skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Alternative Binding Modes Identified for Growth and Differentiation Factor-associated Serum Protein (GASP) Family Antagonism of Myostatin

Journal Article · · Journal of Biological Chemistry
 [1];  [1];  [1];  [2];  [2];  [1]
  1. Univ. of Cincinnati, OH (United States)
  2. Johns Hopkins Univ. School of Medicine, Baltimore, MD (United States)
+ Show Author Affiliations

Myostatin, a member of the TGF-β family of ligands, is a strong negative regulator of muscle growth. As such, it is a prime therapeutic target for muscle wasting disorders. Similar to other TGF-β family ligands, myostatin is neutralized by binding one of a number of structurally diverse antagonists. Included are the antagonists GASP-1 and GASP-2, which are unique in that they specifically antagonize myostatin. However, little is known from a structural standpoint describing the interactions of GASP antagonists with myostatin. In this paper, we present the First low resolution solution structure of myostatin-free and myostatin-bound states of GASP-1 and GASP-2. Our studies have revealed GASP-1, which is 100 times more potent than GASP-2, preferentially binds myostatin in an asymmetrical 1:1 complex, whereas GASP-2 binds in a symmetrical 2:1 complex. Additionally, C-terminal truncations of GASP-1 result in less potent myostatin inhibitors that form a 2:1 complex, suggesting that the C-terminal domains of GASP-1 are the primary mediators for asymmetric complex formation. Overall, this study provides a new perspective on TGF-β antagonism, where closely related antagonists can utilize different ligand-binding strategies.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES); American Heart Association (AHA); Muscular Dystrophy Association (MDA)
Grant/Contract Number:
R01AR060636; R01GM105404; 12PRE11790027; 240087
OSTI ID:
1236259
Journal Information:
Journal of Biological Chemistry, Vol. 290, Issue 12; ISSN 0021-9258
Publisher:
American Society for Biochemistry and Molecular BiologyCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 19 works
Citation information provided by
Web of Science

References (37)

Macromolecular Size-and-Shape Distributions by Sedimentation Velocity Analytical Ultracentrifugation journal June 2006
Uniqueness of ab initio shape determination in small-angle scattering journal April 2003
WFIKKN1 and WFIKKN2 bind growth factors TGFβ1, BMP2 and BMP4 but do not inhibit their signalling activity: WFIKKNs bind several members of the TGFβ family journal November 2010
DAMMIF, a program for rapid ab-initio shape determination in small-angle scattering journal January 2009
High-Throughput SAXS for the Characterization of Biomolecules in Solution: A Practical Approach book October 2013
The structure of myostatin:follistatin 288: insights into receptor utilization and heparin binding journal July 2009
Extracellular Regulation of Myostatin: A Molecular Rheostat for Muscle Mass journal December 2010
Development of a Small-Molecule Screening Method for Inhibitors of Cellular Response to Myostatin and Activin A journal August 2013
Double muscling in cattle due to mutations in the myostatin gene journal November 1997
Regulation of Myostatin in Vivo by Growth and Differentiation Factor-Associated Serum Protein-1: A Novel Protein with Protease Inhibitor and Follistatin Domains journal June 2003
Follistatin complexes Myostatin and antagonises Myostatin-mediated inhibition of myogenesis journal June 2004
Nanoscale structure of the BMP antagonist chordin supports cooperative BMP binding journal August 2014
Combined Affinity and Rate Constant Distributions of Ligand Populations from Experimental Surface Binding Kinetics and Equilibria journal June 2003
Regulation of myostatin activity and muscle growth journal July 2001
GASP/WFIKKN Proteins: Evolutionary Aspects of Their Functions journal August 2012
Gdf-8 Propeptide Binds to GDF-8 and Antagonizes Biological Activity by Inhibiting GDF-8 Receptor Binding journal January 2001
Characterization of Follistatin-Type Domains and Their Contribution to Myostatin and Activin A Antagonism journal July 2012
Regulation of anterior/posterior patterning of the axial skeleton by growth/differentiation factor 11 journal July 1999
Transgenic expression of a myostatin inhibitor derived from follistatin increases skeletal muscle mass and ameliorates dystrophic pathology in mdx mice journal September 2007
Murine GASP-1 N -Glycosylation is not Essential for its Activity on C2C12 Myogenic Cells but Alters its Secretion journal January 2012
A human protein containing multiple types of protease-inhibitory modules journal March 2001
The Myostatin Propeptide and the Follistatin-related Gene Are Inhibitory Binding Proteins of Myostatin in Normal Serum journal August 2002
Improved muscle healing through enhanced regeneration and reduced fibrosis in myostatin-null mice journal August 2005
Characterizing flexible and intrinsically unstructured biological macromolecules by SAS using the Porod-Debye law journal April 2011
Size-Distribution Analysis of Macromolecules by Sedimentation Velocity Ultracentrifugation and Lamm Equation Modeling journal March 2000
Crystal Structure Analysis Reveals How the Chordin Family Member Crossveinless 2 Blocks BMP-2 Receptor Binding journal May 2008
Structure of Myostatin·Follistatin-like 3: N-TERMINAL DOMAINS OF FOLLISTATIN-TYPE MOLECULES EXHIBIT ALTERNATE MODES OF BINDING journal November 2011
Latent myostatin has significant activity and this activity is controlled more efficiently by WFIKKN 1 than by WFIKKN 2 journal July 2013
von Willebrand Factor Type C Domain-containing Proteins Regulate Bone Morphogenetic Protein Signaling through Different Recognition Mechanisms journal May 2007
Biological Activity of Follistatin Isoforms and Follistatin-Like-3 Is Dependent on Differential Cell Surface Binding and Specificity for Activin, Myostatin, and Bone Morphogenetic Proteins journal July 2006
Regulation of GDF-11 and myostatin activity by GASP-1 and GASP-2 journal September 2013
Muscle regeneration in the prolonged absence of myostatin journal February 2005
The Structure of the Follistatin:Activin Complex Reveals Antagonism of Both Type I and Type II Receptor Binding journal October 2005
Direct binding of follistatin to a complex of bone-morphogenetic protein and its receptor inhibits ventral and epidermal cell fates in early Xenopus embryo journal August 1998
The Structure of FSTL3·Activin A Complex journal September 2008
Regulation of skeletal muscle mass in mice by a new TGF-p superfamily member journal May 1997
Structural basis of BMP signalling inhibition by the cystine knot protein Noggin journal December 2002

Cited By (13)

Variation in zygotic CRISPR/Cas9 gene editing outcomes generates novel reporter and deletion alleles at the Gdf11 locus journal December 2019
Molecular characterization of latent GDF8 reveals mechanisms of activation journal January 2018
Crystal structure of the WFIKKN2 follistatin domain reveals insight into how it inhibits growth differentiation factor 8 (GDF8) and GDF11 journal April 2019
GASP‐2 overexpressing mice exhibit a hypermuscular phenotype with contrasting molecular effects compared to GASP‐1 transgenics journal January 2020
Biochemistry and Biology of GDF11 and Myostatin: Similarities, Differences, and Questions for Future Investigation journal April 2016
Structural biology of the TGFβ family journal October 2019
Structural basis for potency differences between GDF8 and GDF11 journal March 2017
Structure of the human myostatin precursor and determinants of growth factor latency journal December 2017
Structure of the human myostatin precursor and determinants of growth factor latency. text January 2018
Structural basis for potency differences between GDF8 and GDF11. journalarticle January 2017
Enhancement of C2C12 myoblast proliferation and differentiation by GASP-2, a myostatin inhibitor journal July 2016
Correction to Binding Properties of the Transforming Growth Factor-β Coreceptor Betaglycan: Proposed Mechanism for Potentiation of Receptor Complex Assembly and Signaling journal July 2017
Beyond the Big Five: Investigating Myostatin Structure, Polymorphism and Expression in Camelus dromedarius journal June 2019

Similar Records

Crystal structure of the WFIKKN2 follistatin domain reveals insight into how it inhibits growth differentiation factor 8 (GDF8) and GDF11
Journal Article · Wed Feb 27 00:00:00 EST 2019 · Journal of Biological Chemistry · OSTI ID:1236259
+1 more
Skeletal muscle-derived progenitors capable of differentiating into cardiomyocytes proliferate through myostatin-independent TGF-{beta} family signaling
Journal Article · Fri Jan 25 00:00:00 EST 2008 · Biochemical and Biophysical Research Communications · OSTI ID:1236259
+7 more
Acute inhibition of myostatin-family proteins preserves skeletal muscle in mouse models of cancer cachexia
Journal Article · Fri Jan 15 00:00:00 EST 2010 · Biochemical and Biophysical Research Communications · OSTI ID:1236259
+2 more

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
Analytical Ultracentrifugation
Myostatin
Small Angle X-ray Scattering (SAXS)
Structural Biology
Transforming Growth Factor Beta (TGF-B)
Growth and Differentiation-associated Serum Protein
Growth and Differentiation factor-8 (GDF-8)
WFIKKN