Structural basis for ALK2/BMPR2 receptor complex signaling through kinase domain oligomerization

Nat Commun. 2021 Aug 16;12(1):4950. doi: 10.1038/s41467-021-25248-5.


Upon ligand binding, bone morphogenetic protein (BMP) receptors form active tetrameric complexes, comprised of two type I and two type II receptors, which then transmit signals to SMAD proteins. The link between receptor tetramerization and the mechanism of kinase activation, however, has not been elucidated. Here, using hydrogen deuterium exchange mass spectrometry (HDX-MS), small angle X-ray scattering (SAXS) and molecular dynamics (MD) simulations, combined with analysis of SMAD signaling, we show that the kinase domain of the type I receptor ALK2 and type II receptor BMPR2 form a heterodimeric complex via their C-terminal lobes. Formation of this dimer is essential for ligand-induced receptor signaling and is targeted by mutations in BMPR2 in patients with pulmonary arterial hypertension (PAH). We further show that the type I/type II kinase domain heterodimer serves as the scaffold for assembly of the active tetrameric receptor complexes to enable phosphorylation of the GS domain and activation of SMADs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Activin Receptors, Type I / chemistry*
  • Activin Receptors, Type I / genetics
  • Activin Receptors, Type I / metabolism*
  • Bone Morphogenetic Protein Receptors / metabolism
  • Bone Morphogenetic Protein Receptors, Type II / chemistry*
  • Bone Morphogenetic Protein Receptors, Type II / genetics
  • Bone Morphogenetic Protein Receptors, Type II / metabolism*
  • Bone Morphogenetic Proteins / metabolism
  • Familial Primary Pulmonary Hypertension / metabolism
  • Humans
  • Ligands
  • Models, Molecular
  • Mutation
  • Phosphorylation
  • Protein Binding
  • Protein Domains
  • Pulmonary Arterial Hypertension
  • Scattering, Small Angle
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Smad Proteins / metabolism
  • X-Ray Diffraction


  • Bone Morphogenetic Proteins
  • Ligands
  • Smad Proteins
  • ACVR1 protein, human
  • Activin Receptors, Type I
  • BMPR2 protein, human
  • Bone Morphogenetic Protein Receptors
  • Bone Morphogenetic Protein Receptors, Type II