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

Physiology

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

85 Citations (Scopus)

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
Article number	19
Number of pages	22
Journal	BMC Biology
Volume	15
Issue number	1
DOIs	https://doi.org/10.1186/s12915-017-0350-1
Publication status	Published - 3 Mar 2017

Keywords

Ligands
Myostatin
Receptor
Structure
Transforming growth factor β (TGFβ)

Access to Document

10.1186/s12915-017-0350-1

29808241-oaFinal published version, 8.15 MB

Cite this

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), Article 19. https://doi.org/10.1186/s12915-017-0350-1

@article{bd88746edeae4c8a814625962aa464a0,

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.}",

year = "2017",

month = mar,

day = "3",

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

language = "English",

volume = "15",

journal = "BMC Biology",

issn = "1741-7007",

publisher = "BioMed Central",

number = "1",

}

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.

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)

UR - http://www.scopus.com/inward/record.url?scp=85014335452&partnerID=8YFLogxK

U2 - 10.1186/s12915-017-0350-1

DO - 10.1186/s12915-017-0350-1

M3 - Article

AN - SCOPUS:85014335452

SN - 1741-7007

VL - 15

JO - BMC Biology

JF - BMC Biology

IS - 1

M1 - 19

ER -

Structural basis for potency differences between GDF8 and GDF11

Abstract

Keywords

Access to Document

Other files and links

Targeting activins to treat cachexia

Cite this

Structural basis for potency differences between GDF8 and GDF11

Abstract

Keywords

Access to Document

Other files and links

Projects

Targeting activins to treat cachexia

Cite this