Structure-function studies of TGF-beta family proteins
One of the major areas of research in the Hinck laboratory is to identify the molecular adaptations that are responsible for the unique functions of representative members of the highly diversified transforming growth factor beta (TGF-β) family of signaling proteins. Previous studies in the lab focused on determining the structures of the disulfide-rich TGF-βs and TGF-β receptors, TβRI and TβRII, alone and as bound to one another. These studies, along with parallel studies carried out in other laboratories on the BMPs, showed that in spite of their similar folds, the ligands and receptors of the different subfamilies bind their receptors and assemble them into complexes in ways that are entirely distinct. TGF-βs bind their receptors, TβRI and TβRII, on underside of the “fingers” and “fingertips”, respectively, while the BMPs bind their type I and type II receptors on the “wrist” and “knuckles”, respectively. The structures of the receptor complexes, together with accompanying functional studies carried out in this and other laboratories, showed that the repositioning of the receptors is driven by relatively minor, but important changes in the loop regions of the receptors. These alternative binding modes increase the range of specificity and are responsible for segregating the actions of the TGF-βs, evolutionary latecomers to the superfamily that activate Smads 2 and 3, from the BMPs and GDFs, the ancestors that activate Smads 1, 5, and 8 (see Review here)
The present studies in this overall area are focused in two areas. The first is focused on understanding how the evolutionary intermediate, activin A, binds and assembles its type I and type II receptors into a signaling complex. This project is of interest, as this will provide insights as to whether the differences in type I and type II receptor binding for the TGF-βs compared to the BMPs arose in a stepwise or concerted manner. The second structural project is focused on understanding the how the co-receptor, betaglycan, potentiates receptor complex assembly and signaling for TGF-β2. This project is of interest, as it will provide insights as to the mechanism by which this accessory binding protein selectively recognizes this TGF-β family member and thus provide a means of targeting it to cells and tissues where this co-receptor is expressed.