Coreceptors for transforming growth factor β (TGF-β) family members. Coreceptors for transforming growth factor β (TGF-β) family members. (A) The carboxy-terminal zona pellucida (ZP-C) domain of betaglycan (3QW9) (Lin et al. 2011). (B) The coreceptor cripto comprises small epidermal growth factor (EGF)-like and CFC domains. The CFC domain of cripto adopts an extended architecture lacking secondary structure and is stabilized by three disulfide bonds (yellow sticks) (2J5H, Calvanese et al. 2006). Two residues involved in binding of the CFC-domain to ALK4, His104, and Trp107, are shown with green side chains. (C) The amino-terminal domain (ND) of RGMb (RGMbND) in cartoon (green), bound to a BMP-2 dimer (surface, with type I and type II receptor binding sites in light green and pink, respectively) (PDB 4UI0 [Healey et al. 2015]). (D) Similar structural elements are used in the interaction of BMP-2 with RGMbND (upper panel) and ALK3 (lower panel). Leu103, conserved in all three repulsive guidance molecules (RGMs), engages in a hydrophobic knob-into-hole interaction resembling that of the phenylalanine residue conserved among BMP type I receptors (Phe85 in ALK3 and Phe66 in ALK6). Moreover, the Phe-Pro motif (surface and side chains in magenta) found in Smad1-, 5-, and/or 8-activating BMPs forms a hydrophobic patch between the 1st and 3rd helix of the RGM three-helix bundle to mimic interaction with ALK3. His106 in RGMb, conserved in all three RGMs, makes a π-stacking interaction with a conserved Trp in bone morphogenetic protein (BMP) and renders BMP-binding by RGMs pH-sensitive. (E) RGM binds via RGMND (green cartoon) to BMP (gray and black monomer surfaces with the type I and type II receptor sites in light green and pink, respectively) and via RGMBCD (cyan cartoon) to neogenin (dark blue cartoon) (PDB 4UI2 [Healey et al. 2015]). RGMbCD links to RGMND with a flexible linker (dashed lines) that is only partially observed in the crystal structure (green cartoon with disulfides to RGMbCD in gold stick). The acid-labile Asp-Pro bond (marked with GD↓PH) is at the carboxy-terminal end of β-strand 1 of the β-sandwich of RGMbCD. This β-strand and two disulfide bonds maintain covalent linkage between RGMbND and RGMbCD despite cleavage at the Asp-Pro bond. (F) As in E, but viewed along the dyad of the BMP GF dimer. Andrew P. Hinck et al. Cold Spring Harb Perspect Biol 2016;8:a022103 ©2016 by Cold Spring Harbor Laboratory Press