Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.11 (AMPK)
 12,425 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acute stimulation of cholesterol transport into mitochondria involves the cAMP-dependent protein kinase (PKA), peripheral-type benzodiazepine receptor (PBR), and the steroidogenesis acute regulatory (StAR) proteins. We investigated the respective role of these proteins in hormone-induced steroidogenesis. Oligonucleotides antisense, but not sense, to PBR and StAR reduced their respective levels in steroidogenic cells and inhibited hormone-stimulated steroid formation in MA-10 mouse Leydig tumor cells. In search of the proteins regulating PBR we identified a protein, PAP7, which interacts with PBR and the PKA regulatory subunit RIalpha, is present in adrenal and gonadal cells and is found in mitochondria. Overexpression of the full length PAP7 increased the hormone-induced steroid production. However, inhibition of PAP7 expression reduced the gonadotropin-induced steroid formation. In search of a PBR functional antagonist that would facilitate the studies on the biological function of PBR, we screened a phage display library. A 7-mer competitive PBR peptide antagonist was identified, which when transduced into Leydig cells inhibited the benzodiazepine and hormone-stimulated steroid production suggesting that the endogenous PBR agonist/receptor interaction is critical for the hormone-dependent steroidogenesis. These data indicate that hormone-induced cholesterol transport and the subsequent steroid formation is a dynamic multistep process involving protein-protein interactions.
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PMID:PBR, StAR, and PKA: partners in cholesterol transport in steroidogenic cells. 1253 Jun 41

Transport of cholesterol into the mitochondria is the rate-determining, hormone-sensitive step in steroid biosynthesis. Here we report that the mechanism underlying mitochondrial cholesterol transport involves the formation of a macromolecular signaling complex composed of the outer mitochondrial membrane translocator protein (TSPO), previously known as peripheral-type benzodiazepine receptor; the TSPO-associated protein PAP7, which binds and brings to mitochondria the regulatory subunit RIalpha of the cAMP-dependent protein kinase (PKARIalpha); and the hormone-induced PKA substrate, steroidogenic acute regulatory protein (StAR). Hormone treatment of MA-10 Leydig cells induced the co-localization of TSPO, PAP7, PKARIalpha, and StAR in mitochondria, visualized by confocal microscopy, and the formation in living cells of a high molecular weight multimeric complex identified using photoactivable amino acids. The hormone-induced recruitment of exogenous TSPO in this complex was found to parallel the increased presence of 7-azi-5alpha-cholestan-3beta-ol in the samples. Co-expression of Tspo, Pap7, PkarIalpha, and Star genes resulted in the stimulation of steroid formation in both steroidogenic MA-10 and non-steroidogenic COS-F2-130 cells that were engineered to metabolize cholesterol. Disruption of these protein-protein interactions and specifically the PKARIalpha-PAP7 and PAP7-TSPO interactions, using PAP7 mutants where the N0 area homologous to dual A-kinase-anchoring protein-1 or the acyl-CoA signature motif were deleted or using the peptide Ht31 known to disrupt the anchoring of PKA, inhibited both basal and hormone-induced steroidogenesis. These results suggest that the initiation of cAMP-induced protein-protein interactions results in the formation of a multivalent scaffold in the outer mitochondrial membrane that mediates the effect of hormones on mitochondrial cholesterol transport and steroidogenesis.
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PMID:Protein-protein interactions mediate mitochondrial cholesterol transport and steroid biosynthesis. 1705 May 26

Cholesterol transport into mitochondria is the rate-determining and hormone-sensitive step in steroid biosynthesis. During the last few years two proteins were shown to be critical for this process: the mitochondrial translocator protein, previously known as peripheral-type benzodiazepine receptor, and the steroidogenic acute regulatory protein. In this manuscript we review evidence suggesting that these two proteins functionally interact to facilitate cholesterol transport and may be part of a larger multimeric mitochondrial complex of proteins assembled to facilitate the hormone-induced cholesterol transfer into mitochondria. This complex might include proteins such as the mitochondrial voltage-dependent anion channel, the translocator protein-associated protein PAP7 which also functions as an A kinase anchor protein that binds and brings into the complex the regulatory subunit Ialpha of the cAMP-dependent protein kinase.
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PMID:Is there a mitochondrial signaling complex facilitating cholesterol import? 1728 Jul 76

The transfer of cholesterol from the outer to the inner mitochondrial membrane is the rate-limiting step in hormone-induced steroid formation. To ensure that this step is achieved efficiently, free cholesterol must accumulate in excess at the outer mitochondrial membrane and then be transferred to the inner membrane. This is accomplished through a series of steps that involve various intracellular organelles, including lysosomes and lipid droplets, and proteins such as the translocator protein (18 kDa, TSPO) and steroidogenic acute regulatory (StAR) proteins. TSPO, previously known as the peripheral-type benzodiazepine receptor, is a high-affinity drug- and cholesterol-binding mitochondrial protein. StAR is a hormone-induced mitochondria-targeted protein that has been shown to initiate cholesterol transfer into mitochondria. Through the assistance of proteins such as the cAMP-dependent protein kinase regulatory subunit Ialpha (PKA-RIalpha) and the PKA-RIalpha- and TSPO-associated acyl-coenzyme A binding domain containing 3 (ACBD3) protein, PAP7, cholesterol is transferred to and docked at the outer mitochondrial membrane. The TSPO-dependent import of StAR into mitochondria, and the association of TSPO with the outer/inner mitochondrial membrane contact sites, drives the intramitochondrial cholesterol transfer and subsequent steroid formation. The focus of this review is on (i) the intracellular pathways and protein-protein interactions involved in cholesterol transport and steroid biosynthesis and (ii) the roles and interactions of these proteins in endocrine pathologies and neurological diseases where steroid synthesis plays a critical role.
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PMID:Cholesterol transport in steroid biosynthesis: role of protein-protein interactions and implications in disease states. 1928 73