3B4V

X-Ray structure of Activin in complex with FSTL3

Summary for 3B4V

• Entry DOI: 10.2210/pdb3b4v/pdb
• Descriptor: Inhibin beta A chain, follistatin-like 3, 1,2-ETHANEDIOL, ... (6 entities in total)
• Functional Keywords: ligand-inhibitor signalling complex, cleavage on pair of basic residues, glycoprotein, growth factor, hormone, secreted, nucleus, proto-oncogene, hormone regulator complex
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 8
• Total formula weight: 152645.57

Authors

Thompson, T.B. (deposition date: 2007-10-24, release date: 2008-09-02, Last modification date: 2024-10-30)

Primary citation

Stamler, R.,Keutmann, H.T.,Sidis, Y.,Kattamuri, C.,Schneyer, A.,Thompson, T.B.
The structure of FSTL3.activin A complex. Differential binding of N-terminal domains influences follistatin-type antagonist specificity.
J.Biol.Chem., 283:32831-32838, 2008

PubMed 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.

PubMed: 18768470
DOI: 10.1074/jbc.M801266200

Experimental method

X-RAY DIFFRACTION (2.48 Å)