Structural basis for ALK2/BMPR2 receptor complex signaling through kinase domain oligomerization.
Structural basis for ALK2/BMPR2 receptor complex signaling through kinase domain oligomerization.
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DOI：
10.1038/s41467-021-25248-5
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发表时间：
2021-08-16
影响因子：
16.6
通讯作者：
Jura N
中科院分区：
文献类型：
--
作者：
Agnew C;Ayaz P;Kashima R;Loving HS;Ghatpande P;Kung JE;Underbakke ES;Shan Y;Shaw DE;Hata A;Jura N
骨形态发生蛋白(BMP)受体与配体结合后形成活性的四聚体复合体，由两个I型和两个II型受体组成，然后将信号传递给SMAD蛋白。然而，受体四聚化和激酶激活机制之间的联系还没有被阐明。在这里，我们利用氢-氚交换质谱仪(HDX-MS)、小角X射线散射(SAXS)和分子动力学(MD)模拟，结合对SMAD信号的分析，证明了I型受体ALK2和II型受体BMPR2的激动域通过它们的C-末端叶形成了一个异二聚体复合体。这种二聚体的形成是配体诱导的受体信号转导所必需的，并且是肺动脉高压(PAH)患者BMPR2突变的靶点。我们进一步证明，I型/II型激酶域异源二聚体作为组装活性四聚体受体复合体的支架，使GS结构域磷酸化和Smads激活。骨形态发生蛋白(BMP)受体是由两个I型和两个II型BMP受体组成的四聚体复合体，是一种单程跨膜丝氨酸/苏氨酸激酶。在这里，作者描述了一种活性的I型/II型激酶四聚体的结构，为深入了解驱动配体诱导的信号转导的分子机制提供了线索。
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. Bone morphogenetic protein (BMP) receptors are single pass transmembrane serine/threonine kinases that form tetrameric complexes comprised of two type I and two type II BMP receptors. Here the authors characterize a structure of an active type I/type II kinase tetramer providing insight into molecular mechanism driving ligand-induced signaling.
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影响因子：
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通讯作者：
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