Activin A forms a non-signaling complex with ACVR1 and type II Activin/BMP receptors via its finger 2 tip loop

Activin A functions in BMP signaling in two ways: it either engages ACVR1B to activate Smad2/3 signaling or binds ACVR1 to form a non-signaling complex (NSC).  Although the former property has been studied extensively, the roles of the NSC remain unexplored.  The genetic disorder fibrodysplasia ossificans progressiva (FOP) provides a unique window into ACVR1/Activin A signaling because in that disease Activin can either signal through FOP-mutant ACVR1 or form NSCs with wild type ACVR1.  To explore the role of the NSC, we generated ‘agonist-only’ Activin A muteins that activate ACVR1B but cannot form the NSC with ACVR1.  Using one of these muteins we demonstrate that failure to form the NSC in FOP results in more severe disease pathology. These results provide the first evidence for a biological role for the NSC in vivo and pave the way for further exploration of the NSC’s physiological role in corresponding knock-in mice.

激活素A（Activin A）可通过两种方式参与骨形态发生蛋白（BMP）信号通路：一是结合活化素受体1B（ACVR1B）以激活Smad2/3信号通路，二是与活化素受体1（ACVR1）结合形成非信号复合物（non-signaling complex, NSC）。
尽管前者的功能已被广泛研究，但非信号复合物的生物学功能仍尚未被阐明。
遗传性疾病进行性骨化性纤维发育不良（fibrodysplasia ossificans progressiva, FOP）为研究ACVR1/激活素A信号通路提供了独特视角——在该疾病中，激活素A既可通过携带FOP突变的ACVR1传导信号，也可与野生型ACVR1形成非信号复合物。
为探究非信号复合物的功能，我们构建了仅具备激动剂活性的激活素A突变体，这类突变体可结合ACVR1B激活信号通路，但无法与ACVR1形成非信号复合物。
利用其中一株突变体，我们证实，在FOP模型中无法形成非信号复合物会导致更严重的疾病病理表型。
本研究首次为非信号复合物在体内的生物学功能提供了实验证据，并为后续通过相应敲入小鼠探索其生理功能铺平了道路。