A conserved electrostatic lock in the kinase domain prevents STKR1 activation.

<p>(<b>a</b>) Scheme of TGFβ/BMP/Activin induced signaling. (<b>b</b>) Structure of FKBP12-ALK2 complex and a close view of the R375-D354 salt bridge, as well as other salt bridges and hydrogen bonds involving R375 in ALK2 are illustrated. A conserved Lys-Glu pair (K235-E248) between β3 sheet and αC helix is also shown here. (<b>c</b>) Structural alignment of the kinase domain from nine crystal structures. R-D salt bridge residues are shown in CPK mode. Five ALK5 crystal structures without FKBP12 bound are taken from PDB 1IAS, 2WOT, 3TZM, 4X2N, and 5E8S. The overlapped A-loop is shown in blue. ALK2 with FKBP12 bound is shown in cyan (PDB 3H9R) and ALK5 with FKBP12 bound is in purple (PDB 1B6C). For STKR2, ActRIIB is shown in orange (PDB 2QLU) and BMPRII in yellow (PDB 3G2F). The missing A-loop in ALK2 crystal structure (residues 362–374) was transplanted from the crystal structure of inactive ALK2 structure PDB 3Q4U. Small molecular inhibitors in ATP binding site of the crystal structures are not shown. (<b>d</b>) Partial sequence alignment of human STKR1 (ALK1-7) and STKR2 isoforms (ActRIIA and B, TGFβR2, BMPRII and AMHRII) showing strict conservation of the positively-charged electrostatic lock in all SKTR1 isoforms while being absent in all constitutively active SKTR2 isoforms.