Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.603738
Title: Structural and functional analyses of follistatin, a secreted antagonist of activins and bone morphogenetic proteins
Author: Harrington, A. E.
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2005
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Abstract:
Follistatin is a secreted glycoprotein that binds to and prevents the activation of cell surface receptors by growth factors of the TGF-β superfamily. It is composed of four disulfide-rich domains, three of which adopt the follistatin (FS) domain fold.  A region in the Fs1 domain, rich in basic residues, is responsible for the protein’s interaction with heparin sulfates (HS) in the extracellular milieu. The nature of this association is investigated in this work by various biophysical studies, which, inter alia, demonstrate that HS and analogues with greater than six disaccharide units are capable of binding two Fs1 domains. This may facilitate the inhibition of dimers of activin and related proteins, by enabling two molecules of follistatin to co-localise adjacent to herparan sulphate glycosaminoglycans. In addition to these studies, the nature of the activin-binding activity of follistatin is explored, and it is revealed to residue in no one domain of the protein. However, a construct of follistatin corresponding to the first two FS domains is shown to be capable of activin binding, and a complex of this Fs12 fragment bound to human activin A has been crystallised. The X-ray crystal structure has been solved by molecular replacement methods to a resolution of 2.6 Å, and reveals in detail the key determinants of activin binding by follistatin. Ultimately, this work enhances our understanding of the mode of action of follistatin, and may illuminate research on its crucial role in the early embryonic development of Xenopus laevis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.603738  DOI: Not available
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