Goebel Erich J, Kattamuri Chandramohan, Gipson Gregory R, Krishnan Lavanya, Chavez Moises, Czepnik Magdalena, Maguire Michelle C, Grenha Rosa, Håkansson Maria, Logan Derek T, Grinberg Asya V, Sako Dianne, Castonguay Roselyne, Kumar Ravindra, Thompson Thomas B
Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, 231 Albert Sabin Way ML 0524, Cincinnati, OH 45267, USA.
Acceleron Pharma, Inc., Cambridge, MA 02139, USA.
iScience. 2021 Dec 9;25(1):103590. doi: 10.1016/j.isci.2021.103590. eCollection 2022 Jan 21.
The 30+ unique ligands of the TGFβ family signal by forming complexes using different combinations of type I and type II receptors. Therapeutically, the extracellular domain of a single receptor fused to an Fc molecule can effectively neutralize subsets of ligands. Increased ligand specificity can be accomplished by using the extracellular domains of both the type I and type II receptor to mimic the naturally occurring signaling complex. Here, we report the structure of one "type II-type I-Fc" fusion, ActRIIB-Alk4-Fc, in complex with two TGFβ family ligands, ActA, and GDF11, providing a snapshot of this therapeutic platform. The study reveals that extensive contacts are formed by both receptors, replicating the ternary signaling complex, despite the inherent low affinity of Alk4. Our study shows that low-affinity type I interactions support altered ligand specificity and can be visualized at the molecular level using this platform.
转化生长因子β（TGFβ）家族的30多种独特配体通过使用I型和II型受体的不同组合形成复合物来发出信号。在治疗方面，与Fc分子融合的单个受体的细胞外结构域可以有效地中和配体亚群。通过使用I型和II型受体的细胞外结构域来模拟天然存在的信号复合物，可以提高配体特异性。在这里，我们报告了一种“II型-I型-Fc”融合蛋白ActRIIB-Alk4-Fc与两种TGFβ家族配体ActA和GDF11形成复合物的结构，提供了这个治疗平台的一个快照。该研究表明，尽管Alk4具有固有的低亲和力，但两种受体都形成了广泛的接触，复制了三元信号复合物。我们的研究表明，低亲和力的I型相互作用支持改变的配体特异性，并且可以使用这个平台在分子水平上可视化。
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