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Three-finger toxin fold for the extracellular ligand-binding domain of the type II activin receptor serine kinase.

Abstract

The transforming growth factor β (TGFβ) superfamily of cytokines elicit diverse biological responses by interacting with two distinct, but structurally related transmembrane receptor serine kinases (type I and type II). The binding of these dimeric ligands to the type II receptor is the first event in transmembrane signaling for this family. Here we report the 1.5 Å resolution crystal structure of the extracellular ligand-binding domain of the type II activin receptor (ActRII-ECD), which reveals a fold similar to that of a class of toxins known as three-finger toxins. This fold is primarily dictated by disulfide bonds formed by eight conserved cysteines, with a characteristic spacing, and thus is likely to be shared by most of the type I and II receptors for the TGFβ family. Sequence comparison with an evolutionarily distant activin binding-protein identifies several conserved residues, including two hydrophobic clusters that may form binding surfaces for activin and the type I receptor.

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Figure 1: a, Stereo ribbon diagram of ActRII-ECD. The strands are numbered in the order that they occur in the sequence.
Figure 2: Alignment between six receptor ECD sequences and cardiotoxin.
Figure 3: Molecular surface representations of ActRII-ECD by GRASP29 showing the conserved features.
Figure 4: Stereo diagram of the experimental electron density maps in the region of the five disulfide bonds in molecule B.

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Acknowledgements

We thank G. Louie, R. Robinson and T. Hunter for helpful discussions and comments on the manuscript; H. Bellamy at SSRL and T. Earnest at ALS for help with data collection. SSRL and ALS are operated by the Department of Energy, Office of Basic Energy Sciences. The SSRL Biotechnology Program is supported by the National Institutes of Health, National Center for Research Resources, Biomedical Technology Program, and by the Department of Energy, Office of Biological and Environmental Research. J.G. is a Howard Hughes Medical Institute Predoctoral Fellow and Markey Fellow. S.C. is a recipient of a Klingenstein Fellowship Award in Neuroscience. This work was supported by a grant from the NIH.Correspondence should be addressed to S.C. choe@sbl.salk.edu

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Correspondence to Senyon Choe.

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Greenwald, J., Fischer, W., Vale, W. et al. Three-finger toxin fold for the extracellular ligand-binding domain of the type II activin receptor serine kinase.. Nat Struct Mol Biol 6, 18–22 (1999). https://doi.org/10.1038/4887

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