Steroidogenic Acute Regulatory Protein and Peripheral-Type Benzodiazepine Receptor Associate at the Mitochondrial Membrane

West, L. A.; Horvat, Regina D.; Roess, Deborah A.; Barisas, B. George; Juengel, Jennifer L.; Niswender, Gordon D.

doi:10.1210/endo.142.1.8052

Cited by 95 publications

(40 citation statements)

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“…Fifth, only limited domains of StAR, encompassing the C-helix and possibly the adjacent ⍀ loops, interact with lipid models of the OMM (15). Sixth, some data also implicate the peripheral benzodiazepine receptor (PBR), a small OMM protein, in the mitochondrial import of cholesterol (37), and recent data indicate that StAR interacts with PBR on the OMM to initiate cholesterol import (38,39).…”

Section: Discussionmentioning

confidence: 99%

A pH-dependent Molten Globule Transition Is Required for Activity of the Steroidogenic Acute Regulatory Protein, StAR

Baker

Yaworsky

Miller

2005

Journal of Biological Chemistry

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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 ␣-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-binding pocket, is stabilized by hydrogen bonding to adjacent loops. Molecular dynamics simulations show that protonation of the C-helix and adjacent loops facilitates opening and closing the sterol-binding pocket. 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 dithiothreitol. These data strongly support the model that StAR activity requires a pH-dependent molten globule transition on the OMM.Molten globules are compact, partially unfolded proteins that retain their secondary structure but have lost some tertiary structure (1); such partially unfolded structures are typically inactive but may be intermediates in membrane insertion (2). Steroidogenic acute regulatory protein (StAR), 3 which is essential for normal adrenal and gonadal steroidogenesis, facilitates the flow of cholesterol from the outer mitochondrial membrane (OMM) to the inner mitochondrial membrane (IMM), where cholesterol is converted to pregnenolone by the cholesterol side chain cleavage enzyme, P450scc (3, 4). Mutation of human StAR causes potentially lethal congenital lipoid adrenal hyperplasia (5, 6); all missense mutations that cause this disease are found in the carboxyl-terminal 50% of the protein, indicating that these sequences are required for StAR activity (7-9). StAR is synthesized as a 37-kDa phosphoprotein with an amino-terminal mitochondrial leader sequence that is cleaved during mitochondrial entry (3, 10, 11).The mechanism by which StAR moves cholesterol from the OMM to IMM remains unclear. The x-ray crystal structures of two closely related proteins, N-216 MLN64 (12) and StarD4 (13), reveal a ␤-barrel structure with a hydrophobic sterol-binding pocket (SBP) that will accommodate one cholesterol molecule, although the apparent access channel to the SBP is too small to accommodate a cholesterol molecule. Models of StAR show the same fold (12,14,15), suggesting action as a transport protein. Recent data suggest that members of the StarD4 family of related proteins, which lack mitochondrial targeting sequences, serve as cytosolic transporters for insoluble lipid molecu...

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Section: Discussionmentioning

confidence: 99%

A pH-dependent Molten Globule Transition Is Required for Activity of the Steroidogenic Acute Regulatory Protein, StAR

Baker

Yaworsky

Miller

2005

Journal of Biological Chemistry

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“…There is evidence for the involvement of human peripheral benzodiazepine receptor (PBR) in steroidogenesis (26), and there are indications that StAR protein and PBR interact at mitochondrial membranes (27). This finding led to speculation about the possible involvement of an insect PBR in ecdysteroidogenesis (4).…”

Section: Discussionmentioning

confidence: 99%

The Drosophila gene Start1 : A putative cholesterol transporter and key regulator of ecdysteroid synthesis

Roth

Gierl

Vollborn

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…Although a physical interaction between StAR and PBR/TSPO has not been established, FRET measurements indicated that StAR/StarD1 and PBR/TSPO come within the 100 A o of each other [89]. Moreover, Hauet et al [87] reported that isolated mitochondria from mouse Leydig MA-10 cells that express the Tom20/StAR fusion construct produce steroids at a maximal level, but if the cells are treated with PBRantisense oligonucleotides, their ability to synthesize the steroid is lost; on the contrary, re-introduction of recombinant PBR into the mitochondria in vitro rescued the steroidogenesis [87,90].…”

Section: Hormonal Regulation Of Steroidogenesismentioning

confidence: 99%

Impact of Aging on Steroid Hormone Biosynthesis and Secretion

Zaidi¹

2013

TOLSJ

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Steroid hormones are lipophilic, low-molecular weight organic compounds all of which are derived from cholesterol. They are primarily synthesized by steroidogenic glands such as gonads (ovary and testis), the adrenal gland and, during pregnancy, by the placental trophoblasts. Limited steroid synthesis also takes place in the brain. Steroid hormones are crucial for the proper functioning of the body. They mediate a wide variety of vital physiological functions, ranging from maintaining normal reproductive function and secondary sexual characteristics, to regulating virtually every metabolic process in the body. Like many age-related endocrine disorders, aging also progressively impacts the tissue-specific synthesis and secretion of steroid hormones. The goal of this review is to summarize the effects of aging on steroid hormone synthesis and secretion by the adrenal gland and gonads of both human and experimental animal models, to describe the potential involvement of excessive oxidative stress in mediating age-related alterations in steroidogenesis, and to discuss the possible underlying mechanisms involved.

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Steroidogenic Acute Regulatory Protein and Peripheral-Type Benzodiazepine Receptor Associate at the Mitochondrial Membrane

Cited by 95 publications

References 0 publications

A pH-dependent Molten Globule Transition Is Required for Activity of the Steroidogenic Acute Regulatory Protein, StAR

A pH-dependent Molten Globule Transition Is Required for Activity of the Steroidogenic Acute Regulatory Protein, StAR

The Drosophila gene Start1 : A putative cholesterol transporter and key regulator of ecdysteroid synthesis

Impact of Aging on Steroid Hormone Biosynthesis and Secretion

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