Chris Fromme, Molecular Biology and Genetics, is probing the regulatory mysteries of the Golgi complex, the central sorting station for nearly a third of all proteins in eukaryotic cells. The elucidated mechanisms in this project, essential for cell viability, will move the field toward a better understanding of the many human diseases that arise from defects in the membrane and protein sorting machinery and its regulators.

Protein and membrane traffic at the Golgi is controlled by a class of enzymes, Arf GTPases, that function by recruiting effector molecules to make outgoing vesicles and tether incoming vesicles. In order to understand the molecular logic of Golgi trafficking, researchers must understand the details of how these Arf GTPases are activated.

The master regulators that activate these crucial Arf GTPase pathways are another class of protein, Arf-GEFs (guanine nucleotide exchange factors). One of the main goals of the project is to uncover precisely how the Golgi Arf-GEFs are regulated to make the molecular decision of where and when to activate their substrate Arf proteins.

Fromme has already uncovered intriguing regulatory mechanisms that govern the function of a particular Arf-GEF—the trans-Golgi network-localized, Sec 7 Arf-GEF—which involves direct interactions between the activated forms of four different Golgi GTPases. This collection of interactions represents a previously unappreciated level of crosstalk between prominent Golgi GTPase pathways.

Key questions remain regarding the biochemical basis for regulation and the cell biology underpinning these interactions. Using in vitro and in vivo assays and structural analyses, the outcome of these studies will be new and refined mechanistic models for regulation of trafficking at the Golgi complex. NIH Award Number: 2R01GM098621-06