Monogamy in the TGF-β Receptor Relationship

Abstract

The transforming growth factor-β (TGF-β) superfamily includes bone morphogenetic proteins (BMPs), nodals, and activins, as well as TGF-βs. Unlike the other type I and type II receptors, which bind promiscuously to several members of the BMP, activin, and nodal families, the TGF-β receptor I (TβRI) and TGF-β receptor II (TβRII) bind only the TGF-βs (see Massagué). In addition to this ligand selectivity, only the type II receptor subunit TβRII has high affinity for the TGF-β ligand, and the TGF-β:TβRII complex recruits TβRI, whereas the receptors that interact with the other family members exhibit binding of ligands to both the type I and type II receptors. Groppe et al . provide insight into the mechanism for this cooperative and selective interaction by crystallizing the extracellular domains of TβRI, TβRII, and TGF-β3. The crystal showed a dimer of the ligand bound in a symmetrical complex with two of each receptor subunit. In contrast to the other ligands in the superfamily, TGF-β3 induced an interaction between an N-terminal extension in TβRII with TβRI that docks the TβRI subunit to the complex. Experiments with TβRII with mutations in the N-terminal extension region showed that this region was not necessary for binding of TGF-β3 to TβRII but was necessary for mediating the recruitment of TβRI (based on in vitro binding assays) and activation of the receptor complex (based on cellular receptor activation assays). Thus, a cooperative induced fit allows a subset of TGF-β ligands to selectively activate a specific receptor complex. J. Groppe, C. S. Hinck, P. Samavarchi-Tehrani, C. Zubieta, J. P. Schuermann, A. B. Taylor, P. M. Schwarz, J. L. Wrana, A. P. Hinck, Cooperative assembly of TGF-β superfamily signaling complexes is mediated by two disparate mechanisms and distinct modes of receptor binding. Mol. Cell 29 , 157-168 (2008). [PubMed] J. Massagué, A very private TGF-β receptor embrace. Mol. Cell 29 , 149-150 (2008). [PubMed]