Structural/functional characterization of TGFB superfamily signaling and regulation

The TGFb family of signaling ligands orchestrate numerous biological processes in fetal development and adult homeostasis. Aberrant signaling results in many human diseases, highlighting the need to better understand the molecular mechanisms of signaling and regulation. Ligands in the family are generally divided into three classes (TGFbs, Bone Morphogenetic Proteins or BMPs and Activins) and signal by directing the assembly of two Type I and two Type II serine/threonine kinase receptors. The laboratory uses a combination of structural biology, computational biology, biophysics, and cell-based signaling assays to investigate several fundamental areas of signaling and regulation within the broader TGFb family. We are focused on four overarching questions: What are variations to ligand-receptor interactions that support ligand selectivity? How do different prodomains regulate their corresponding ligand? What are the molecular mechanisms that allow heterodimers to form and how are the interaction of heterodimers with receptors different than homodimers? How do structurally dissimilar antagonists bind and modulate specific ligands? Our approaches will couple structural techniques, such as cryoEM, X-ray crystallography and HDX/MS with in vitro cell-based assays and biochemical interrogation. In addition, we are incorporating deep learning and artificial intelligence technology to enhance de novo protein design strategies. Structural and functional studies of prodomain-ligand and antagonist- ligand interactions will continue to improve our knowledge of the diverse molecular mechanisms that regulate TGFb ligands. Overall, our multi-faceted research program aims to unravel the complexities and governance of molecular interactions in the TGFβ family. Project Number: 1R35GM161787-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: THOMAS THOMPSON | Institution: UNIVERSITY OF CINCINNATI, CINCINNATI, OH | Award Amount: $756,933 | Activity Code: R35 | Study Section: Maximizing Investigators' Research Award - E Study Section[MRAE] View on NIH RePORTER: https://reporter.nih.gov/project-details/11260691