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Cell Rep 2016 Aug 23;168:2077-2086. doi: 10.1016/j.celrep.2016.07.046.
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Structure of Gremlin-2 in Complex with GDF5 Gives Insight into DAN-Family-Mediated BMP Antagonism.

Nolan K , Kattamuri C , Rankin SA , Read RJ , Zorn AM , Thompson TB .

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.

PubMed ID: 27524626
PMC ID: PMC5001929
Article link: Cell Rep
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: aopep bmp2 bmpr1a bmpr2 fst gdf5 grem1 nbl1 nog spr szl tnni3

Article Images: [+] show captions
References [+] :
Aykul, New Ligand Binding Function of Human Cerberus and Role of Proteolytic Processing in Regulating Ligand-Receptor Interactions and Antagonist Activity. 2016, Pubmed