3 years ago

Molecular characterization of latent GDF8 reveals mechanisms of activation

Walton, Lee, Czepnik, J. C., R. G., C. A., Thompson, K. L., A., Mills, McCoy, Walker, M. J., T., Gregorevic, Harrison, Hagg, P., Cotton, M., Hyvonen, R. T.
Growth/differentiation factor 8 (GDF8) or myostatin negatively regulates of muscle mass. GDF8 is held in a latent state through interactions with its N-terminal prodomain, much like TGF-{beta}. Using a combination of small angle X-ray scattering and mutagenesis, we characterized the interactions of GDF8 with its prodomain. Our results show that the prodomain:GDF8 complex can exist in a fully latent state and an activated or triggered state where the prodomain remains in complex with the mature domain. However, these states are not reversible, indicating the latent GDF8 is spring-loaded. Structural analysis shows that the prodomain:GDF8 complex adopts an open configuration, distinct from the latency state of TGF-{beta} and more similar to the open state of Activin A and BMP9 (non-latent complexes). We determined that GDF8 maintains similar features for latency, including the alpha-1 helix and fastener elements, and identified a series of mutations in the prodomain of GDF8 that alleviate latency, including I56E, which does not require activation by the protease Tolloid. Activating GDF8 mutations were analyzed in vivo and show increased effects on the muscle (e.g. decreased fiber size) compared to wild-type GDF8. Collectively, these results help characterize the latency and activation mechanisms of GDF8.

Publisher URL: http://biorxiv.org/cgi/content/short/155614v1

DOI: 10.1101/155614

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