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Protein Essential For Making Steroids Turns Out To Be A "Molten Globule"

June 24, 1999
University Of California, San Francisco
Researchers at UC San Francisco are working to find out how cells make steroid hormones, chemicals that are essential for life, for health and for reproduction because they control the body's salt balance, sugar balance and sexual function.

StAR appears to do its best work when it takes the shape ofa molten globule.

That is not news from astronomers or cosmologists, but fromthe molecular biology lab of Walter L. Miller, MD, professorof pediatric endocrinology at UC San Francisco. Miller'sgroup is working to find out how cells make steroidhormones, chemicals that are essential for life, for healthand for reproduction because they control the body's saltbalance, sugar balance and sexual function. StAR -steroidogenic acute regulatory protein -- is an unusualprotein that recently has been shown to perform a key rolein the steroid-making system.

In a paper in the June 22, 1999 issue of the journalProceedings of the National Academy of Sciences, Miller,UCSF postdoctoral fellow Himangshu Bose and their colleaguesreport that the StAR protein partially unfolds from itsfinished shape in order to take a shape that allows it towork inside the cell. In protein-folding jargon, apartially unfolded protein is called a "molten globule."

Cells in the adrenal and sex glands manufacture steroidhormones by changing cholesterol into related chemicals, ina process that involves many steps. For the first step,cholesterol has to be transported into mitochondria, smallenergy-generating spheres inside the cell. In work publishedover the past few years, Miller's group and their colleaguesfrom other universities have demonstrated that StAR helpsspeed up this cholesterol-transfer process.

These groups also have cloned the gene that controls theStAR protein, and have shown that a rare inherited diseaseis caused by mutations of that gene. The disease providesstark proof of the essential role of steroid hormones.

Children born with the rare disease, congenital lipoidadrenal hyperplasia (lipoid CAH) cannot make steroidhormones in part because they lack a functioning StARprotein. "Many of these children die in infancy for lack ofmineralcorticoids, the hormones that regulate salt balancein the body," Miller said. "Hormone replacement therapy cansave their lives, but the children also must receivemineralcorticoid and glucocorticoid replacements throughouttheir lives to help maintain salt and sugar balance."

Miller's lab has been working in cooperation with MichaelBaldwin, PhD, and Thomas James, PhD, in the department ofpharmaceutical chemistry at UCSF to determine the structureof StAR and learn how it works.

Miller credits Bose, a postdoctoral fellow with a backgroundin physical chemistry, for enlisting help from Baldwin,James and other UCSF experts in protein spectroscopy tostudy how the StAR protein is folded into its final shape.Most proteins are not active in this incompletely foldedstate, but Bose concluded that StAR does its work ofushering cholesterol into the mitochondria when it ispartially unfolded.

That may be because the ports that allow entry intomitochondria are very small, Bose said. "Think of a proteinas a ball of spaghetti. It can only get into themitochondria one strand at a time." A section of theprotein called the "mitochondrial leader" enters a port.Inside the mitochondria, import machinery begins to pull theprotein in - as if it were slurping in a strand ofspaghetti. StAR unfolds to enter the port, but a compactlyfolded section of the protein unfolds more slowly andcreates a pause in the process.

In their article for The Proceedings of the National Academyof Sciences, Bose, Miller and their colleagues propose thatthis flexible, "molten globule" conformation lowers theenergy required for a channel to open in the mitochondrialmembrane. In this form, StAR appears to function as anon/off switch for cholesterol flowing from the cell into themitochondria. If so, it may be the first protein found thatdoes its work in a molten globule state.

More studies are necessary to determine StAR's exactstructure and to work out the details of how it shepherdscholesterol into the mitochondria to become the raw materialfor steroids.

"We know that we have a very intriguing protein with acrucial function," Bose said. "This research is a start ondetermining how it looks and how it works."

REPORTERS' NOTE: For more information about the work of the Miller lab, see their website at

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University Of California, San Francisco. "Protein Essential For Making Steroids Turns Out To Be A "Molten Globule"." ScienceDaily. ScienceDaily, 24 June 1999. <>.
University Of California, San Francisco. (1999, June 24). Protein Essential For Making Steroids Turns Out To Be A "Molten Globule". ScienceDaily. Retrieved July 4, 2015 from
University Of California, San Francisco. "Protein Essential For Making Steroids Turns Out To Be A "Molten Globule"." ScienceDaily. (accessed July 4, 2015).

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