A pH-dependent molten globule transition is required for activity of the steroidogenic acute regulatory protein, StAR

doi:10.1074/jbc.M510241200

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Papers In Press, published online ahead of print October 18, 2005
J. Biol. Chem, 10.1074/jbc.M510241200
Submitted on September 19, 2005
Revised on October 13, 2005
Accepted on October 18, 2005

A pH-dependent molten globule transition is required for activity of the steroidogenic acute regulatory protein, StAR

Bo Y. Baker, Dustin C. Yaworsky, and Walter L. Miller

Dept. of Pediatrics, University of California (UCSF), San Francisco, CA 94143-0978

Corresponding Author: wlmlab{at}itsa.ucsf.edu

The steroidogenic acute regulatory protein (StAR) simulates steroid biosynthesis by increasing the flow of cholesterol from the outer mitochondrial membrane (OMM) to the inner membrane. StAR acts exclusively on the OMM, and only StAR’s carboxyl-terminal $alpha$ -helix (C-helix) interacts with membranes. Biophysical studies have shown that StAR becomes a molten globule at acidic pH, but a physiologic role for this structural transition has been controversial. Molecular modeling shows that the C-helix, which forms the floor of the sterol-bonding pocket (SBP), is stabilized by hydrogen bonding to adjacent loops. Molecular dynamics (MD) simulations show that protonation of the C-helix and adjacent loops facilitates opening and closing the SBP. Two disulfide mutants, S100C/S261C (SS) and D106C/A268C (DA), designed to limit the mobility of the C-helix but not disrupt overall conformation, were prepared in bacteria and their correct folding and positioning of the disulfide bonds was confirmed. The SS mutant lost half, and the DA mutant lost all cholesterol-binding capacity and steroidogenic activity with isolated mitochondria in vitro, but full binding and activity was restored to each mutant by disrupting the disulfide bonds with DTT. These data strongly support the model that StAR activity requires a pH-dependant molten globule transition on the OMM.

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