Gremlin1 preferentially binds to Bone Morphogenetic Protein-2 (BMP-2) and BMP-4 over BMP-7

Rachel H. Church, Arjun Krishnakumar, Annika Urbanek, Stefan Geschwinder, Julie Meneely, Alessandro Bianchi, Barbro Basta, Sean Monaghan, Christopher Elliott, Maria Stromstedt, Neil Ferguson, Finian Martin, Derek P. Brazil

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Abstract

Gremlin (Grem1) is a member of the DAN family of secreted bone morphogenetic protein (BMP) antagonists. Bone morphogenetic protein-7 (BMP-7) mediates protective effects during renal fibrosis-associated with diabetes and other renal diseases. The pathogenic mechanism of Grem1 during DN has been suggested to be binding and inhibition of BMP-7. However, the precise interactions between Grem1, BMP-7 and other BMPs have not been accurately defined. Here we show the affinity of Grem1 for BMP-7 is lower than that of BMP-2 and BMP-4, using a combination of surface plasmon resonance and cell culture techniques. Using kidney proximal tubule cells and HEK-293 cell Smad1/5/8 phosphorylation and BMP-dependent gene expression as readout, Grem1 consistently demonstrated a higher affinity for BMP-2>4>7. Cell-associated Grem1 did not inhibit BMP-2 or BMP-4 mediated signalling, suggesting that Grem1-BMP-2 binding occurred in solution, preventing BMP receptor activation. These data suggest that Grem1 preferentially binds to BMP-2 and this may be the dominant complex in a disease situation where levels of Grem1 and BMPs are elevated.
Original languageEnglish
Pages (from-to)55-68
Number of pages14
JournalBiochemical Journal
Volume466
Issue number1
Early online date07 Nov 2014
DOIs
Publication statusPublished - 15 Feb 2015

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