Structural basis for potency differences between GDF8 and GDF11

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Abstract

Background

Growth/differentiation factor 8 (GDF8) and GDF11 are two highly similar members of the transforming growth factor β (TGFβ) family. While GDF8 has been recognized as a negative regulator of muscle growth and differentiation, there are conflicting studies on the function of GDF11 and whether GDF11 has beneficial effects on age-related dysfunction. To address whether GDF8 and GDF11 are functionally identical, we compared their signaling and structural properties.

Results

Here we show that, despite their high similarity, GDF11 is a more potent activator of SMAD2/3 and signals more effectively through the type I activin-like receptor kinase receptors ALK4/5/7 than GDF8. Resolution of the GDF11:FS288 complex, apo-GDF8, and apo-GDF11 crystal structures reveals unique properties of both ligands, specifically in the type I receptor binding site. Lastly, substitution of GDF11 residues into GDF8 confers enhanced activity to GDF8.

Conclusions

These studies identify distinctive structural features of GDF11 that enhance its potency, relative to GDF8; however, the biological consequences of these differences remain to be determined.

Electronic supplementary material

The online version of this article (doi:10.1186/s12915-017-0350-1) contains supplementary material, which is available to authorized users.

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Most cited references 76

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Latent TGF-β structure and activation.

Minlong Shi, Jianghai Zhu, Rui Wang … (2011)

Transforming growth factor (TGF)-β is stored in the extracellular matrix as a latent complex with its prodomain. Activation of TGF-β1 requires the binding of α(v) integrin to an RGD sequence in the prodomain and exertion of force on this domain, which is held in the extracellular matrix by latent TGF-β binding proteins. Crystals of dimeric porcine proTGF-β1 reveal a ring-shaped complex, a novel fold for the prodomain, and show how the prodomain shields the growth factor from recognition by receptors and alters its conformation. Complex formation between α(v)β(6) integrin and the prodomain is insufficient for TGF-β1 release. Force-dependent activation requires unfastening of a 'straitjacket' that encircles each growth-factor monomer at a position that can be locked by a disulphide bond. Sequences of all 33 TGF-β family members indicate a similar prodomain fold. The structure provides insights into the regulation of a family of growth and differentiation factors of fundamental importance in morphogenesis and homeostasis.

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Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene.

S Dennler, S Itoh, D Vivien … (1998)

Smad proteins play a key role in the intracellular signalling of transforming growth factor beta (TGF beta), which elicits a large variety of cellular responses. Upon TGF beta receptor activation, Smad2 and Smad3 become phosphorylated and form heteromeric complexes with Smad4. These complexes translocate to the nucleus where they control expression of target genes. However, the mechanism by which Smads mediate transcriptional regulation is largely unknown. Human plasminogen activator inhibitor-1 (PAI-1) is a gene that is potently induced by TGF beta. Here we report the identification of Smad3/Smad4 binding sequences, termed CAGA boxes, within the promoter of the human PAI-1 gene. The CAGA boxes confer TGF beta and activin, but not bone morphogenetic protein (BMP) stimulation to a heterologous promoter reporter construct. Importantly, mutation of the three CAGA boxes present in the PAI-1 promoter was found to abolish TGF beta responsiveness. Thus, CAGA elements are essential and sufficient for the induction by TGF beta. In addition, TGFbeta induces the binding of a Smad3/Smad4-containing nuclear complex to CAGA boxes. Furthermore, bacterially expressed Smad3 and Smad4 proteins, but not Smad1 nor Smad2 protein, bind directly to this sequence in vitro. The presence of this box in TGF beta-responsive regions of several other genes suggests that this may be a widely used motif in TGF beta-regulated transcription.

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Double muscling in cattle due to mutations in the myostatin gene.

A. McPherron, S Lee (1997)

Myostatin (GDF-8) is a member of the transforming growth factor beta superfamily of secreted growth and differentiation factors that is essential for proper regulation of skeletal muscle mass in mice. Here we report the myostatin sequences of nine other vertebrate species and the identification of mutations in the coding sequence of bovine myostatin in two breeds of double-muscled cattle, Belgian Blue and Piedmontese, which are known to have an increase in muscle mass relative to conventional cattle. The Belgian Blue myostatin sequence contains an 11-nucleotide deletion in the third exon which causes a frameshift that eliminates virtually all of the mature, active region of the molecule. The Piedmontese myostatin sequence contains a missense mutation in exon 3, resulting in a substitution of tyrosine for an invariant cysteine in the mature region of the protein. The similarity in phenotypes of double-muscled cattle and myostatin null mice suggests that myostatin performs the same biological function in these two species and is a potentially useful target for genetic manipulation in other farm animals.

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Author and article information

Contributors

Thomas B. Thompson: 513-558-4517 , Tom.Thompson@uc.edu

Journal

Journal ID (nlm-ta): BMC Biol

Journal ID (iso-abbrev): BMC Biol

Title: BMC Biology

Publisher: BioMed Central (London )

ISSN (Electronic): 1741-7007

Publication date (Electronic): 3 March 2017

Publication date PMC-release: 3 March 2017

Publication date Collection: 2017

Volume: 15

Electronic Location Identifier: 19

Affiliations

[1 ]ISNI 0000 0001 2179 9593, GRID grid.24827.3b, Department of Molecular Genetics, Biochemistry, and Microbiology, , University of Cincinnati, ; Cincinnati, OH 45267 USA

[2 ]ISNI 000000041936754X, GRID grid.38142.3c, Harvard Stem Cell Institute and Department of Stem Cell and Regenerative Biology, , Harvard University, ; Cambridge, MA 02138 USA

[3 ]ISNI 000000041936754X, GRID grid.38142.3c, , Paul F. Glenn Center for the Biology of Aging, Harvard Medical School, ; Boston, MA 02115 USA

[4 ]ISNI 0000 0001 2150 1785, GRID grid.17088.36, Department of Biochemistry and Molecular Biology, , Michigan State University, ; East Lansing, MI 48824 USA

[5 ]GRID grid.452824.d, , Hudson Institute of Medical Research, ; Clayton, Australia

[6 ]ISNI 0000 0004 1936 8649, GRID grid.14709.3b, Department of Pharmacology and Therapeutics, , McGill University, ; Montréal, Quebec Canada

[7 ]ISNI 0000 0004 1936 9000, GRID grid.21925.3d, Department of Structural Biology, , University of Pittsburgh School of Medicine, ; Pittsburgh, PA 15260 USA

[8 ]ISNI 0000 0004 1936 7857, GRID grid.1002.3, Department of Physiology, , Monash University, ; Clayton, Australia

[9 ]ISNI 0000 0001 2179 9593, GRID grid.24827.3b, , University of Cincinnati, ; 231 Albert Sabin Way ML 0524, Cincinnati, OH 45267 USA

Article

Publisher ID: 350

DOI: 10.1186/s12915-017-0350-1

PMC ID: 5336696

PubMed ID: 28257634

SO-VID: 9f276d45-6eaf-44ce-9d9a-236cabe6c170

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 21 November 2016

Date accepted : 18 January 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000049, National Institute on Aging;

Award ID: R56AG048917

Award ID: R01AG048917

Award ID: R01AG047131

Award ID: R01AG040019

Award ID: R03AG049657

Award Recipient : Amy J. Wagers Richard T. Lee

Funded by: Paul F. Glenn

Award ID: Center Grant

Award Recipient : Amy J. Wagers

Funded by: FundRef http://dx.doi.org/10.13039/100000069, National Institute of Arthritis and Musculoskeletal and Skin Diseases;

Award ID: R41AR06880401

Award Recipient : Erik Martinez-Hackert

Funded by: FundRef http://dx.doi.org/10.13039/100000057, National Institute of General Medical Sciences;

Award ID: R01GM58670

Award ID: R01GM114640

Award Recipient : Andrew P. Hinck Thomas B. Thompson

Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;

Award ID: R01CA172886

Award Recipient : Andrew P. Hinck

Funded by: FundRef http://dx.doi.org/10.13039/501100000024, Canadian Institutes of Health Research;

Award ID: MOP-133394

Award Recipient : Daniel J. Bernard

Funded by: FundRef http://dx.doi.org/10.13039/501100000925, National Health and Medical Research Council;

Award ID: 1078907

Award Recipient : Craig A. Harrison

Funded by: FundRef http://dx.doi.org/10.13039/100005202, Muscular Dystrophy Association;

Award ID: 240087

Award Recipient : Thomas B. Thompson

Custom metadata

ScienceOpen disciplines: Life sciences

Keywords: ligands,myostatin,receptor,structure,transforming growth factor β (tgfβ)

Data availability:

ScienceOpen disciplines: Life sciences

Keywords: ligands, myostatin, receptor, structure, transforming growth factor β (tgfβ)

Structural basis for potency differences between GDF8 and GDF11

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Abstract

Background

Results

Conclusions

Electronic supplementary material

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Resource Identification

Most cited references 76

Latent TGF-β structure and activation.

Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene.

Double muscling in cattle due to mutations in the myostatin gene.

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