title: The structure of FSTL3.activin A complex. Differential binding of N-terminal domains influences follistatin-type antagonist specificity.
abstract: Transforming growth factor beta family ligands are neutralized by a number of structurally divergent antagonists. Follistatin-type antagonists, which include splice variants of follistatin (FS288 and FS315) and follistatin-like 3 (FSTL3), have high affinity for activin A but differ in their affinity for other ligands, particularly bone morphogenetic proteins. To understand the structural basis for ligand specificity within FS-type antagonists, we determined the x-ray structure of activin A in complex with FSTL3 to a resolution of 2.5 A. Similar to the previously resolved FS.activin A structures, the ligand is encircled by two antagonist molecules blocking all ligand receptor-binding sites. Recently, the significance of the FS N-terminal domain interaction at the ligand type I receptor site has been questioned; however, our data show that for FSTL3, the N-terminal domain forms a more intimate contact with activin A, implying that this interaction is stronger than that for FS. Furthermore, binding studies revealed that replacing the FSTL3 N-terminal domain with the corresponding FS domain considerably lowers activin A affinity. Therefore, both structural and biochemical evidence support a significant interaction of the N-terminal domain of FSTL3 with activin A. In addition, structural comparisons with bone morphogenetic proteins suggest that the interface where the N-terminal domain binds may be the key site for determining FS-type antagonist specificity.
authors.affiliation: Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati Medical Sciences Building, Cincinnati, Ohio 45267, USA.
authors.forename: Robin
authors.initials: R
authors.lastname: Stamler
authors.forename: Henry T
authors.initials: HT
authors.lastname: Keutmann
authors.forename: Yisrael
authors.initials: Y
authors.lastname: Sidis
authors.forename: Chandramohan
authors.initials: C
authors.lastname: Kattamuri
authors.forename: Alan
authors.initials: A
authors.lastname: Schneyer
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Thompson