STRUCTURAL STUDIES OF FOLLISTATIN ISOFORMS BY SAXS IN SOLUTION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Follistatin splice variants, FS288 and FS315, exhibit unique functional and physiological characteristics, such as differences in TGF-b ligand and heparan sulfate binding and serum vs. tissue localization. The addition of 28 amino acids to the FS288 C-terminus may influence follistatin functions by altering the conformation of the protein, thereby decreasing its affinity for both of its known ligands. Based on our analysis of the FS315:activin A crystal structure, we hypothesize that FSD3 may bind to and present the FS315 C-terminal tail to an internal interaction site that overlaps the FSD1 heparin binding site. This model would explain the functional differences between FS isoforms and should be testable using biophysical approaches. In order to influence the ligand binding affinity of FS, the FS315 C-terminus likely induces significant conformational changes in the free FS structure, such as compacting or constraining the structure of the polypeptide chain. The interaction of the tail with the HBS would be predicted to significantly change the shape of the monomeric protein, potentially reducing the overall diameter of the molecule and producing a more globular arrangement of the domains. We propose to test this possibility for the protein in solution using small angle x-ray scattering.