Miller's lab has been working in cooperation with Michael Baldwin, PhD, and Thomas James, PhD, in the department of pharmaceutical chemistry at UCSF to determine the structure of StAR and learn how it works.
Miller credits Bose, a postdoctoral fellow with a background in physical chemistry, for enlisting help from Baldwin, James and other UCSF experts in protein spectroscopy to study how the StAR protein is folded into its final shape. Most proteins are not active in this incompletely folded state, but Bose concluded that StAR does its work of ushering cholesterol into the mitochondria when it is partially unfolded.
That may be because the ports that allow entry into mitochondria are very small, Bose said. "Think of a protein as a ball of spaghetti. It can only get into the mitochondria one strand at a time." A section of the protein called the "mitochondrial leader" enters a port. Inside the mitochondria, import machinery begins to pull the protein in - as if it were slurping in a strand of spaghetti. StAR unfolds to enter the port, but a compactly folded section of the protein unfolds more slowly and creates a pause in the process.
In their article for The Proceedings of the National Academy of Sciences, Bose,
Miller and their colleagues propose that this flexible, "molten globule"
conformation lowers the energy required for a channel to open in the
mitochondrial membrane. In this form, StAR appears to function as an on/off
switch for cholesterol flowing from the cell into the mitochondria. If so, it
may be the first protein found that does its work in a molten globule state.
More studies are necessary to determine StAR's exact structure and to work out
the details of how it shepherds cholesterol into the mitochondria to be
Contact: Janet Basu
University of California - San Francisco