Dataset Information

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

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) 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.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Eric Underbakke

LAB HEAD: Eric S. Underbakke

PROVIDER: PXD022944 | Pride | 2021-08-16

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	Alk2-BMPR2vsGS-Alk2-BMPR2CSVfiles.zip	Other
	Alk2_or_BMPR2_vs_complex-Complex-0s-A.raw	Raw
	Alk2_or_BMPR2_vs_complex-Complex-15s-A.raw	Raw
	Alk2_or_BMPR2_vs_complex-Complex-15s-B.raw	Raw
	Alk2_or_BMPR2_vs_complex-Complex-15s-C.raw	Raw

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

Agnew Christopher C Ayaz Pelin P Kashima Risa R Loving Hanna S HS Ghatpande Prajakta P Kung Jennifer E JE Underbakke Eric S ES Shan Yibing Y Shaw David E DE Hata Akiko A Jura Natalia N

Nature communications 20210816 1

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 ...[more]

PMID: 34400635

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