Crystal Structure of the WFIKKN2 Follistatin Domain Reveals Insight into How It Inhibits Growth Differentiation Factor 8 (GDF8) and GDF11

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2019 Mar 1

PMID 30814254

Citations 9

Authors

Jason C McCoy

Ryan G Walker

Nathan H Murray

Thomas B Thompson

Affiliations

Soon will be listed here.

Abstract

Growth differentiation factor 8 (GDF8; also known as myostatin) and GDF11 are closely related members of the transforming growth factor β (TGF-β) family. GDF8 strongly and negatively regulates skeletal muscle growth, and GDF11 has been implicated in various age-related pathologies such as cardiac hypertrophy. GDF8 and GDF11 signaling activities are controlled by the extracellular protein antagonists follistatin; follistatin-like 3 (FSTL3); and WAP, follistatin/kazal, immunoglobulin, Kunitz, and netrin domain-containing (WFIKKN). All of these proteins contain a follistatin domain (FSD) important for ligand binding and antagonism. Here, we investigated the structure and function of the FSD from murine WFIKKN2 and compared it with the FSDs of follistatin and FSTL3. Using native gel shift and surface plasmon resonance analyses, we determined that the WFIKKN2 FSD can interact with both GDF8 and GDF11 and block their interactions with the type II receptor activin A receptor type 2B (ActRIIB). Further, we solved the crystal structure of the WFIKKN2 FSD to 1.39 Å resolution and identified surface-exposed residues that, when substituted with alanine, reduce antagonism of GDF8 in full-length WFIKKN2. Comparison of the WFIKKN2 FSD with those of follistatin and FSTL3 revealed differences in both the FSD structure and position of residues within the domain that are important for ligand antagonism. Taken together, our results indicate that both WFIKKN and follistatin utilize their FSDs to block the type II receptor but do so via different binding interactions.

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References

Walker R, Czepnik M, Goebel E, McCoy J, Vujic A, Cho M . Structural basis for potency differences between GDF8 and GDF11. BMC Biol. 2017; 15(1):19. PMC: 5336696. DOI: 10.1186/s12915-017-0350-1. View

Rinaldi F, Zhang Y, Mondragon-Gonzalez R, Harvey J, Perlingeiro R . Treatment with rGDF11 does not improve the dystrophic muscle pathology of mdx mice. Skelet Muscle. 2016; 6:21. PMC: 4906773. DOI: 10.1186/s13395-016-0092-8. View

Pariani S, Contreras M, Rossi F, Sander V, Corigliano M, Simon F . Characterization of a novel Kazal-type serine proteinase inhibitor of Arabidopsis thaliana. Biochimie. 2016; 123:85-94. DOI: 10.1016/j.biochi.2016.02.002. View

Wagner K, Fleckenstein J, Amato A, Barohn R, Bushby K, Escolar D . A phase I/IItrial of MYO-029 in adult subjects with muscular dystrophy. Ann Neurol. 2008; 63(5):561-71. DOI: 10.1002/ana.21338. View

Ozek C, Krolewski R, Buchanan S, Rubin L . Growth Differentiation Factor 11 treatment leads to neuronal and vascular improvements in the hippocampus of aged mice. Sci Rep. 2018; 8(1):17293. PMC: 6251885. DOI: 10.1038/s41598-018-35716-6. View

Keutmann H, Schneyer A, Sidis Y . The role of follistatin domains in follistatin biological action. Mol Endocrinol. 2003; 18(1):228-40. DOI: 10.1210/me.2003-0112. View

Syed Ibrahim B, Pattabhi V . Crystal structure of trypsin-turkey egg white inhibitor complex. Biochem Biophys Res Commun. 2003; 313(1):8-16. DOI: 10.1016/j.bbrc.2003.11.082. View

Walker R, McCoy J, Czepnik M, Mills M, Hagg A, Walton K . Molecular characterization of latent GDF8 reveals mechanisms of activation. Proc Natl Acad Sci U S A. 2018; 115(5):E866-E875. PMC: 5798348. DOI: 10.1073/pnas.1714622115. View

Mendell J, Sahenk Z, Malik V, Gomez A, Flanigan K, Lowes L . A phase 1/2a follistatin gene therapy trial for becker muscular dystrophy. Mol Ther. 2014; 23(1):192-201. PMC: 4426808. DOI: 10.1038/mt.2014.200. View

10.

Williams C, Headd J, Moriarty N, Prisant M, Videau L, Deis L . MolProbity: More and better reference data for improved all-atom structure validation. Protein Sci. 2017; 27(1):293-315. PMC: 5734394. DOI: 10.1002/pro.3330. View

11.

McPherron A, Lawler A, Lee S . Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature. 1997; 387(6628):83-90. DOI: 10.1038/387083a0. View

12.

Lee S, Lee Y, Zimmers T, Soleimani A, Matzuk M, Tsuchida K . Regulation of muscle mass by follistatin and activins. Mol Endocrinol. 2010; 24(10):1998-2008. PMC: 2954636. DOI: 10.1210/me.2010-0127. View

13.

Johansson M, Keyser P, Soderhall K . Purification and cDNA cloning of a four-domain Kazal proteinase inhibitor from crayfish blood cells. Eur J Biochem. 1994; 223(2):389-94. DOI: 10.1111/j.1432-1033.1994.tb19005.x. View

14.

Geng Y, Dong Y, Yu M, Zhang L, Yan X, Sun J . Follistatin-like 1 (Fstl1) is a bone morphogenetic protein (BMP) 4 signaling antagonist in controlling mouse lung development. Proc Natl Acad Sci U S A. 2011; 108(17):7058-63. PMC: 3084141. DOI: 10.1073/pnas.1007293108. View

15.

LARKIN M, Blackshields G, Brown N, Chenna R, McGettigan P, McWilliam H . Clustal W and Clustal X version 2.0. Bioinformatics. 2007; 23(21):2947-8. DOI: 10.1093/bioinformatics/btm404. View

16.

Terwilliger T, Adams P, Read R, McCoy A, Moriarty N, Grosse-Kunstleve R . Decision-making in structure solution using Bayesian estimates of map quality: the PHENIX AutoSol wizard. Acta Crystallogr D Biol Crystallogr. 2009; 65(Pt 6):582-601. PMC: 2685735. DOI: 10.1107/S0907444909012098. View

17.

Zimmers T, Jiang Y, Wang M, Liang T, Rupert J, Au E . Exogenous GDF11 induces cardiac and skeletal muscle dysfunction and wasting. Basic Res Cardiol. 2017; 112(4):48. PMC: 5833306. DOI: 10.1007/s00395-017-0639-9. View

18.

Cash J, Angerman E, Keutmann H, Thompson T . Characterization of follistatin-type domains and their contribution to myostatin and activin A antagonism. Mol Endocrinol. 2012; 26(7):1167-78. PMC: 3385792. DOI: 10.1210/me.2012-1061. View

19.

Chang C, Eggen B, Weinstein D, Brivanlou A . Regulation of nodal and BMP signaling by tomoregulin-1 (X7365) through novel mechanisms. Dev Biol. 2003; 255(1):1-11. DOI: 10.1016/s0012-1606(02)00075-1. View

20.

Chen V, Arendall 3rd W, Headd J, Keedy D, Immormino R, Kapral G . MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr D Biol Crystallogr. 2010; 66(Pt 1):12-21. PMC: 2803126. DOI: 10.1107/S0907444909042073. View