xiaodi
authors.initials: X
authors.lastname: Deng
authors.forename: Amrita
authors.initials: A
authors.lastname: Jagpal
authors.forename: Fuming
authors.initials: F
authors.lastname: Zhang
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Linhardt
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kenny
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Zorn
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Thompson
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000502:physiology; D018797:Cell Cycle Proteins; D018360:Crystallography, X-Ray; D016207:Cytokines; D006493:Heparin / Q000737:chemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000502:physiology; D053838:Scattering, Small Angle; D040681:Structural Homology, Protein; D013499:Surface Properties; D029867:Xenopus Proteins / Q000737:chemistry; D014982:Xenopus laevis
chemical_list: C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D018797:Cell Cycle Proteins; D016207:Cytokines; C490088:Grem2 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; C490089:Nbl1 protein, mouse; D011506:Proteins; D029867:Xenopus Proteins; C100866:cer1 protein, Xenopus; D006493:Heparin