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J. Biol. Chem., Vol. 280, Issue 44, 36626-36632, November 4, 2005

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An Activin-A/C Chimera Exhibits Activin and Myostatin Antagonistic Properties^*

Uwe Muenster, Craig A. Harrison, Cynthia Donaldson, Wylie Vale, and Wolfgang H. Fischer1

From the Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, California 92037 and Prince Henry's Institute of Medical Research, Monash Medical Centre, Clayton, Victoria 3168, Australia

Activins are involved in many physiological and pathological processes and, like other members of the transforming growth factor- superfamily, signal via type II and I receptor serine kinases. Ligand residues involved in type II receptor binding are located in the two anti-parallel strands of the TGF- proteins, also known as the fingers. Activin-A mutants able to bind ActRII but unable to bind the activin type I receptor ALK4 define ligand residues involved in ALK4 binding and could potentially act as antagonists. Therefore, a series of FLAG-tagged activin-A/C chimeras were constructed, in each of which eight residues in the wrist loop and helix region (A/C 46–53, 54–61, 62–69, and 70–78) were replaced. Additionally, a chimera was generated in which the entire wrist region (A/C 46–78) was changed from activin-A to activin-C. The chimeras were assessed for ActRII binding, activin bioactivity, as well as antagonistic properties. All five chimeras retained high affinity for mouse ActRII. Of these, only A/C 46–78 was devoid of significant activin bioactivity in an A3 Lux reporter assay in 293T cells at concentrations up to 40 nM. A/C 46–53, 54–61, 62–69, and 70–78 showed activity comparable with wild type activin-A. When tested for the ability to antagonize ligands that signal via activin type II receptors, such as activin-A and myostatin, only the A/C 46–78 chimera showed antagonism (IC₅₀, 1–10 nM). Additionally, A/C 46–78 decreased follicle-stimulating hormone release from the LT2 cell line and rat anterior pituitary cells in primary culture in a concentration-dependent manner. These data indicate that activin residues in the wrist are involved in ALK4-mediated signaling. The activin antagonist A/C 46–78 may be useful for the study and modulation of activin-dependent processes.

Received for publication, July 5, 2005

^* This work was supported by the Foundation for Medical Research, California Division, and by National Institutes of Health Grant HD-13527. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, 10010 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.:858-453-4100; Fax: 858-552-1546; E-mail: fischer{at}salk.edu.

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