The Molecular Mechanisms of Protein Sorting

The Golgi complex is the protein postal service of eukaryotic cells. The organelle takes in hundreds of proteins and then directs them to various subcellular destinations. A key component of the Golgi’s sorting machinery is guanine-nucleotide exchange factor proteins (GEFs). Certain molecular markers function as a mailing address on the protein to be delivered, and GEFs must correctly interpret these markers and “decide” where and when to activate the enzymes that will get the protein to its appropriate destination.

J. Christopher Fromme, Molecular Biology and Genetics, is investigating how GEFs make these molecular decisions. This project uses a broad set of tools, including biochemical reconstitution reactions, structural biology, in vivo functional assays, live-cell imaging, and genetic experiments. Taken together, the combined results of in vivo and in vitro experiments will enable researchers to determine the mechanisms that GEFs use to localize to their site of action, identify their substrate, and regulate their activity.

The Golgi complex is essential to cell viability. Many human diseases arise from defects in the Golgi’s sorting machinery, yet the mechanisms that govern the flow of material through the Golgi remain unknown. This research will define how GEFs sense and integrate signals and inform a holistic view of how GEFs work together. By uncovering the molecular logic that underpins how the Golgi functions, this research will provide insights with important implications for medicine, drug development, and human health.

NIH Award Number: 1R35GM136258-01

Cornell Researchers

Funding Received

$2.6 Million spanning 5 years