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The finger 2 tip loop of Activin A is required for the formation of its non-signaling complex with ACVR1 and type II Bone Morphogenetic Protein receptors

Activin A, a ligand that belongs to the BMP/TGFß family, functions in BMP signaling in two distinctly different ways: it binds to its cognate type II receptors – ACVR2A, ACVR2B, and BMPR2 – and the resulting complex either engages the type I receptor ACVR1B to activate Smad2/3 signaling or binds with the type I receptor ACVR1 to form a non-signaling complex. In order to set the stage for exploring potential biological roles of the non-signaling complex, we engineered Activin A variants that retain their ability to activate ACVR1B but are unable to generate the Activin A•type II receptor•ACVR1 non-signaling complex. This was accomplished by designing Activin A muteins wherein type I-binding regions were replaced with those of Nodal, a BMP/TGFß family member that utilizes ACVR1B but not ACVR1 as its type I receptor. Of the resulting muteins, an Activin A utilizing the finger 2 tip loop of Nodal (Activin A.Nod.F2TL) fulfilled our specifications; it failed to generate the non-signaling complex, yet activated ACVR1B akin to wild type Activin A. Furthermore, a single amino acid, D406, appears to be a main driver of this interaction, as its deletion results in a mutein that is similar in activity to Activin A.Nod.F2TL. These results define a region of Activin A that is important for the formation of the non-signaling complex and set the stage for engineering knock-in mice where the role of the non-signaling complex can be explored.