Structural basis for potency differences between GDF8 and GDF11

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

doi:10.1186/s12915-017-0350-1

Structural basis for potency differences between GDF8 and GDF11

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

Research output: Contribution to journal › Article › peer-review

66 Scopus citations

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.

Original language	English (US)
Article number	19
Journal	BMC Biology
Volume	15
Issue number	1
DOIs	https://doi.org/10.1186/s12915-017-0350-1
State	Published - Mar 3 2017
Externally published	Yes

Keywords

Ligands
Myostatin
Receptor
Structure
Transforming growth factor β (TGFβ)

ASJC Scopus subject areas

Agricultural and Biological Sciences(all)
Ecology, Evolution, Behavior and Systematics
Biochemistry, Genetics and Molecular Biology(all)
Structural Biology
Physiology
Biotechnology
Plant Science
Cell Biology
Developmental Biology

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10.1186/s12915-017-0350-1

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Walker, R. G., Czepnik, M., Goebel, E. J., McCoy, J. C., Vujic, A., Cho, M., Oh, J., Aykul, S., Walton, K. L., Schang, G., Bernard, D. J., Hinck, A. P., Harrison, C. A., Martinez-Hackert, E., Wagers, A. J., Lee, R. T., & Thompson, T. B. (2017). Structural basis for potency differences between GDF8 and GDF11. BMC Biology, 15(1), [19]. https://doi.org/10.1186/s12915-017-0350-1

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title = "Structural basis for potency differences between GDF8 and GDF11",

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.",

keywords = "Ligands, Myostatin, Receptor, Structure, Transforming growth factor β (TGFβ)",

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

note = "Funding Information: This study was supported, in part, by the National Institutes of Health, the National Health and Medical Research Council Australia Grant, Michigan State University, the Paul F. Glenn Center for the Biology of Aging, the Muscular Dystrophy Association, the University of Cincinnati Graduate Dean Fellowship, and the American Heart Association (R01AG047131, R01AG040019, and R03AG049657 to RTL; Paul F. Glenn Center Grant and R56AG048917, R56AG052979 and R01AG048917 to AJW; R41AR06880401 to EMH; GM58670 and CA172886 to APH; CIHR MOP-133394 to DJB; 1078907 to CAH; R01GM114640 and Muscular Dystrophy Association Grant 240087 to TBT; Graduate Dean Fellowship and 12PRE11790027 to RGW). Publisher Copyright: {\textcopyright} 2017 Thompson et al.",

year = "2017",

month = mar,

day = "3",

doi = "10.1186/s12915-017-0350-1",

language = "English (US)",

volume = "15",

journal = "BMC Biology",

issn = "1741-7007",

publisher = "BioMed Central",

number = "1",

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TY - JOUR

T1 - Structural basis for potency differences between GDF8 and GDF11

AU - Walker, Ryan G.

AU - Czepnik, Magdalena

AU - Goebel, Erich J.

AU - McCoy, Jason C.

AU - Vujic, Ana

AU - Cho, Miook

AU - Oh, Juhyun

AU - Aykul, Senem

AU - Walton, Kelly L.

AU - Schang, Gauthier

AU - Bernard, Daniel J.

AU - Hinck, Andrew P.

AU - Harrison, Craig A.

AU - Martinez-Hackert, Erik

AU - Wagers, Amy J.

AU - Lee, Richard T.

AU - Thompson, Thomas B.

N1 - Funding Information: This study was supported, in part, by the National Institutes of Health, the National Health and Medical Research Council Australia Grant, Michigan State University, the Paul F. Glenn Center for the Biology of Aging, the Muscular Dystrophy Association, the University of Cincinnati Graduate Dean Fellowship, and the American Heart Association (R01AG047131, R01AG040019, and R03AG049657 to RTL; Paul F. Glenn Center Grant and R56AG048917, R56AG052979 and R01AG048917 to AJW; R41AR06880401 to EMH; GM58670 and CA172886 to APH; CIHR MOP-133394 to DJB; 1078907 to CAH; R01GM114640 and Muscular Dystrophy Association Grant 240087 to TBT; Graduate Dean Fellowship and 12PRE11790027 to RGW). Publisher Copyright: © 2017 Thompson et al.

PY - 2017/3/3

Y1 - 2017/3/3

N2 - 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.

AB - 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.

KW - Ligands

KW - Myostatin

KW - Receptor

KW - Structure

KW - Transforming growth factor β (TGFβ)

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U2 - 10.1186/s12915-017-0350-1

DO - 10.1186/s12915-017-0350-1

M3 - Article

C2 - 28257634

AN - SCOPUS:85014335452

SN - 1741-7007

VL - 15

JO - BMC Biology

JF - BMC Biology

IS - 1

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ER -

Structural basis for potency differences between GDF8 and GDF11

Abstract

Keywords

ASJC Scopus subject areas

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