Journal of Biological Chemistry
Volume 275, Issue 5, 4 February 2000, Pages 3206-3212
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MECHANISMS OF SIGNAL TRANSDUCTION
Identification of a Binding Site on the Type II Activin Receptor for Activin and Inhibin*

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Type II activin receptors (ActRII and ActRIIB) are single-transmembrane domain serine/threonine kinase receptors that bind activin to initiate the signaling and cellular responses triggered by this hormone. Inhibin also binds type II activin receptors and antagonizes many activin effects. Here we describe alanine scanning mutagenesis of the ActRII extracellular domain. We identify a cluster of three hydrophobic residues (Phe42, Trp60, and Phe83) that, when individually mutated to alanine in the context of the full-length receptor, cause the disruption of activin and inhibin binding to ActRII. Each of the alanine-substituted ActRII mutants retaining activin binding maintains the ability to form cross-linked complexes with activin and supports activin cross-linking to the type I activin receptor ALK4. Unlike wild-type ActRII, the three mutants unable to bind activin do not cause an increase in activin signaling when transiently expressed in a corticotroph cell line. Together, our results implicate these residues in forming a critical binding surface on ActRII required for functional interactions with both activin and inhibin. This first identification of a transforming growth factor-β family member binding site may provide a general basis for characterizing binding sites for other members of the superfamily.

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*

This work was supported by a George E. Hewitt Foundation for Medical Research fellowship (to P. C. G.), a Howard Hughes Medical Institute predoctoral fellowship and a Markey fellowship (to J. G.), a Klingenstein Fellowship Award in Neuroscience (to S. C.), and National Institutes of Health Grant HD-13527 from the Foundation for Medical Research, California Division.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.