Molecular Biosciences

Research Summary: 

One area of interest focuses on how the machinery for sulfation, a common posttranslational modification of proteins, lipids and carbohydrates is organized and controlled in higher organisms. The integrated pathway for sulfate uptake, activation and utilization encompasses multiple components and multiple intracellular compartments. At the center of this process is the bifunctional PAPS synthetase which synthesizes phosphoadenosylphosulfate (PAPS) from ATP and SO42- in a two-step process, catalyzed by ATP-sulfurylase and APS-kinase activities. We discovered the PAPS synthetase gene family, identified mutations in PAPS synthetase that lead to both human and animal chondrodystrophies and elucidated unique enzymatic properties, including channeling of the intermediate APS more recently using i) a systems approach, we have identified a trifunctional single polypeptide enzyme which includes a pyrophosphotase activity; ii) loss-and-gain of function models, we have determined that defects in PAPS-synthetase, resulting in an undersulfated matrix in some tissues, causes aberrant trafficking and signaling of secreted morphogens. Overall, the long-term goal is to provide a model of the temporal and topological organization of this critically important pathway, how it is regulated, and to correlate defects in the overall pathway with abnormal growth and development. Our new findings open up a new field focused on regulation of key morphogens by the extracellular environment, whose composition is partly determined by PAPS synthetase, and through which they must migrate to deliver signals from source to target cells.