Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 412, Issue 4, Pages 601-618Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2011.07.046
Keywords
TGF-beta; type I receptor; cis-proline; specificity; cooperative binding
Categories
Funding
- National Institutes of Health [GM58670, RR13879, CA54174]
- Robert A. Welch Foundation [AQ-1431]
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Transforming growth factor beta isoforms (TGF-beta) are among the most recently evolved members of a signaling superfamily with more than 30 members. TGF-beta play vital roles in regulating cellular growth and differentiation, and they signal through a highly restricted subset of receptors known as TGF-beta type I receptor (T beta R-I) and TGF-beta type II receptor T beta R-II. TGF-beta's specificity for T beta R-I has been proposed to arise from its pre-helix extension, a five-residue loop that binds in the cleft between TGF-beta and T beta R-II. The structure and backbone dynamics of the unbound form of the T beta R-I extracellular domain were determined using NW to investigate the extension's role in binding. This showed that the unbound form is highly similar to the bound form in terms of both the beta-strand framework that defines the three-finger toxin fold and the extension and its characteristic cis-IIe54-Pro55 peptide bond. The NMR data further showed that the extension and two flanking 310 helices are rigid on the nanosecond-to-picosecond timescale. The functional significance of several residues within the extension was investigated by binding studies and reporter gene assays in cultured epithelial cells. These demonstrated that the pre-helix extension is essential for binding, with Pro55 and Pro59 each playing a major role. These findings suggest that the pre-helix extension and its flanking prolines evolved to endow the TGF-beta signaling complex with its unique specificity, departing from the ancestral promiscuity of the bone morphogenetic protein subfamily, where the binding interface of the type I receptor is highly flexible. (C) 2011 Elsevier Ltd. All rights reserved.
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