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J. Biol. Chem., Vol. 276, Issue 21, 17718-17726, May 25, 2001
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From the Follistatin is recognized to be an
important regulator of cellular differentiation and secretion through
its potent ability to bind and bioneutralize activin with which it is
colocalized in many tissue systems. The 288-residue follistatin
molecule is comprised of a 63-residue N-terminal segment followed by
three repeating 10-cysteine "follistatin domains" also represented
in several extracellular matrix proteins. We have used chemical
modifications and mutational analyses to define structural requirements
for follistatin bioactivity that previously have not been investigated systematically. Mutant follistatins were stably expressed from Chinese
hamster ovary cell cultures and assayed for activin binding in a
solid-phase competition assay. Biological activities were determined by
inhibition of activin-mediated transcriptional activity and by
suppression of follicle-stimulating hormone secretion by cultured
anterior pituitary cells. Deletion of the entire N-terminal domain,
disruption of N-terminal disulfides, and deletion of the first two
residues each reduced activin binding to <5 % of expressed wild-type
follistatin and abolished the ability of the respective mutants to
suppress activin-mediated responses in both bioassay systems. Hence,
the three follistatin domains inherently lack the ability to bind or
neutralize activin. Activin binding was impaired after oxidation of at
least one tryptophan, at position 4, in FS-288. Mutation of Trp to Ala
or Asp at either positions 4 or 36 eliminated activin binding and
bioactivity. Mutation of a third hydrophobic residue, Phe-52, reduced
binding to 20%, whereas substitutions for the individual Lys and Arg
residues in the N-terminal region were tolerated. These results
establish that hydrophobic residues within the N-terminal domain
constitute essential activin-binding determinants in the follistatin
molecule. The correlation among the effects of mutation on activin
binding, activin transcriptional responses, and follicle-stimulating
hormone secretion substantiates the concept that, at
least in the pituitary, the biological activity of follistatin is
attributable to its ability to bind and bioneutralize activin.
Follistatin: Essential Role for the N-terminal Domain in Activin
Binding and Neutralization*
,,, Reproductive Endocrine Unit and National
Center for Infertility Research and the § Endocrine Unit,
Massachusetts General Hospital and Harvard Medical School, Boston,
Massachusetts 02114
*
Supported by Grant DK-53828 from the National Institutes of
Health.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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