The Structure of FSTL3·Activin A Complex: DIFFERENTIAL BINDING OF N-TERMINAL DOMAINS INFLUENCES FOLLISTATIN-TYPE ANTAGONIST SPECIFICITY*S⃞
| Autor: | Stamler, Robin, Keutmann, Henry T., Sidis, Yisrael, Kattamuri, Chandramohan, Schneyer, Alan, Thompson, Thomas B. |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
Models
Molecular Follistatin Binding Sites Follistatin-Related Proteins Protein Conformation Surface Properties Activin Receptors Electrons Crystallography X-Ray Ligands Activins Cell Line Protein Structure Tertiary embryonic structures Protein Structure and Folding Humans hormones hormone substitutes and hormone antagonists Protein Binding |
| Popis: | Transforming growth factor β 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 Å. 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|