UC San Diego

The TGF-beta superfamily of proteins plays a crucial role in development. Given their wide-range of activities, the understanding of how these ligands are able to elicit such diverse biological responses using a very limited number of receptors is paramount. Structural studies have provided valuable insight into how some of these ligands function, however there still remains many ligands that have not been able to be studied given their difficulty to be produced in quantities suitable for structural as well as functional analysis. The focus of this work is on TGF- beta ligands that play a role in the development of the musculoskeletal system. Using a novel technique termed Random Assembly of Heteromer Chimeras, or RASCH, functionally equivalent ligands of TGF-beta ligands Nodal and Activin, two ligands involved in chondrogenic and osteogenic signaling pathways, have been produced, and their structures solved. This technique has also yielded chimeras with novel properties, such as enhanced osteogenesis. The structure of one such chimera, termed AB204, is presented. Additionally, structures of two members of another subset of the BMP ligands, GDF6 and GDF7, both involved in tenogenic signaling, were solved. In addition to the structures presented, mechanistic models that explain how these ligands assemble their signaling complexes are presented based on the information obtained from these structures