Translocator protein: pharmacology and steroidogenesis

2015 ◽  
Vol 43 (4) ◽  
pp. 572-578 ◽  
Author(s):  
Andrew Midzak ◽  
Barry Zirkin ◽  
Vassilios Papadopoulos
Keyword(s):  
Drug Binding ◽  
Translocator Protein ◽  
Biological Research ◽  
Cholesterol Transport ◽  
Steroid Biosynthesis ◽  
Steroid Production ◽  
Steroid Synthesis ◽  
Binding Partners ◽  
Evolutionarily Conserved ◽  
Mitochondrial Cholesterol

The translocator protein (TSPO; 18k Da) is an evolutionarily conserved outer mitochondrial membrane (OMM) protein highly expressed in steroid-synthesizing cells and found to possess a number of physiological and drug-binding partners. Extensive pharmacological, biochemical and cell biological research over the years has led to a model of TSPO involvement in mitochondrial cholesterol transport and promotion of steroid synthesis, a model guiding the design of drugs useful in stimulating neurosteroid synthesis and alleviating psychopathological symptoms. The involvement of TSPO in these processes has been called into question; however, with the publication of TSPO-deletion mouse models which saw no changes in steroid production. Here, we review work characterizing TSPO in steroidogenesis and offer perspective to research into TSPO pharmacology and its involvement in steroid biosynthesis.

scholarly journals Cryo-EM structure of human Wntless in complex with Wnt3a

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Qing Zhong ◽  
Yanyu Zhao ◽  
Fangfei Ye ◽  
Zaiyu Xiao ◽  
Gaoxingyu Huang ◽  
...  
Keyword(s):  
Transmembrane Domain ◽  
Transmembrane Protein ◽  
Multiple Interfaces ◽  
Wnt Proteins ◽  
Binding Partners ◽  
Multiple Binding Sites ◽  
Evolutionarily Conserved ◽  
Multiple Binding ◽  
Hydrophobic Tunnel ◽  
Conserved Core

AbstractWntless (WLS), an evolutionarily conserved multi-pass transmembrane protein, is essential for secretion of Wnt proteins. Wnt-triggered signaling pathways control many crucial life events, whereas aberrant Wnt signaling is tightly associated with many human diseases including cancers. Here, we report the cryo-EM structure of human WLS in complex with Wnt3a, the most widely studied Wnt, at 2.2 Å resolution. The transmembrane domain of WLS bears a GPCR fold, with a conserved core cavity and a lateral opening. Wnt3a interacts with WLS at multiple interfaces, with the lipid moiety on Wnt3a traversing a hydrophobic tunnel of WLS transmembrane domain and inserting into membrane. A β-hairpin of Wnt3a containing the conserved palmitoleoylation site interacts with WLS extensively, which is crucial for WLS-mediated Wnt secretion. The flexibility of the Wnt3a loop/hairpin regions involved in the multiple binding sites indicates induced fit might happen when Wnts are bound to different binding partners. Our findings provide important insights into the molecular mechanism of Wnt palmitoleoylation, secretion and signaling.

scholarly journals TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria

2016 ◽  
Vol 473 (2) ◽  
pp. 107-121 ◽  
Author(s):  
Jemma Gatliff ◽  
Michelangelo Campanella
Keyword(s):  
Neurological Diseases ◽  
Anion Channel ◽  
Translocator Protein ◽  
Endocrine Regulation ◽  
Voltage Dependent Anion Channel ◽  
Steroid Synthesis ◽  
Cellular Processes ◽  
Cellular Events ◽  
Voltage Dependent

The 18-kDa translocator protein (TSPO) localizes in the outer mitochondrial membrane (OMM) of cells and is readily up-regulated under various pathological conditions such as cancer, inflammation, mechanical lesions and neurological diseases. Able to bind with high affinity synthetic and endogenous ligands, its core biochemical function resides in the translocation of cholesterol into the mitochondria influencing the subsequent steps of (neuro-)steroid synthesis and systemic endocrine regulation. Over the years, however, TSPO has also been linked to core cellular processes such as apoptosis and autophagy. It interacts and forms complexes with other mitochondrial proteins such as the voltage-dependent anion channel (VDAC) via which signalling and regulatory transduction of these core cellular events may be influenced. Despite nearly 40 years of study, the precise functional role of TSPO beyond cholesterol trafficking remains elusive even though the recent breakthroughs on its high-resolution crystal structure and contribution to quality-control signalling of mitochondria. All this along with a captivating pharmacological profile provides novel opportunities to investigate and understand the significance of this highly conserved protein as well as contribute the development of specific therapeutics as presented and discussed in the present review.

scholarly journals Minireview: Translocator Protein (TSPO) and Steroidogenesis: A Reappraisal

2015 ◽  
Vol 29 (4) ◽  
pp. 490-501 ◽  
Author(s):  
Vimal Selvaraj ◽  
Douglas M. Stocco ◽  
Lan N. Tu
Keyword(s):  
Positive Impact ◽  
Transmembrane Protein ◽  
Steroid Hormone ◽  
Benzodiazepine Receptor ◽  
Translocator Protein ◽  
Research Progress ◽  
Peripheral Benzodiazepine Receptor ◽  
Hormone Production ◽  
Recent Developments ◽  
Mitochondrial Cholesterol

Abstract The 18-kDa translocator protein (TSPO), also known as the peripheral benzodiazepine receptor, is a transmembrane protein in the outer mitochondrial membrane. TSPO has long been described as being indispensable for mitochondrial cholesterol import that is essential for steroid hormone production. In contrast to this initial proposition, recent experiments reexamining TSPO function have demonstrated that it is not involved in steroidogenesis. This fundamental change has forced a reexamination of the functional interpretations made for TSPO that broadly impacts both basic and clinical research across multiple fields. In this minireview, we recapitulate the key studies from 25 years of TSPO research and concurrently examine their limitations that perhaps led towards the incorrect association of TSPO and steroid hormone production. Although this shift in understanding raises new questions regarding the molecular function of TSPO, these recent developments are poised to have a significant positive impact for research progress in steroid endocrinology.

scholarly journals NPC1 regulates ER contacts with endocytic organelles to mediate cholesterol egress

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
D. Höglinger ◽  
T. Burgoyne ◽  
E. Sanchez-Heras ◽  
P. Hartwig ◽  
A. Colaco ◽  
...  
Keyword(s):  
Dietary Cholesterol ◽  
Cholesterol Transport ◽  
Cholesterol Accumulation ◽  
C Protein ◽  
Membrane Contact Sites ◽  
Sterol Transport ◽  
Membrane Contact ◽  
Mitochondrial Cholesterol ◽  
Niemann Pick ◽  
The Impact

Abstract Transport of dietary cholesterol from endocytic organelles to the endoplasmic reticulum (ER) is essential for cholesterol homoeostasis, but the mechanism and regulation of this transport remains poorly defined. Membrane contact sites (MCS), microdomains of close membrane apposition, are gaining attention as important platforms for non-vesicular, inter-organellar communication. Here we investigate the impact of ER-endocytic organelle MCS on cholesterol transport. We report a role for Niemann-Pick type C protein 1 (NPC1) in tethering ER-endocytic organelle MCS where it interacts with the ER-localised sterol transport protein Gramd1b to regulate cholesterol egress. We show that artificially tethering MCS rescues the cholesterol accumulation that characterises NPC1-deficient cells, consistent with direct lysosome to ER cholesterol transport across MCS. Finally, we identify an expanded population of lysosome-mitochondria MCS in cells depleted of NPC1 or Gramd1b that is dependent on the late endosomal sterol-binding protein STARD3, likely underlying the mitochondrial cholesterol accumulation in NPC1-deficient cells.

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