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Structure of Gremlin-1 and analysis of its interaction with BMP-2

DOI: 10.1042/BCJ20160254 DOI Help

Authors: Migle Kisonaite (Department of Biochemistry, University of Cambridge) , Xuelu Wang (Department of Biochemistry, University of Cambridge) , Marko Hyvonen (Department of Biochemistry, University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Biochemical Journal

State: Published (Approved)
Published: April 2016
Diamond Proposal Number(s): 9537

Abstract: Bone morphogenetic protein 2 (BMP-2) is a member of the transforming growth factor-β (TGF-β) signaling family and has a very broad biological role in development. Its signaling is regulated by many effectors: transmembrane proteins, membrane attached proteins and soluble secreted antagonists such as Gremlin-1. Very little is known about the molecular mechanism by which Gremlin-1 and other DAN family proteins inhibit BMP signaling. We analyzed the interaction of Gremlin-1 with BMP-2 using a range of biophysical techniques, and used mutagenesis to map the binding site on BMP-2. We have also determined the crystal structure of Gremlin-1, revealing a similar conserved dimeric structure as has been seen in other DAN family inhibitors. Measurements using biolayer interferometry indicate that Gremlin-1 and BMP-2 can form larger complexes, beyond the expected 1:1 stoichiometry of dimers, forming oligomers that assemble in alternating fashion. These results suggest that inhibition of BMP-2 by Gremlin-1 occurs by a mechanism that is distinct from other known inhibitors such as Noggin and Chordin and we propose a novel model of BMP-2/Gremlin-1 interaction yet not seen among any BMP antagonists, and cannot rule out that several different oligomeric states could be found, depending on the concentration of the two proteins.

Journal Keywords: Gremlin; bone morphogenetic protein (BMP); transforming growth factor-β; extracellular antagonism; X-ray crystallography

Subject Areas: Biology and Bio-materials


Instruments: B21-High Throughput SAXS , I04-Macromolecular Crystallography

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