5HK5

Structure of the Grem2-GDF5 Inhibitory Complex

Summary for 5HK5

• Entry DOI: 10.2210/pdb5hk5/pdb
• Descriptor: Gremlin-2, Growth/differentiation factor 5 (2 entities in total)
• Functional Keywords: dan-family, bone morphogenetic proteins, cytokine
• Biological source: Mus musculus (Mouse); More
• Total number of polymer chains: 8
• Total formula weight: 122424.48

Authors

Nolan, K.,Thompson, T.B.,Read, R.J. (deposition date: 2016-01-13, release date: 2016-08-24, Last modification date: 2024-11-13)

Primary citation

Nolan, K.,Kattamuri, C.,Rankin, S.A.,Read, R.J.,Zorn, A.M.,Thompson, T.B.
Structure of Gremlin-2 in Complex with GDF5 Gives Insight into DAN-Family-Mediated BMP Antagonism.
Cell Rep, 16:2077-2086, 2016

PubMed 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.

PubMed: 27524626
DOI: 10.1016/j.celrep.2016.07.046

Experimental method

X-RAY DIFFRACTION (2.9 Å)