Fig. 8: Conservation of the electrostatic C-lobe interfaces and the N dimer interface in the TGFβ superfamily receptors.

a The electrostatic surface potential at the C1 dimer interface calculated using APBS and the available crystal structures of the TGFβ superfamily of kinases. Type I receptors: ALK1 (PDB: 3MY0), ALK6 (PDB: 3MDY) and TGFβR1 (PDB: 5E8S). Type II receptors: ACVR2a (PDB: 3Q4T), ACVR2b (PDB: 2QLU), and TGFβR2 (PDB: 5E8V). All type I kinases are oriented the same way as the ALK2 kinase and type II kinases as the BMPR2 kinase in Fig. 1c. b Sequence alignment of the regions within the human TGFβ superfamily of receptors that correspond to the C dimer interface. Identical residues are highlighted by a gray background. Similar residues are colored as light blue in type I and light orange in type II receptors. Residues tested by mutations in our experiments are marked by circles and numbered. The position of the TGFβR1 NANDOR (non-activating non-down-regulating) box is highlighted in dark blue below the sequence alignment. c The proposed model for the oligomeric transitions between the ALK2 and BMPR2 kinase domains in response to ligand binding. The interaction of ALK2 and BMPR2 in the C1 dimer provides an autoinhibitory mechanism in which the GS domain of ALK2 is protected from BMPR2-mediated phosphorylation. Upon ligand-induced formation of the receptor tetramer, the kinase domains are brought into close proximity promoting interactions between ALK2 and BMPR2 via the N dimer, and the presentation of the GS domains to the active sites of the BMPR2 kinases for phosphorylation. When the GS domains are phosphorylated, the tetramer could dissociate to two C1 dimers in which the ALK2 kinases are now active, cartooned as a magenta rim around them.