CryoEM structure of ALK2:BMP6 reveals distinct mechanisms that allow ALK2 to interact with both BMP and Activin ligands

Abstract

Ligands in the TGF{beta} family (activins, BMPs and TGF{beta}s), signal by bringing together two type I and two type II receptors. ALK2 is the only type I receptor among the seven TGF{beta} type I receptors that interacts with both activin and BMP ligands. With BMPs, ALK2 acts as a signaling receptor to activate SMAD1/5/8 signaling. Alternatively, with activins, such as Activin A (ActA), ALK2 forms nonsignaling complexes that negatively regulate ALK2 and ActA signaling. To gain insight into how ALK2 interacts with two distinct classes of ligands, we resolved the cryoelectron microscopy structure of ALK2 in complex with the type II receptor, ActRIIB, and the ligand, BMP6, in parallel with the corresponding structure with ALK3 for direct comparison. These structures demonstrate that ALK2 and ALK3 utilize different mechanisms to interact with BMP6 at the wrist interface, with ALK2 relying on BMP6 glycosylation and ALK3 relying on a salt bridge. Modeling of ALK2:ActA reveals that binding relies on ActAs fingertip region, mirroring the interaction of ActA with its other receptor, ALK4. Our results demonstrate that ALK2 is a hybrid receptor that incorporates features of BMP type I receptors such as ALK3 at the wrist interface, and an activin type I receptor such as ALK4 at the fingertip. SignificanceALK2 interacts with two different classes of TGF{beta} ligands: the BMPs and the activins. With BMP ligands, ALK2 signals to play roles in bone modeling, while with activins, ALK2 negatively regulates signaling by forming nonsignaling complexes. We demonstrate that ALK2 binds to favored ligand, BMP6, by utilizing the ligand wrist-helix stabilized by a glycosylation, rather than a charged interaction observed with similar receptor, ALK3. We also show that ALK2 interaction with activin ligand, ActA, is reliant on a single interaction at the other side of the receptor - the fingertip interface. Thus, this study elucidates first structure of ALK2 in complex with a ligand and provides the molecular insight into how ALK2 is able to bind to BMP and activin ligands.