Type II BMP and activin receptors BMPR2 and ACVR2A share a conserved mode of growth factor recognition.
Type II BMP and activin receptors BMPR2 and ACVR2A share a conserved mode of growth factor recognition.
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DOI：
10.1016/j.jbc.2022.102076
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发表时间：
2022-07
影响因子：
4.8
通讯作者：
Martinez-Hackert, Erik
中科院分区：
文献类型：
--
作者：
Chu, Kit-Yee;Malik, Anjali;Thamilselvan, Vijayalakshmi;Martinez-Hackert, Erik
BMPR2是一种II型转化生长因子(TGF)-β家族受体，与人类肺动脉高压（PAH）有根本关系。BMPR2与II型激活素受体ACVR2A和ACVR2B具有功能上的相似性，因为它与一组重叠的TGF-β家族生长因子（GFs）相互作用。然而，BMPR2如何识别GFs仍然知之甚少。在这里，我们解决了BMPR2与GF激活素B的配合物和ACVR2A与相关GF激活素a的配合物的晶体结构。我们发现BMPR2和ACVR2A都使用保守的疏水热点以几乎相同的几何形状结合GF，而接触残基的差异主要存在于环路区域。在进一步探索这两种受体的gf结合谱后，我们发现，尽管许多GFs结合了这两种受体，但高亲和力的BMPR2 GFs包括BMP15、BMP10和Nodal，而ACVR2A的GFs是激活素A、激活素B和GDF11。最后，我们评估了人类PAH患者中发现的gf结合域BMPR2变异。我们证明，GF结合界面内的突变导致GF结合丧失，而环区突变允许BMPR2保留高亲和力结合同源GF的能力。总之，BMPR2变体的体外活性和本文报道的晶体结构表明，生物化学相关复合物解释了一些gf结合结构域变体如何导致多环芳烃。
BMPR2 is a type II Transforming Growth Factor (TGF)-β family receptor that is fundamentally associated with pulmonary arterial hypertension (PAH) in humans. BMPR2 shares functional similarities with the type II activin receptors ACVR2A and ACVR2B, as it interacts with an overlapping group of TGF-β family growth factors (GFs). However, how BMPR2 recognizes GFs remains poorly understood. Here, we solved crystal structures of BMPR2 in complex with the GF activin B and of ACVR2A in complex with the related GF activin A. We show that both BMPR2 and ACVR2A bind GFs with nearly identical geometry using a conserved hydrophobic hot spot, while differences in contacting residues are predominantly found in loop areas. Upon further exploration of the GF-binding spectrum of the two receptors, we found that although many GFs bind both receptors, the high-affinity BMPR2 GFs comprise BMP15, BMP10, and Nodal, whereas those of ACVR2A are activin A, activin B, and GDF11. Lastly, we evaluated GF-binding domain BMPR2 variants found in human PAH patients. We demonstrate that mutations within the GF-binding interface resulted in loss of GF binding, while mutations in loop areas allowed BMPR2 to retain the ability to bind cognate GFs with high affinity. In conclusion, the in vitro activities of BMPR2 variants and the crystal structures reported here indicate biochemically relevant complexes that explain how some GF-binding domain variants can lead to PAH.
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发表时间：
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影响因子：
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