Structure of the bone morphogenetic protein receptor ALK2 and implications for fibrodysplasia ossificans progressiva.
Structure of the bone morphogenetic protein receptor ALK2 and implications for fibrodysplasia ossificans progressiva.
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DOI：
10.1074/jbc.m112.365932
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发表时间：
2012-10-26
期刊：
影响因子：
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通讯作者：
Bullock AN
中科院分区：
文献类型：
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作者：
Chaikuad A;Alfano I;Kerr G;Sanvitale CE;Boergermann JH;Triffitt JT;von Delft F;Knapp S;Knaus P;Bullock AN
背景：ALK2激酶中的突变会导致骨架外骨形成。
结果：我们解决了与抑制剂FKBP12复合物中ALK2的结构。
结论：疾病突变破坏了关键相互作用，稳定了无活跃的ALK2-FKBP12复合物，导致激酶激活。
意义：我们为突变的效果和针对小分子抑制剂设计的结构模板提供了解释。
骨形态发生蛋白（BMP）受体激酶受到紧密调节，以控制发育和组织稳态。 BMP受体ALK2中FOP相关的突变降低了抑制剂FKBP12的结合，并促进了泄漏的信号缺乏配体来建立受体调节的结构机制，并解决了FOP突变的影响，我们确定了与抑制剂FKBP12和抑制作用的晶体结构。激酶，从而支持减少FKBP12结合并促进富含甘氨酸 - 丝氨酸富环和αC的正确定位的结构重排激活螺旋的螺旋效应是R206H和L196P的可比活性结构提供了一个有价值的模板，用于进一步设计BMP信号的特定抑制剂。
Background: Mutations in the ALK2 kinase cause extraskeletal bone formation. Results: We solved the structure of ALK2 in complex with the inhibitor FKBP12. Conclusion: Disease mutations break critical interactions that stabilize the inactive ALK2-FKBP12 complex leading to kinase activation. Significance: We offer an explanation for the effects of mutation and a structural template for the design of small molecule inhibitors. Bone morphogenetic protein (BMP) receptor kinases are tightly regulated to control development and tissue homeostasis. Mutant receptor kinase domains escape regulation leading to severely degenerative diseases and represent an important therapeutic target. Fibrodysplasia ossificans progressiva (FOP) is a rare but devastating disorder of extraskeletal bone formation. FOP-associated mutations in the BMP receptor ALK2 reduce binding of the inhibitor FKBP12 and promote leaky signaling in the absence of ligand. To establish structural mechanisms of receptor regulation and to address the effects of FOP mutation, we determined the crystal structure of the cytoplasmic domain of ALK2 in complex with the inhibitors FKBP12 and dorsomorphin. FOP mutations break critical interactions that stabilize the inactive state of the kinase, thereby facilitating structural rearrangements that diminish FKBP12 binding and promote the correct positioning of the glycine-serine-rich loop and αC helix for kinase activation. The balance of these effects accounts for the comparable activity of R206H and L196P. Kinase activation in the clinically benign mutant L196P is far weaker than R206H but yields equivalent signals due to the stronger interaction of FKBP12 with R206H. The presented ALK2 structure offers a valuable template for the further design of specific inhibitors of BMP signaling.