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

Authors
  • Le, Viet Q1, 2
  • Iacob, Roxana E3
  • Tian, Yuan1, 2
  • McConaughy, William4
  • Jackson, Justin4
  • Su, Yang1, 2
  • Zhao, Bo1, 2
  • Engen, John R3
  • Pirruccello-Straub, Michelle4
  • Springer, Timothy A5, 2
  • 1 Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.
  • 2 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA.
  • 3 Department of Chemistry & Chemical Biology, Northeastern University, Boston, MA, USA.
  • 4 Scholar Rock, Cambridge, MA, USA.
  • 5 Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA [email protected]
Type
Published Article
Journal
The EMBO Journal
Publisher
EMBO
Publication Date
Feb 01, 2018
Volume
37
Issue
3
Pages
384–397
Identifiers
DOI: 10.15252/embj.201797931
PMID: 29343545
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Growth differentiation factor 8 (GDF8)/myostatin is a latent TGF-β family member that potently inhibits skeletal muscle growth. Here, we compared the conformation and dynamics of precursor, latent, and Tolloid-cleaved GDF8 pro-complexes to understand structural mechanisms underlying latency and activation of GDF8. Negative stain electron microscopy (EM) of precursor and latent pro-complexes reveals a V-shaped conformation that is unaltered by furin cleavage and sharply contrasts with the ring-like, cross-armed conformation of latent TGF-β1. Surprisingly, Tolloid-cleaved 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'- and β7'-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. © 2018 The Authors.

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