Williams Eleanor, Riesebos Elise, Kerr Georgina, Bullock Alex N
Centre for Medicines Discovery, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 BT Amsterdam, The Netherlands.
Biomedicines. 2021 Jan 29;9(2):129. doi: 10.3390/biomedicines9020129.
The immunophilin FKBP12 is a known inhibitor of type I BMP and TGF-β receptors that competes for binding with their substrate SMADs. FKBP12 and the close paralog FKBP12.6 additionally assemble with ryanodine receptors to control Ca release. Binding of FKBP12.6 to BMP/TGF-β receptors has yet to be investigated, but appears plausible given its high sequence similarity to FKBP12. Here, we found that FKBP12.6 can assemble with BMP and TGF-β-family type I receptors, but not with type II receptors. Cellular immunoprecipitation confirmed similar binding of FKBP12 and FKBP12.6 to the BMP receptor ALK2 (ACVR1), a known target of mutations in the congenital syndrome fibrodysplasia ossificans progressiva (FOP), as well as the pediatric brain tumor diffuse intrinsic pontine glioma (DIPG). SEC-MALS analyses using purified proteins indicated a direct 1:1 interaction between FKBP12.6 and the receptor's cytoplasmic domains. The 2.17 Å structure of this ALK2-FKBP12.6 complex bound to the inhibitor dorsomorphin showed FKBP12.6 binding to the GS domain of ALK2 in a manner equivalent to the FKBP12 complex, with ALK2 residues Phe198 and Leu199 extending into the FK506-binding pocket of FKBP12.6. These findings suggest a level of redundancy in FKBP-family regulation of BMP and TGF-β signaling.
亲免蛋白FKBP12是已知的I型骨形态发生蛋白（BMP）和转化生长因子-β（TGF-β）受体抑制剂，它能竞争与其底物SMADs结合。FKBP12和关系密切的旁系同源物FKBP12.6还能与雷诺丁受体组装在一起，以控制钙离子释放。FKBP12.6与BMP/TGF-β受体的结合情况尚未得到研究，但鉴于其与FKBP12的高度序列相似性，这种结合似乎是有可能的。在这里，我们发现FKBP12.6可以与BMP和TGF-β家族的I型受体组装在一起，但不能与II型受体组装。细胞免疫沉淀证实，FKBP12和FKBP12.6与BMP受体ALK2（ACVR1）的结合相似，ALK2是先天性进行性骨化性纤维发育不良（FOP）综合征以及儿童脑肿瘤弥漫性固有桥脑胶质瘤（DIPG）中已知的突变靶点。使用纯化蛋白进行的尺寸排阻色谱-多角度光散射（SEC-MALS）分析表明，FKBP12.6与受体的胞质结构域之间存在直接的1:1相互作用。这种与抑制剂多形蛋白结合的ALK2-FKBP12.6复合物的2.17 Å结构显示，FKBP12.6以与FKBP12复合物等效的方式与ALK2的GS结构域结合，ALK2的苯丙氨酸198和亮氨酸199残基延伸到FKBP12.6的FK506结合口袋中。这些发现表明，FKBP家族对BMP和TGF-β信号的调节存在一定程度的冗余。
