Crystal structure of the WFIKKN2 follistatin domain reveals insight into how it inhibits growth differentiation factor 8 (GDF8) and GDF11

McCoy, Jason C.; Walker, Ryan G.; Murray, Nathan H.; Thompson, Thomas B.

doi:10.1074/jbc.RA118.005831

Title: Crystal structure of the WFIKKN2 follistatin domain reveals insight into how it inhibits growth differentiation factor 8 (GDF8) and GDF11

Journal Article · Wed Feb 27 00:00:00 EST 2019 · Journal of Biological Chemistry

DOI:https://doi.org/10.1074/jbc.RA118.005831· OSTI ID:1596148

McCoy, Jason C. ^[1]; Walker, Ryan G. ^[2]; Murray, Nathan H. ^[3];

^[1]

Univ. of Cincinnati, OH (United States)
Univ. of Cincinnati, OH (United States); Harvard Univ., Cambridge, MA (United States)
Univ. of Cincinnati, OH (United States); Univ. of Wisconsin, Madison, WI (United States)

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. Furthermore, 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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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: National Inst. of Health; American Heart Association

Grant/Contract Number:: R01 GM114640; 12PRE11790027; 18PRE33990312

OSTI ID:: 1596148

Journal Information:: Journal of Biological Chemistry, Vol. 294, Issue 16; ISSN 0021-9258

Publisher:: American Society for Biochemistry and Molecular BiologyCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 10 works

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
transforming growth factor beta (TGF-β)
protein structure
X-ray crystallography
inhibitor
myostatin
structural biology
muscle development
tissue homeostasis
GDF8
GDF11
WFIKKN
follistatin
antagonism

Title: Crystal structure of the WFIKKN2 follistatin domain reveals insight into how it inhibits growth differentiation factor 8 (GDF8) and GDF11

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