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Tolloid cleavage activates latent GDF8 by priming the pro-complex for dissociation

Viet Q. Le, Roxana E. Iacob, Yuan Tian, William McConaughy, Justin Jackson, Yang Su, Bo Zhao, John R. Engen, Michelle Pirruccello-Straub, Timothy A. Springer
doi: https://doi.org/10.1101/154823
Viet Q. Le
1Program in Cellular and Molecular Medicine, Boston Children’s Hospital and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;
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Roxana E. Iacob
2Department of Chemistry & Chemical Biology, Northeastern University, Boston, MA 02115;
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Yuan Tian
1Program in Cellular and Molecular Medicine, Boston Children’s Hospital and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;
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William McConaughy
3Scholar Rock, Cambridge, MA 02139.
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Justin Jackson
3Scholar Rock, Cambridge, MA 02139.
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Yang Su
1Program in Cellular and Molecular Medicine, Boston Children’s Hospital and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;
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Bo Zhao
1Program in Cellular and Molecular Medicine, Boston Children’s Hospital and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;
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John R. Engen
2Department of Chemistry & Chemical Biology, Northeastern University, Boston, MA 02115;
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Michelle Pirruccello-Straub
3Scholar Rock, Cambridge, MA 02139.
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Timothy A. Springer
1Program in Cellular and Molecular Medicine, Boston Children’s Hospital and Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;
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  • For correspondence: springer_lab@crystal.harvard.edu
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Abstract

Growth differentiation factor 8 (GDF8)/Myostatin is a latent TGF­β family member that potently inhibits skeletal muscle growth. Here, we compared the conformation and dynamics of precursor, latent, and Tolloid­cleaved GDF8 pro­complexes to understand structural mechanisms underlying latency and activation of GDF8. Negative stain electron microscopy (EM) of precursor and latent pro­complexes reveals a V­shaped conformation that is unaltered by furin cleavage and sharply contrasts with the ring­like, cross­armed conformation of latent TGF­β1. Surprisingly, Tolloid­cleaved GDF8 does not immediately dissociate, but in EM exhibits structural heterogeneity consistent with partial dissociation. Hydrogen–deuterium exchange was not affected by furin cleavage. In contrast, Tolloid cleavage, in the absence of prodomain–growth factor dissociation, increased exchange in regions that correspond in pro-TGF-β1 to the α1-helix, latency lasso, and β1 strand in the prodomain and to the β6’–7’ strands in the growth factor. Thus, these regions are important in maintaining GDF8 latency. Our results show that Tolloid cleavage activates latent GDF8 by destabilizing specific prodomain–growth factor interfaces and primes the growth factor for release from the prodomain.

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Posted August 03, 2017.
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Tolloid cleavage activates latent GDF8 by priming the pro-complex for dissociation
Viet Q. Le, Roxana E. Iacob, Yuan Tian, William McConaughy, Justin Jackson, Yang Su, Bo Zhao, John R. Engen, Michelle Pirruccello-Straub, Timothy A. Springer
bioRxiv 154823; doi: https://doi.org/10.1101/154823
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Tolloid cleavage activates latent GDF8 by priming the pro-complex for dissociation
Viet Q. Le, Roxana E. Iacob, Yuan Tian, William McConaughy, Justin Jackson, Yang Su, Bo Zhao, John R. Engen, Michelle Pirruccello-Straub, Timothy A. Springer
bioRxiv 154823; doi: https://doi.org/10.1101/154823

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