Molecular characterization of latent GDF8 reveals mechanisms of activation

RG Walker; JC McCoy; M Czepnik; MJ Mills; A Hagg; KL Walton; TR Cotton; M Hyvönen; RT Lee; P Gregorevic; CA Harrison; TB Thompson

Journal article

Molecular characterization of latent GDF8 reveals mechanisms of activation

RG Walker, JC McCoy, M Czepnik, MJ Mills, A Hagg, KL Walton, TR Cotton, M Hyvönen, RT Lee, P Gregorevic, CA Harrison, TB Thompson

Proceedings of the National Academy of Sciences of the United States of America | NATL ACAD SCIENCES | Published : 2018

DOI: 10.1073/pnas.1714622115

Abstract

Growth/differentiation factor 8 (GDF8), or myostatin, negatively regulates muscle mass. GDF8 is held in a latent state through interactions with its N-terminal prodomain, much like TGF-β. 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..

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University of Melbourne Researchers

Paul Gregorevic Author

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Grants

Awarded by National Institutes of Health

Funding Acknowledgements

We thank Monash Micro Imaging staff, Alfred Medical Research and Education Precinct (AMREP) campus, for technical guidance and AMREP Precinct Animal Centre staff for animal husbandry; Dr. Hongwei Qian (Baker Heart and Diabetes Institute) for assistance with production of recombinant AAV vectors; and Georgia Goodchild for help with the histological analysis. This work was supported, in part, by NIH; a National Health and Medical Research Council (NHMRC) grant; the Muscular Dystrophy Association; the University of Cincinnati Graduate Dean Fellowship; American Heart Association Grants R01AG047131, R01AG040019, R03AG049657 (to R.T.L.), and 1078907 (to C.A.H.); App 1117835 for Gregorevic Senior Research Fellowship from NHMRC; Graduate Dean Fellowship and Grant 12PRE11790027 (to R.G.W.); and Grant R01GM114640 and Muscular Dystrophy Association Grant 240087 (to T.B.T.). This work was also supported by the Integrated Diffraction Analysis Technologies Program of the Department of Energy Office of Basic Energy Sciences awarded to the Advanced Light Source at Lawrence Berkeley National Laboratory. The Baker Heart and Diabetes Institute is supported in part by the Operational Infrastructure Support Program of the Victorian Government.