Figure 7

Model of mechanism of BMP selectivity in axon orienting ability. (A-D) Ball and stick structural representations of BMP7, BMP6 and BMP7 bound to the AcRIIA ECD. The images were generated with Cn3D v4.3 software (http://www.ncbi.nlm.nih.gov), shown at low and high magnification. (A) Views of the BMP7 monomer (PDB: 1LX1, [23] focusing on the region containing Arg⁴⁸ (residue highlighted in yellow). (B) Views of the BMP6 monomer (PDB: 2R52, [33]) in the proximity of Gln⁴⁸ (yellow). (C) Enlargement and overlay of the boxed areas in the lower panels in A and B illustrating the differences in the configuration of residues in this region: for BMP7, Arg⁴⁸ and Glu⁶⁰ (blue); for BMP6, Gln⁴⁸ (red) and Lys⁶⁰ (brown). The arrangement of residues in this region is likely to influence binding specificity and subsequent functional outcomes. (D) High magnification view of the BMP7/ActRIIA ECD complex (PDB: 1LX5; [23]. BMP7 is rotated with respect to the view in A to illustrate the predicted interaction of Arg⁴⁸ in BMP7 and Lys⁷⁶ in ActRIIA. (E) Axon orientation and growth cone collapse is evoked by BMP7 but not by BMP6 and involves signaling dependent on PI3K [9] and, by analogy with BMP7-evoked monocyte chemotaxis [8], likely depends on activation of ActRIIA. Our model proposes that BMP7 and other orienting BMPs are able selectively to activate a receptor complex comprising ActRIIA, BMPRII and BMPRIB (see [8, 9, 13]) but that Gln⁴⁸ in BMP6 prevents interaction with this complex. (F) The induction pathway, activated by both BMP7 and BMP6, and all other BMPs, leads to stimulation of the Smad cascade and induction of target genes. This transduction mechanism has a high threshold for activity, is not selectively dependent on any of the type II BMPRs [8, 9] and is unaffected by chimeric BMPs that alter orienting activity.