Randy Schekman, an HHMI investigator at the University of California, Berkeley, shifted his lab from studying membranes in yeast to studying membranes in human cells.

The vesicles that transport proteins from the ER to their next destination—the Golgi apparatus, a stack of membranes where proteins are further processed—are called COPII vesicles. A specific set of proteins coat their surface. Schekman has characterized these COPII coat proteins, showing that one of them, called sec24, decides whether proteins leave the ER in vesicles. Human cells have four variations of sec24 and each recognizes different proteins. If no sec24 variant recognizes a protein, that protein remains in the ER.

That can cause a problem during organism development, according to a recent collaboration between Schekman and David Ginty at the Johns Hopkins University School of Medicine.

In 2008, Schekman got a call from Ginty, an HHMI investigator who studies, among other things, the development of the neural system. A graduate student in Ginty's lab had been studying an extreme form of spina bifida, in which the neural tube fails to close during fetal development. In his search for gene mutations leading to this birth defect, the student turned up sec24b—one of the four sec24 variants.

Neural tube closure during development relies on a precise gradient of molecules to distinguish areas of the fetus. Together, Ginty and Schekman's labs revealed that without sec24, one of these molecules, vangl2, remains stuck in the ER and never establishes the gradient the cell banks on. Though earlier fetal development can progress with a, c, and d variants of sec24, neural tube closure stalls without sec24b. The results were published online in Nature Cell Biology on December 6, 2009.

Schekman's group is also exploring ER management of a macromolecule that is important to human health: cholesterol. When a cell doesn't need cholesterol, it stores SREBP, a protein involved in cholesterol production, in the ER. When the cell requires cholesterol, vesicles transport SREBP out of the ER, allowing it to turn on cholesterol-producing machinery. Current cholesterol-lowering drugs block that final production machinery, but Schekman would like to see drugs that block the creation of the vesicles that carry SREBP out of the ER in the first place. His lab is collaborating with HHMI investigator David Ginsburg at the University of Michigan to identify which sec24 variant wraps SREBP in membranes and to determine how to block the interaction between SREBP and that variant.

“There is really an increasing overlap between trafficking in the cell and human metabolic diseases,” says Schekman. All forms of hyperlipidemia—including high cholesterol in the blood—relate to how membranes move lipid molecules around, he says. Brain disorders may also involve cell membranes (see Web Extra “Dropping the Payload”).

		Dropping the Payload What happens when a vesicle arrives at its destination? Read More

Photo: Mark Richards

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