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Crystal structure of the human TβR2 ectodomain–TGF-β3 complex

Abstract

Transforming growth factor-β (TGF-β) is the prototype of a large family of structurally related cytokines that play key roles in maintaining cellular homeostasis by signaling through two classes of functionally distinct Ser/Thr kinase receptors, designated as type I and type II. TGF-β initiates receptor assembly by binding with high affinity to the type II receptor. Here, we present the 2.15 Å crystal structure of the extracellular ligand-binding domain of the human TGF-β type II receptor (ecTβR2) in complex with human TGF-β3. ecTβR2 interacts with homodimeric TGF-β3 by binding identical finger segments at opposite ends of the growth factor. Relative to the canonical 'closed' conformation previously observed in ligand structures across the superfamily, ecTβR2-bound TGF-β3 shows an altered arrangement of its monomeric subunits, designated the 'open' conformation. The mode of TGF-β3 binding shown by ecTβR2 is compatible with both ligand conformations. This, in addition to the predicted mode for TGF-β binding to the type I receptor ectodomain (ecTβR1), suggests an assembly mechanism in which ecTβR1 and ecTβR2 bind at adjacent positions on the ligand surface and directly contact each other via protein–protein interactions.

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Acknowledgements

We thank L. Flaks and J. Berendzen at beamline X8-C at the NSLS, Brookhaven National Laboratory; Z. Dauter and D. Cascio for valuable discussions; OSI Pharmaceuticals for providing E. coli recombinant TGF-β3; and past and present colleagues who commented on the manuscript. This work was supported by an NIGMS grant to A.P.H. and Robert A. Welch Foundation grants to A.P.H. and P.J.H.

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The authors declare no competing financial interests.

Correspondence to Andrew P. Hinck.

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Figure 1: Structure of the (ecTβR2)2–TGF-β3 complex.
Figure 2: Sequence alignment of TGF-β superfamily members and type II receptor ectodomains.
Figure 3: Contacts at the (ecTβR2)2–TGF-β3 interface.
Figure 4: Model for the relative positioning of the type I and type II receptor ectodomains in the TGF-β–receptor signaling complex.