Validation of the mechanism of cholesterol binding by StAR using short molecular dynamics simulations

Barbar, Élie; Lavigne, Pierre; Lehoux, Jean‐Guy

doi:10.1016/j.jsbmb.2008.11.008

Cited by 8 publications

(9 citation statements)

References 36 publications

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“…As discussed above, these mutants were expected to lead to the weakening of the hydrophobic interface and hence to a reduction in the amount of α-helical content and stable tertiary structure (Roostaee et al, 2008). Also, short molecular dynamics simulations have indicated that the L275P mutation confers a higher flexibility to STARD1's α-helix 4 (Barbar et al, 2009b), which suggests a more open state of the helix, thereby reducing its gating capacity, which is related to the decrease in cholesterol binding and the steroidogenic activity previously studied (Bose et al, 1998; Roostaee et al, 2008). …”

Section: Mechanism Of Cholesterol Transfer By Stard1mentioning

confidence: 98%

Thirty-Eight-Year Follow-Up of Two Sibling Lipoid Congenital Adrenal Hyperplasia Patients Due to Homozygous Steroidogenic Acute Regulatory (STARD1) Protein Mutation. Molecular Structure and Modeling of the STARD1 L275P Mutation

et al. 2016

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Objective: Review the impact of StAR (STARD1) mutations on steroidogenesis and fertility in LCAH patients. Examine the endocrine mechanisms underlying the pathology of the disorder and the appropriate therapy for promoting fertility and pregnancies.Design: Published data in the literature and a detailed 38-year follow-up of two sibling LCAH patients. Molecular structure and modeling of the STARD1 L275P mutation.Setting: University hospital.Patients: Patient A (46,XY female phenotype) and patient B (46,XX female) with LCAH bearing the L275P mutation in STARD1.Interventions: Since early-age diagnosis, both patients underwent corticoid replacement therapy. Patient A received estrogen therapy at pubertal age. Clomiphene therapy was given to Patient B to induce ovulation. Pregnancies were protected with progesterone administration.Main Outcome Measures: Clinical and molecular assessment of adrenal and gonadal functions.Results: Both patients have classic manifestations of corticosteroid deficiency observed in LCAH. Time of onset and severity were different. Patient A developed into a female phenotype due to early and severe damage of Leydig cells. Patient B started a progressive pubertal development, menarche and regular non-ovulatory cycle. She was able to have successful pregnancies.Conclusions: Understanding the molecular structure and function of STARD1 in all steroidogenic tissues is the key for comprehending the heterogeneous clinical manifestations of LCAH, and the development of an appropriate strategy for the induction of ovulation and protecting pregnancies in this disease.

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Section: Mechanism Of Cholesterol Transfer By Stard1mentioning

confidence: 98%

Thirty-Eight-Year Follow-Up of Two Sibling Lipoid Congenital Adrenal Hyperplasia Patients Due to Homozygous Steroidogenic Acute Regulatory (STARD1) Protein Mutation. Molecular Structure and Modeling of the STARD1 L275P Mutation

et al. 2016

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“…This initial START domain structure carries over to subsequently obtained crystal structures of the cholesterol‐associated STAR, STARD4 and STARD5 proteins . Molecular modeling and dynamics studies have been used to support a model of STAR as a sterol transporter, with its C‐terminal α‐helix serving as a lid over its hydrophobic cavity . The model of STAR as a cholesterol transporter was initially supported by biochemical work showing the transfer of radiolabeled cholesterol and fluorescent sterol from donor to acceptor membranes by wild‐type, but not mutated, STAR .…”

Section: The Star and The Start Domainmentioning

confidence: 99%

Binding Domain‐Driven Intracellular Trafficking of Sterols for Synthesis of Steroid Hormones, Bile Acids and Oxysterols

Midzak

Papadopoulos

2014

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Steroid hormones, bioactive oxysterols and bile acids are all derived from the biological metabolism of lipid cholesterol. The enzymatic pathways generating these compounds have been an area of intense research for almost a century, as cholesterol and its metabolites have substantial impacts on human health. Owing to its high degree of hydrophobicity and the chemical properties that it confers to biological membranes, the distribution of cholesterol in cells is tightly controlled, with subcellular organelles exhibiting highly divergent levels of cholesterol. The manners in which cells maintain such sterol distributions are of great interest in the study of steroid and bile acid synthesis, as limiting cholesterol substrate to the enzymatic pathways is the principal mechanism by which production of steroids and bile acids is regulated. The mechanisms by which cholesterol moves within cells, however, remain poorly understood. In this review, we examine the subcellular machinery involved in cholesterol metabolism to steroid hormones and bile acid, relating it to both lipid-and protein-based mechanisms facilitating intracellular and intraorganellar cholesterol movement and delivery to these pathways. In The lipid cholesterol has generated some of the greatest research interest regarding the chemicals that make up life. Providing profoundly critical physical properties as a component of the membranes that separate the biotic from the abiotic, cholesterol exerts significant physiological effects in its own right. Moreover, cholesterol is enzymatically metabolized in cells to structurally diverse families of steroids, oxysterols and bile acids, each of which have specific and highly potent signaling capabilities. Our understanding of the ways through which cells handle cholesterol and respond to cholesterol metabolite signaling has expanded enormously over the past half century. However, the manner in which cells synthesize steroids and other cholesterol metabolites, despite the progress made, has yet to fully integrate the advances of cholesterol biophysics and cellular biology into its theoretical framework. These issues have captured the interest of researchers in the field (1), and in this review, we look to extend on this www.traffic.dk 895

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“…In liver mitochondria, cholesterol is hydroxylated on the side chain at position C27 or C25 by the cytochrome P450 enzyme CYP27A1 to produce the oxysterols 27-hydroxycholesterol (27HC) or 25-hydroxycholesterol (25HC) (Li et al 2007). In addition to simply serving as intermediates in bile acid biosynthetic pathway, 27HC and 25HC are cellular signals (Tsujishita & Hurley 2000, Roderick et al 2002, Olayioye et al 2005, Murcia et al 2006, Bose et al 2008a,b, Kudo et al 2008, Rodriguez-Agudo et al 2008, Barbar et al 2009, Horibata & Sugimoto 2010, Thorsell et al 2011 (Kirkby et al 2010).…”

Section: Cholesterol Trafficking and Homeostasismentioning

confidence: 99%

“…Structural modeling and biophysical studies indicate that conformational changes, e.g. movement of the C-terminal a-helix, a pH-dependent molten globule transition, are important to promote cholesterol release and activate cholesterol transfer across the mitochondrial membranes (Bose et al 1999, Murcia et al 2006, Barbar et al 2009, Fluck et al 2011. Cholesterol desorption into the intramembrane space for uptake by the inner membrane has been suggested for StAR functioning independent of cholesterol transfer (Christenson & Strauss 2001).…”

Section: Cholesterol Trafficking and Homeostasismentioning

confidence: 99%

The mammalian START domain protein family in lipid transport in health and disease

Clark¹

2011

Journal of Endocrinology

132

109

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Lipid transfer proteins of the steroidogenic acute regulatory protein-related lipid transfer (START) domain family are defined by the presence of a conserved w210 amino acid sequence that folds into an a/b helix-grip structure forming a hydrophobic pocket for ligand binding. The mammalian START proteins bind diverse ligands, such as cholesterol, oxysterols, phospholipids, sphingolipids, and possibly fatty acids, and have putative roles in non-vesicular lipid transport, thioesterase enzymatic activity, and tumor suppression. However, the biological functions of many members of the START domain protein family are not well established. Recent research has focused on characterizing the cell-type distribution and regulation of the START proteins, examining the specificity and directionality of lipid transport, and identifying disease states associated with dysregulation of START protein expression. This review summarizes the current concepts of the proposed physiological and pathological roles for the mammalian START domain proteins in cholesterol and lipid trafficking.

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Validation of the mechanism of cholesterol binding by StAR using short molecular dynamics simulations

Cited by 8 publications

References 36 publications

Thirty-Eight-Year Follow-Up of Two Sibling Lipoid Congenital Adrenal Hyperplasia Patients Due to Homozygous Steroidogenic Acute Regulatory (STARD1) Protein Mutation. Molecular Structure and Modeling of the STARD1 L275P Mutation

Thirty-Eight-Year Follow-Up of Two Sibling Lipoid Congenital Adrenal Hyperplasia Patients Due to Homozygous Steroidogenic Acute Regulatory (STARD1) Protein Mutation. Molecular Structure and Modeling of the STARD1 L275P Mutation

Binding Domain‐Driven Intracellular Trafficking of Sterols for Synthesis of Steroid Hormones, Bile Acids and Oxysterols

The mammalian START domain protein family in lipid transport in health and disease

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