Structural basis for potency differences between GDF8 and GDF11

Walker, Ryan G.; Czepnik, Magdalena; Goebel, Erich J.; McCoy, Jason C.; Vujic, Ana; Cho, Miook; Oh, Juhyun; Aykul, Senem; Walton, Kelly L.; Schang, Gauthier; Bernard, Daniel J.; Hinck, Andrew P.; Harrison, Craig A.; Martinez-Hackert, Erik; Wagers, Amy J.; Lee, Richard T.; Thompson, Thomas B.

doi:10.1186/s12915-017-0350-1

Title: Structural basis for potency differences between GDF8 and GDF11

Journal Article · Fri Mar 03 00:00:00 EST 2017 · BMC Biology

DOI:https://doi.org/10.1186/s12915-017-0350-1· OSTI ID:1357654

Walker, Ryan G. ^[1]; Czepnik, Magdalena ^[1]; Goebel, Erich J. ^[1]; McCoy, Jason C. ^[1]; Vujic, Ana ^[2]; Cho, Miook ^[3]; Oh, Juhyun ^[3]; Aykul, Senem ^[4]; Walton, Kelly L. ^[5]; Schang, Gauthier ^[6]; Bernard, Daniel J. ^[6]; Hinck, Andrew P. ^[7]; Harrison, Craig A. ^[5]; Martinez-Hackert, Erik ^[4]; Wagers, Amy J. ^[3]; Lee, Richard T. ^[2]; Thompson, Thomas B. ^[1]

Univ. of Cincinnati, OH (United States)
Harvard Univ., Cambridge, MA (United States)
Harvard Univ., Cambridge, MA (United States); Harvard Medical School, Boston, MA (United States)
Michigan State Univ., East Lansing, MI (United States)
Hudson Inst. of Medical Research, Clayton (Australia); Monash Univ., Melbourne, VIC (Australia)
McGill Univ., Montreal, QC (Canada)
Univ. of Pittsburgh School of Medicine, Pittsburgh, PA (United States)

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, in this paper, 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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH); National Health and Medical Research Council Australia; Michigan State University; Paul F. Glenn Center for the Biology of Aging; Muscular Dystrophy Association (MDA); University of Cincinnati Graduate Dean Fellowship; American Heart Association (AHA); Paul F. Glenn Center Grant

Grant/Contract Number:: R01AG047131; R01AG040019; R03AG049657; R56AG048917; R56AG052979; R01AG048917; R41AR06880401; GM58670; CA172886; CIHR MOP-133394; 1078907; R01GM114640; 240087; 12PRE11790027

OSTI ID:: 1357654

Journal Information:: BMC Biology, Vol. 15, Issue 1; ISSN 1741-7007

Publisher:: BioMed CentralCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 73 works

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A Transforming Growth Factor β Type I Receptor that Signals to Activate Gene Expression Bassing, Craig H.; Yingling, Jonathan M.; Howe, David J. Science, Vol. 263, Issue 5143 https://doi.org/10.1126/science.8272871	journal	January 1994
Type I receptors specify growth-inhibitory and transcriptional responses to transforming growth factor beta and activin. Cárcamo, J.; Weis, F. M.; Ventura, F. Molecular and Cellular Biology, Vol. 14, Issue 6 https://doi.org/10.1128/mcb.14.6.3810	journal	June 1994
GDF11 Forms a Bone Morphogenetic Protein 1-Activated Latent Complex That Can Modulate Nerve Growth Factor-Induced Differentiation of PC12 Cells Ge, G.; Hopkins, D. R.; Ho, W. -B. Molecular and Cellular Biology, Vol. 25, Issue 14 https://doi.org/10.1128/mcb.25.14.5846-5858.2005	journal	June 2005
Is Growth Differentiation Factor 11 a Realistic Therapeutic for Aging-Dependent Muscle Defects? Harper, Shavonn C.; Brack, Andrew; MacDonnell, Scott Circulation Research, Vol. 118, Issue 7 https://doi.org/10.1161/circresaha.116.307962	journal	April 2016
Biochemistry and Biology of GDF11 and Myostatin: Similarities, Differences, and Questions for Future Investigation Walker, Ryan G.; Poggioli, Tommaso; Katsimpardi, Lida Circulation Research, Vol. 118, Issue 7 https://doi.org/10.1161/circresaha.116.308391	journal	April 2016
Redundancy of myostatin and growth/differentiation factor 11 function McPherron, Alexandra C.; Huynh, Thanh V.; Lee, Se-Jin BMC Developmental Biology, Vol. 9, Issue 1 https://doi.org/10.1186/1471-213x-9-24	journal	March 2009
Distinct Expression Pattern of Two Related Human Proteins Containing Multiple Types of Protease-Inhibitory Modules Trexler, Mária; Bányai, László; Patthy, László Biological Chemistry, Vol. 383, Issue 1 https://doi.org/10.1515/bc.2002.023	journal	January 2002

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Mutations in GDF11 and the extracellular antagonist, Follistatin, as a likely cause of Mendelian forms of orofacial clefting in humans Cox, Timothy C.; Lidral, Andrew C.; McCoy, Jason C. Human Mutation, Vol. 40, Issue 10 https://doi.org/10.1002/humu.23793	journal	June 2019
Precise editing of myostatin signal peptide by CRISPR/Cas9 increases the muscle mass of Liang Guang Small Spotted pigs Li, Ruiqiang; Zeng, Wu; Ma, Miao Transgenic Research, Vol. 29, Issue 1 https://doi.org/10.1007/s11248-020-00188-w	journal	January 2020
The Growth Differentiation Factor 11 is Involved in Skin Fibroblast Ageing and is Induced by a Preparation of Peptides and Sugars Derived from Plant Cell Cultures Tito, Annalisa; Barbulova, Ani; Zappelli, Claudia Molecular Biotechnology, Vol. 61, Issue 3 https://doi.org/10.1007/s12033-019-00154-w	journal	January 2019
Variation in zygotic CRISPR/Cas9 gene editing outcomes generates novel reporter and deletion alleles at the Gdf11 locus Goldstein, Jill M.; Valido, Austin; Lewandowski, Jordan P. Scientific Reports, Vol. 9, Issue 1 https://doi.org/10.1038/s41598-019-54766-y	journal	December 2019
Advances in the molecular regulation of endothelial BMP9 signalling complexes and implications for cardiovascular disease Wood, Jennifer H.; Guo, Jingxu; Morrell, Nicholas W. Biochemical Society Transactions, Vol. 47, Issue 3 https://doi.org/10.1042/bst20180137	journal	May 2019
Blockade of activin type II receptors with a dual anti-ActRIIA/IIB antibody is critical to promote maximal skeletal muscle hypertrophy Morvan, Frederic; Rondeau, Jean-Michel; Zou, Chao Proceedings of the National Academy of Sciences, Vol. 114, Issue 47 https://doi.org/10.1073/pnas.1707925114	journal	November 2017
Molecular characterization of latent GDF8 reveals mechanisms of activation Walker, Ryan G.; McCoy, Jason C.; Czepnik, Magdalena Proceedings of the National Academy of Sciences, Vol. 115, Issue 5 https://doi.org/10.1073/pnas.1714622115	journal	January 2018
Structural characterization of an activin class ternary receptor complex reveals a third paradigm for receptor specificity Goebel, Erich J.; Corpina, Richard A.; Hinck, Cynthia S. Proceedings of the National Academy of Sciences, Vol. 116, Issue 31 https://doi.org/10.1073/pnas.1906253116	journal	July 2019
Growth differentiation factor 8 regulates SMAD2/3 signaling and improves oocyte quality during porcine oocyte maturation in vitro† Yoon, Junchul David; Hwang, Seon-Ung; Kim, Mirae Biology of Reproduction, Vol. 101, Issue 1 https://doi.org/10.1093/biolre/ioz066	journal	April 2019
Relationship between serum level of growth differentiation factors 8, 11 and bone mineral density in girls with anorexia nervosa Wu, Yali; Qu, Jian; Li, Huabing Clinical Endocrinology, Vol. 90, Issue 1 https://doi.org/10.1111/cen.13871	journal	October 2018
Follistatin-288-Fc Fusion Protein Promotes Localized Growth of Skeletal Muscle Castonguay, Roselyne; Lachey, Jennifer; Wallner, Samantha Journal of Pharmacology and Experimental Therapeutics, Vol. 368, Issue 3 https://doi.org/10.1124/jpet.118.252304	journal	December 2018
GDF11 Decreases Pressure Overload–Induced Hypertrophy, but Can Cause Severe Cachexia and Premature Death Harper, Shavonn C.; Johnson, Jaslyn; Borghetti, Giulia Circulation Research, Vol. 123, Issue 11 https://doi.org/10.1161/circresaha.118.312955	journal	November 2018
Structural biology of the TGFβ family Goebel, Erich J.; Hart, Kaitlin N.; McCoy, Jason C. Experimental Biology and Medicine, Vol. 244, Issue 17 https://doi.org/10.1177/1535370219880894	journal	October 2019
Structure of the human myostatin precursor and determinants of growth factor latency Cotton, Thomas R.; Fischer, Gerhard; Wang, Xuelu The EMBO Journal, Vol. 37, Issue 3 https://doi.org/10.15252/embj.201797883	journal	December 2017
Tolloid cleavage activates latent GDF8 by priming the pro‐complex for dissociation Le, Viet Q.; Iacob, Roxana E.; Tian, Yuan The EMBO Journal, Vol. 37, Issue 3 https://doi.org/10.15252/embj.201797931	journal	December 2017
Targeting TGF-β Mediated SMAD Signaling for the Prevention of Fibrosis Walton, Kelly L.; Johnson, Katharine E.; Harrison, Craig A. Frontiers in Pharmacology, Vol. 8 https://doi.org/10.3389/fphar.2017.00461	journal	July 2017
GDF11 Modulates Ca2+-Dependent Smad2/3 Signaling to Prevent Cardiomyocyte Hypertrophy Duran, Javier; Troncoso, Mayarling; Lagos, Daniel International Journal of Molecular Sciences, Vol. 19, Issue 5 https://doi.org/10.3390/ijms19051508	journal	May 2018
A counter gradient of Activin A and follistatin instructs the timing of hair cell differentiation in the murine cochlea Prajapati-DiNubila, Meenakshi; Benito-Gonzalez, Ana; Golden, Erin Jennifer eLife, Vol. 8 https://doi.org/10.7554/elife.47613	journal	June 2019
JNK regulates muscle remodeling via myostatin/SMAD inhibition Lessard, Sarah J.; MacDonald, Tara L.; Pathak, Prerana Nature Communications, Vol. 9, Issue 1 https://doi.org/10.1038/s41467-018-05439-3	journal	August 2018
Growth Differentiation Factor 11 treatment leads to neuronal and vascular improvements in the hippocampus of aged mice Ozek, Ceren; Krolewski, Richard C.; Buchanan, Sean M. Scientific Reports, Vol. 8, Issue 1 https://doi.org/10.1038/s41598-018-35716-6	journal	November 2018
Structure of the human myostatin precursor and determinants of growth factor latency. Cotton, Thomas R.; Fischer, Gerhard; Wang, Xuelu Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.20635	text	January 2018
Advances in the molecular regulation of endothelial BMP9 signalling complexes and implications for cardiovascular disease Wood, Jennifer; Guo, Jingxu; Morrell, Nicholas Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.39431	text	January 2019
Exogenous GDF11, but not GDF8, reduces body weight and improves glucose homeostasis in mice Walker, Ryan G.; Barrandon, Ornella; Poggioli, Tommaso Scientific Reports, Vol. 10, Issue 1 https://doi.org/10.1038/s41598-020-61443-y	journal	March 2020
GDF11 promotes osteogenesis as opposed to MSTN, and follistatin, a MSTN/GDF11 inhibitor, increases muscle mass but weakens bone Suh, Joonho; Kim, Na-Kyung; Lee, Seung-Hoon Proceedings of the National Academy of Sciences, Vol. 117, Issue 9 https://doi.org/10.1073/pnas.1916034117	journal	February 2020
GDF11 Implications in Cancer Biology and Metabolism. Facts and Controversies Simoni-Nieves, Arturo; Gerardo-Ramírez, Monserrat; Pedraza-Vázquez, Gibrán Frontiers in Oncology, Vol. 9 https://doi.org/10.3389/fonc.2019.01039	journal	October 2019
Commentary: Blockade of activin type II receptors with a dual anti-ActRIIA/IIB antibody is critical to promote maximal skeletal muscle hypertrophy Durán, Javier; Estrada, Manuel Frontiers in Pharmacology, Vol. 9 https://doi.org/10.3389/fphar.2018.00381	journal	April 2018
GDF11 induces differentiation and apoptosis and inhibits migration of C17.2 neural stem cells via modulating MAPK signaling pathway Wang, Zongkui; Dou, Miaomiao; Liu, Fengjuan PeerJ, Vol. 6 https://doi.org/10.7717/peerj.5524	journal	September 2018

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59 BASIC BIOLOGICAL SCIENCES
Ligands
Myostatin
Receptor
Structure
Transforming growth factor β (TGFβ)

Structural basis for potency differences between GDF8 and GDF11 Walker, Ryan; Czepnik, Magdalena; Goebel, Erich https://doi.org/10.6084/m9.figshare.c.3709096 The current record is supplemented by this collection	collection	January 2017
Structural basis for potency differences between GDF8 and GDF11 Walker, Ryan; Czepnik, Magdalena; Goebel, Erich https://doi.org/10.6084/m9.figshare.c.3709096.v1 The current record is supplemented by this collection	collection	January 2017
Additional file 1: Table S1. of Structural basis for potency differences between GDF8 and GDF11 Walker, Ryan; Czepnik, Magdalena; Goebel, Erich https://doi.org/10.6084/m9.figshare.c.3709096_d1.v1 The current record is supplemented by this text	text	January 2017
Additional file 2: Figure S1. of Structural basis for potency differences between GDF8 and GDF11 Walker, Ryan; Czepnik, Magdalena; Goebel, Erich https://doi.org/10.6084/m9.figshare.c.3709096_d2.v1 The current record is supplemented by this image	image	January 2017
Additional file 3: Figure S2. of Structural basis for potency differences between GDF8 and GDF11 Walker, Ryan; Czepnik, Magdalena; Goebel, Erich https://doi.org/10.6084/m9.figshare.c.3709096_d3.v1 The current record is supplemented by this image	image	January 2017
Additional file 4: Figure S3. of Structural basis for potency differences between GDF8 and GDF11 Walker, Ryan; Czepnik, Magdalena; Goebel, Erich https://doi.org/10.6084/m9.figshare.c.3709096_d4.v1 The current record is supplemented by this image	image	January 2017
Additional file 5: Figure S4. of Structural basis for potency differences between GDF8 and GDF11 Walker, Ryan; Czepnik, Magdalena; Goebel, Erich https://doi.org/10.6084/m9.figshare.c.3709096_d5.v1 The current record is supplemented by this image	image	January 2017
Additional file 6: Figure S5. of Structural basis for potency differences between GDF8 and GDF11 Walker, Ryan; Czepnik, Magdalena; Goebel, Erich https://doi.org/10.6084/m9.figshare.c.3709096_d6.v1 The current record is supplemented by this image	image	January 2017
Additional file 1: Table S1. of Structural basis for potency differences between GDF8 and GDF11 Walker, Ryan; Czepnik, Magdalena; Goebel, Erich https://doi.org/10.6084/m9.figshare.c.3709096_d1 The current record is supplemented by this text	text	January 2017
Additional file 2: Figure S1. of Structural basis for potency differences between GDF8 and GDF11 Walker, Ryan; Czepnik, Magdalena; Goebel, Erich https://doi.org/10.6084/m9.figshare.c.3709096_d2 The current record is supplemented by this image	image	January 2017
Additional file 6: Figure S5. of Structural basis for potency differences between GDF8 and GDF11 Walker, Ryan; Czepnik, Magdalena; Goebel, Erich https://doi.org/10.6084/m9.figshare.c.3709096_d6 The current record is supplemented by this image	image	January 2017
Additional file 4: Figure S3. of Structural basis for potency differences between GDF8 and GDF11 Walker, Ryan; Czepnik, Magdalena; Goebel, Erich https://doi.org/10.6084/m9.figshare.c.3709096_d4 The current record is supplemented by this image	image	January 2017
Additional file 5: Figure S4. of Structural basis for potency differences between GDF8 and GDF11 Walker, Ryan; Czepnik, Magdalena; Goebel, Erich https://doi.org/10.6084/m9.figshare.c.3709096_d5 The current record is supplemented by this image	image	January 2017
Additional file 3: Figure S2. of Structural basis for potency differences between GDF8 and GDF11 Walker, Ryan; Czepnik, Magdalena; Goebel, Erich https://doi.org/10.6084/m9.figshare.c.3709096_d3 The current record is supplemented by this image	image	January 2017