title: Structure of Gremlin-2 in Complex with GDF5 Gives Insight into DAN-Family-Mediated BMP Antagonism.
abstract: The DAN family, including Gremlin-1 and Gremlin-2 (Grem1 and Grem2), represents a large family of secreted BMP (bone morphogenetic protein) antagonists. However, how DAN proteins specifically inhibit BMP signaling has remained elusive. Here, we report the structure of Grem2 bound to GDF5 at 2.9-Å resolution. The structure reveals two Grem2 dimers binding perpendicularly to each GDF5 monomer, resembling an H-like structure. Comparison to the unbound Grem2 structure reveals a dynamic N terminus that undergoes significant transition upon complex formation, leading to simultaneous interaction with the type I and type II receptor motifs on GDF5. Binding studies show that DAN-family members can interact with BMP-type I receptor complexes, whereas Noggin outcompetes the type I receptor for ligand binding. Interestingly, Grem2-GDF5 forms a stable aggregate-like structure in vitro that is not clearly observed for other antagonists, including Noggin and Follistatin. These findings exemplify the structural and functional diversity across the various BMP antagonist families.
authors.affiliation: Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, OH 45267, USA.
authors.forename: Kristof
authors.initials: K
authors.lastname: Nolan
authors.affiliation: Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, OH 45267, USA.
authors.forename: Chandramohan
authors.initials: C
authors.lastname: Kattamuri
authors.affiliation: Perinatal Institute, Cincinnati Children's Research Foundation, and Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Rankin
authors.affiliation: Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, England.
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Read
authors.affiliation: Perinatal Institute, Cincinnati Children's Research Foundation, and Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45229, USA.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Zorn
authors.affiliation: Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, OH 45267, USA. Electronic address: tom.thompson@uc.edu.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Thompson
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D055396:Bone Morphogenetic Protein 2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins; D002460:Cell Line; D018360:Crystallography, X-Ray; D016207:Cytokines; D004625:Embryo, Nonmammalian; D038681:Follistatin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D055428:Growth Differentiation Factor 5 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D011506:Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis; D000099176:Noggin Protein
chemical_list: D055396:Bone Morphogenetic Protein 2; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D016207:Cytokines; D038681:Follistatin; D055428:Growth Differentiation Factor 5; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D011994:Recombinant Proteins; D000099176:Noggin Protein; C525718:BMP2 protein, human; C525893:GDF5 protein, human; C495107:GREM2 protein, human; C490087:NBL1 protein, human