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The Role of Chordin and Twisted Gastrulation in Regulating BMP Family Growth Factors

Troilo, Helen

[Thesis]. Manchester, UK: The University of Manchester; 2014.

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Abstract

Bone morphogenetic proteins (BMPs) are growth factors of the TGF-β superfamily. They are essential to early embryonic patterning, and are of interest in a range of pathologies. The secreted glycoprotein chordin binds to BMPs and antagonizes their signalling by preventing them from interacting with their cell surface receptors. This antagonism is relieved by cleavage of chordin at two specific points by tolloid family metalloproteinases. Twisted gastrulation has a dual role in regulating this pathway. It binds to both chordin and BMPs strengthening their interaction but also promotes cleavage of chordin by tolloids through an unknown mechanism.In this study the structures of chordin and twisted gastrulation are investigated using a range of in solution techniques including analytical ultracentrifugation, small angle X-ray scattering and multiangle light scattering. These show that chordin is bowl shaped with the C-terminal region looping back toward the N-terminus while twisted gastrulation is more linear. It is shown for the first time that the vWC domains of chordin have self-affinity and that the C-terminal vWC containing region is flexible. We propose a mechanism by which this flexibility may allow more than one binding arrangement between chordin and BMPs depending on BMP specificity. This in turn allows for selective regulation by tolloids. In addition potentially novel functions for the chordin fragments including conformational change and fibre formation in the presence of Tsg were investigated.