Abstract
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.
Highlights
Upon ligand binding, bone morphogenetic protein (BMP) receptors form active tetrameric complexes, comprised of two type I and two type II receptors, which transmit signals to SMAD proteins
We describe a heterodimeric complex formed by the kinase domains of type I receptor ALK2 and type II receptor BMPR2, which engages the C-terminal lobes of both kinases
Using molecular dynamics (MD) simulations, we show that two such autoinhibited ALK2/BMPR2 heterodimers can interact across a newly identified interface that engages the N-terminal lobes (N-lobes) of the type-I and type-II kinases, resulting in the dissociation of the GS domains of the type I kinases and their subsequent positioning into the active sites of the type II kinases for phosphorylation
Summary
Bone morphogenetic protein (BMP) receptors form active tetrameric complexes, comprised of two type I and two type II receptors, which transmit signals to SMAD proteins. 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 the type I/type II tetramer promotes transphosphorylation of the intracellular portions of the receptors, resulting in recruitment and activation of the receptor-specific SMAD (R-SMAD) transcription factors This tetrameric receptor arrangement around a dimeric ligand is unique to the RSTKs and significantly differs from known mechanisms of RTK activation, which tend to activate via the formation of dimeric complexes upon growth factor binding.
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