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Steroidogenic Acute Regulatory Protein: Structure, Functioning, and Regulation

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Abstract

Steroidogenesis takes place mainly in adrenal and gonadal cells that produce a variety of structurally similar hormones regulating numerous body functions. The rate-limiting stage of steroidogenesis is cholesterol delivery to the inner mitochondrial membrane, where it is converted by cytochrome P450scc into pregnenolone, a common precursor of all steroid hormones. The major role of supplying mitochondria with cholesterol belongs to steroidogenic acute regulatory protein (STARD1). STARD1, which is synthesized de novo as a precursor containing mitochondrial localization sequence and sterol-binding domain, significantly accelerates cholesterol transport and production of pregnenolone. Despite a tremendous interest in STARD1 fueled by its involvement in hereditary diseases and extensive efforts of numerous laboratories worldwide, many aspects of STARD1 structure, functioning, and regulation remain obscure and debatable. This review presents current concepts on the structure of STARD1 and other lipid transfer proteins, the role of STARD1 in steroidogenesis, and the mechanism of its functioning, as well as identifies the most controversial and least studied questions related to the activity of this protein.

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Abbreviations

hCG:

human chorionic gonadotropin

IMM:

inner mitochondrial membrane

LAM proteins:

LTPs anchored at membrane contact sites

LCAH:

lipoid congenital adrenal hyperplasia

LTPs:

lipid transfer proteins

nsLTPs:

non-specific LTPs

OMM:

outer mitochondrial membrane

P450scc (CYP11A1):

cytochrome P450 cholesterol hydroxylase/20,22-lyase (scc, side chain cleavage)

STARD1 (StAR):

steroidogenic acute regulatory protein 1

TF:

transcription factor

TSPO:

translocator protein (peripheral benzodiazepine receptor)

VDAC:

voltage-dependent anion channel

References

  1. Tkachuk, V. A., Vorotnikov, A. V., and Tyurin–Kuzmin, P. A. (2017) Bases of Molecular Endocrinology. Reception and Intracellular Signalization (Tkachuk, V. A., ed.) [in Russian], GEOTAR Media, Moscow.

    Google Scholar 

  2. Bose, H. S., Lingappa, V. R., and Miller, W. L. (2002) Rapid regulation of steroidogenesis by mitochondrial pro–tein import, Nature, 417, 87–91.

    Article  CAS  PubMed  Google Scholar 

  3. Miller, W. L. (2018) Mechanisms in endocrinology: rare defects in adrenal steroidogenesis, Eur. J. Endocrinol., 179, R125–R141.

    Google Scholar 

  4. Auchus, R. J. (2015) The classic and nonclassic congenital adrenal hyperplasias, Endocrin. Pract., 21, 383–389.

    Article  Google Scholar 

  5. King, S. R., Bhangoo, A., and Stocco, D. M. (2010) Functional and physiological consequences of StAR defi–ciency: role in lipoid congenital adrenal hyperplasia, Pediatr. Adrenal Dis., 20, 47–53.

    Article  Google Scholar 

  6. Nakae, J., Tajima, T., Sugawara, T., Arakane, F., Hanaki, K., Hotsubo, T., Igarashi, N., Igarashi, Y., Ishii, T., Koda, N., Kondo, T., Kohno, H., Nakagawa, Y., Tachibana, K., Takeshima, Y., Tsubouchi, K., Strauss, J. F., and Fujieda, K. (1997) Analysis of the steroidogenic acute regulatory protein (StAR) gene in Japanese patients with congenital lipoid adrenal hyperplasia, Hum. Mol. Genet., 6, 571–576.

    Article  CAS  PubMed  Google Scholar 

  7. Bose, H. S., Sugawara, T., Strauss, J. F., and Miller, W. L. (1996) The pathophysiology and genetics of congenital lipoid adrenal hyperplasia, N. Engl. J. Med., 335, 1870–1878.

    Article  CAS  PubMed  Google Scholar 

  8. Bose, H. S., Sato, S., Aisenberg, J., Shalev, S. A., Matsuo, N., and Miller, W. L. (2000) Mutations in the steroidogenic acute regulatory protein (StAR) in six patients with con–genital lipoid adrenal hyperplasia, J. Clin. Endocrinol. Metab., 85, 3636–3639.

    CAS  PubMed  Google Scholar 

  9. Kim, J. M., Choi, J. H., Lee, J. H., Kim, G. H., Lee, B. H., Kim, H. S., Shin, J. H., Shin, C. H., Kim, C. J., Yu, J., Lee, D. Y., Cho, W. K., Suh, B. K., Lee, J. E., Chung, H. R., and Yoo, H. W. (2011) High allele frequency of the p.Q258X mutation and identification of a novel mis–splic–ing mutation in the STAR gene in Korean patients with congenital lipoid adrenal hyperplasia, Eur. J. Endocrinol., 165, 771–778.

    Article  CAS  PubMed  Google Scholar 

  10. Achermann, J. C., Meeks, J. J., Jeffs, B., Das, U., Clayton, P. E., Brook, C. G., and Jameson, J. L. (2001) Molecular and structural analysis of two novel StAR mutations in patients with lipoid congenital adrenal hyperplasia, Mol. Genet. Metab., 73, 354–357.

    Article  CAS  PubMed  Google Scholar 

  11. Baquedano, M. S., Guercio, G., Marino, R., Berensztein, E., Costanzo, M., Ramirez, P., Bailez, M., Vaiani, E., Maceiras, M., Rivarola, M. A., and Belgorosky, A. (2013) Novel heterozygous mutation in the steroidogenic acute regulatory protein gene in a 46,XY patient with congenital lipoid adrenal hyperplasia, Medicina, 73, 297–302.

    CAS  PubMed  Google Scholar 

  12. Lekarev, O., Mallet, D., Yuen, T., Morel, Y., and New, M. I. (2012) Congenital lipoid adrenal hyperplasia (a rare formof adrenal insufficiency and ambiguous genitalia) caused by a novel mutation of the steroidogenic acute regulatory pro–tein gene, Eur. J. Pediatr., 171, 787–793.

    Article  PubMed  Google Scholar 

  13. Khoury, K., Barbar, E., Ainmelk, Y., Ouellet, A., Lavigne, P., and LeHoux, J.–G. (2016) 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 STARD1L275P mutation, Front. Neurosci., 10, 527–543.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Radiuk, V. G., Shkumatov, V. M., Chashchin, V. L., and Akhrema, A. A. (1982) Interaction between cytochrome P–450scc and adrenodoxin in solution under effects of low spin effectors, Biokhimiya, 47, 1700–1709.

    CAS  Google Scholar 

  15. Novikova, L. A., Faletrov, Y. V., Kovaleva, I. E., Mauersberger, Sh., Luzikov, V. N., and Shkumatov, V. M. (2009) From the structure and function of steroid biosyn–thesis enzymes to new genetic engineering technologies, Biochemistry (Moscow), 74, 1482–1504.

    Article  CAS  Google Scholar 

  16. Kraan, G. P. B., Dullaart, R. P. F., Pratt, J. J., Wolthers, B. G., Drayer, N. M., and De Bruin, R. (1998) The daily cor–tisol production reinvestigated in healthy men. The serum and urinary cortisol production rates are not significantly different, J. Clin. Endocrinol. Metab., 83, 1247–1252.

    CAS  PubMed  Google Scholar 

  17. Miller, W. L. (2017) Disorders in the initial steps of steroid hormone synthesis, J. Steroid Biochem. Mol. Biol., 165, 18–37.

    Article  CAS  PubMed  Google Scholar 

  18. Alberta, J. A., Epstein, L. F., Pon, L. A., and Orme–Johnson, N. R. (1989) Mitochondrial localization of a phosphoprotein that rapidly accumulates in adrenal cortex cells exposed to adrenocorticotropic hormone or to cAMP, J. Biol. Chem., 264, 2368–2372.

    CAS  PubMed  Google Scholar 

  19. Epstein, L. F., and Roberts, N. (1991) Regulation of steroid hormone biosynthesis. Identification of precursors of a phosphoprotein targeted to the mitochondrion in stimulat–ed rat adrenal cortex cells, J. Biol. Chem., 266, 19739–19745.

    CAS  PubMed  Google Scholar 

  20. Epstein, L. F., and Orme–Johnson, N. R. (1991) Acute action of luteinizing hormone on mouse Leydig cells: accu–mulation of mitochondrial phosphoproteins and stimula–tion of testosterone synthesis, Mol. Cell. Endocrinol., 81, 113–126.

    Article  CAS  PubMed  Google Scholar 

  21. Stocco, D. M., Zhao, A. H., Tu, L. N., Morohaku, K., and Selvaraj, V. (2017) A brief history of the search for the pro–tein(s) involved in the acute regulation of steroidogenesis, Mol. Cell. Endocrinol., 441, 7–16.

    Article  CAS  PubMed  Google Scholar 

  22. Conneely, O. M., Headon, D. R., Olsont, C. D., Ungart, F., and Dempseytt, M. E. (1984) Intramitochondrial move–ment of adrenal sterol carrier protein with cholesterol in response to corticotropin, Proc. Natl. Acad. Sci. USA, 81, 2970–2974.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Scallen, T. J., Pastuszyn, A., Noland, B. J., Chanderbhan, R., Kharroubi, A., and Vahouny, G. V (1985) Sterol carrier and lipid transfer proteins, Chem. Phys. Lipids, 38, 239–261.

    Article  CAS  PubMed  Google Scholar 

  24. Chanderbhan, R. F., Kharroubi, A. T., Noland, B. J., Scallen, T. J., and Vahouny, G. V. (1986) Sterol carrier pro–tein 2: further evidence for its role in adrenal steroidogene–sis, Endocrin. Res., 12, 351–370.

    Article  CAS  Google Scholar 

  25. Pedersen, R. C., and Brownie, A. C. (1984) Steroidogenesis–activator polypeptide isolated from a rat Leydig cell tumor, Science, 236, 188–190.

    Article  Google Scholar 

  26. Papadopoulos, V. (1993) Peripheral–type benzodi–azepine/diazepam binding inhibitor receptor: biological role in steroidogenic cell function, Endocrin. Rev., 14, 222–240.

    CAS  Google Scholar 

  27. Selvaraj, V., Stocco, D. M., and Tu, L. N. (2015) Minireview: Translocator protein (TSPO) and steroidogen–esis: a reappraisal, Mol. Endocrinol., 29, 490–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Tu, L. N., Morohaku, K., Manna, P. R., Pelton, S. H., Butler, W. R., Stocco, D. M., and Selvaraj, V. (2014) Peripheral benzodiazepine receptor/translocator protein global knock–out mice are viable with no effects on steroid hormone biosynthesis, J. Biol. Chem., 289, 27444–27454.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Clark, B. J., Wells, J., King, S. R., and Stocco, D. M. (1994) The purification, cloning, and expression of a novel luteinizing hormone–induced mitochondrial protein in MA–10 mouse Leydig tumor cells: characterization of the steroidogenic acute regulatory protein (StAR), J. Biol. Chem., 269, 28314–28322.

    CAS  PubMed  Google Scholar 

  30. Clark, B. J., and Stocco, D. M. (1995) Expression of the steroidogenic acute regulatory (StAR) protein: a novel LH–induced mitochondrial protein required for the acute regu–lation of steroidogenesis in mouse Leydig tumor cells, Endocrin. Res., 21, 243–257.

    Article  CAS  Google Scholar 

  31. Lin, D., Sugawara, T., Strauss, J. F., Clark, B. J., Stocco, D. M., Saenger, P., Rogol, A., and Miller, W. L. (1995) Role of steroidogenic acute regulatory protein in adrenal and gonadal steroidogenesis, Science, 267, 1828–1831.

    Article  CAS  PubMed  Google Scholar 

  32. Sugawara, T., Holt, J. A., Driscoll, D., Strauss, J. F., Lin, D., Miller, W. L., Patterson, D., Clancy, K. P., Hart, I. M., Clark, B. J., and Stocco, D. M. (1995) Human steroido–genic acute regulatory protein: functional activity in COS–1 cells, tissue–specific expression, and mapping of the structural gene to 8p11.2 and a pseudogene to chromosome 13, Proc. Natl. Acad. Sci. USA, 92, 4778–4782.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Anuka, E., Gal, M., Stocco, D. M., and Orly, J. (2013) Expression and roles of steroidogenic acute regulatory (StAR) protein in “non–classical”, extra–adrenal and extra–gonadal cells and tissues, Mol. Cell. Endocrinol., 371, 47–61.

    Article  CAS  PubMed  Google Scholar 

  34. King, S. R., and Stocco, D. M. (2011) Steroidogenic acute regulatory protein expression in the central nervous system, Front. Endocrinol. (Lausanne), 2, 72.

    Article  Google Scholar 

  35. Miller, W. L. (2017) Steroidogenesis: unanswered ques–tions, Trends Endocrinol. Metab., 28, 771–793.

    Article  CAS  PubMed  Google Scholar 

  36. Stocco, D. M., and Clark, B. J. (1996) Regulation of the acute production of steroids in steroidogenic cells, Endocrin. Rev., 17, 221–244.

    CAS  Google Scholar 

  37. Sanderson, J. T. (2009) Placental and fetal steroidogenesis, Methods Mol. Biol., 550, 127–136.

    Article  CAS  PubMed  Google Scholar 

  38. Reddy, D. S. (2010) Neurosteroids. Endogenous role in the human brain and therapeutic potentials, Progress Brain Res., 186, 113–137.

    Article  CAS  Google Scholar 

  39. Tsutsui, K. (2008) Minireview: Progesterone biosynthesis and action in the developing neuron, Endocrinology, 149, 2757–2761.

    Article  CAS  PubMed  Google Scholar 

  40. Stocco, D. M. (1999) An update on the mechanism of action of the steroidogenic acute regulatory (StAR) pro–tein, Exp. Clin. Endocrinol. Diabetes, 107, 229–235.

    Article  CAS  PubMed  Google Scholar 

  41. Farkash, Y., Timberg, R., and Orlyf, J. (1986) Preparation of antiserum to rat cytochrome P–450 cholesterol side chain cleavage, and its use for ultrastructural localization of the immunoreactive enzyme by protein A–gold technique, Endocrinology, 118, 1353–1365.

    Article  CAS  PubMed  Google Scholar 

  42. Bollag, W. B. (2014) Regulation of aldosterone synthesis and secretion, Compr. Physiol., 4, 1017–1055.

    Article  PubMed  Google Scholar 

  43. Krause, M. R., and Regen, S. L. (2014) The structural role of cholesterol in cell membranes: from condensed bilayers to lipid rafts, Acc. Chem. Res., 47, 3512–3521.

    Article  CAS  PubMed  Google Scholar 

  44. Maxfield, F. R., and Wustner, D. (2002) Intracellular cho–lesterol transport, J. Clin. Invest., 110, 891–898.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Horvath, S. E., and Daum, G. (2013) Lipids of mitochon–dria, Prog. Lipid Res., 52, 590–614.

    Article  CAS  PubMed  Google Scholar 

  46. Papadopoulos, V., and Miller, W. L. (2012) Role of mito–chondria in steroidogenesis, Best Pract. Res. Clin. Endocrinol. Metab., 26, 771–790.

    Article  CAS  PubMed  Google Scholar 

  47. Shen, W. J., Azhar, S., and Kraemer, F. B. (2016) Lipid droplets and steroidogenic cells, Exp. Cell Res., 340, 209–214.

    Article  CAS  PubMed  Google Scholar 

  48. Miller, W. L. (1988) Molecular biology of steroid hormone synthesis, Endocrin. Rev., 9, 295–318.

    Article  CAS  Google Scholar 

  49. Lev, S. (2010) Non–vesicular lipid transport by lipid–trans–fer proteins and beyond, Nat. Rev. Mol. Cell Biol., 11, 739–750.

    Article  CAS  PubMed  Google Scholar 

  50. Iaea, D. B., Mao, S., Lund, F. W., and Maxfield, F. R. (2017) Role of STARD4 in sterol transport between the endocytic recycling compartment and the plasma mem–brane, Mol. Biol. Cell, 28, 1111–1122.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Elustondo, P., Martin, L. A., and Karten, B. (2017) Mitochondrial cholesterol import, Biochim. Biophys. Acta Mol. Cell Biol. Lipids, 1862, 90–101.

    Article  CAS  PubMed  Google Scholar 

  52. Lahiri, S., Toulmay, A., and Prinz, W. A. (2015) Membrane contact sites, gateways for lipid homeostasis, Curr. Opin. Cell Biol., 33, 82–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Chiapparino, A., Maeda, K., Turei, D., Saez–Rodriguez, J., and Gavin, A. C. (2016) The orchestra of lipid–transfer proteins at the crossroads between metabolism and signal–ing, Progr. Lipid Res., 61, 30–39.

    Article  CAS  Google Scholar 

  54. Van Meer, G., Voelker, D. R., and Feigenson, G. W. (2008) Membrane lipids: where they are and how they behave, Nature Rev. Mol. Cell Biol., 9, 112–124.

    Article  CAS  Google Scholar 

  55. Wong, L. H., Copic, A., and Levine, T. P. (2017) Advances on the transfer of lipids by lipid transfer proteins, Trends Biochem. Sci., 42, 516–530.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Mesmin, B., and Maxfield, F. R. (2009) Intracellular sterol dynamics, Biochim. Biophys. Acta Mol. Cell Biol. Lipids, 1791, 636–645.

    Article  CAS  Google Scholar 

  57. Salminen, T. A., Blomqvist, K., and Edqvist, J. (2016) Lipid transfer proteins: classification, nomenclature, struc–ture, and function, Planta, 244, 971–997.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Li, N. C., Fan, J., and Papadopoulos, V. (2016) Sterol car–rier protein–2, a nonspecific lipid–transfer protein, in intra–cellular cholesterol trafficking in testicular leydig cells, PLoS One, 11, e0149728.

    Google Scholar 

  59. Schrick, K., Nguyen, D., Karlowski, W. M., and Mayer, K. F. X. (2004) START lipid/sterol–binding domains are amplified in plants and are predominantly associated with homeodomain transcription factors, Genome Biol., 5, R41.

    Google Scholar 

  60. Soccio, R. E., and Breslow, J. L. (2003) StAR–related lipid transfer (START) proteins: mediators of intracellular lipid metabolism, J. Biol. Chem., 278, 22183–22186.

    Article  CAS  PubMed  Google Scholar 

  61. Alpy, F., and Tomasetto, C. (2005) Give lipids a START: the StAR–related lipid transfer (START) domain in mammals, J. Cell Sci., 118, 2791–2801.

    Article  CAS  PubMed  Google Scholar 

  62. Kallen, C. B., Billheimer, J. T., Summerst, S. A., Stayrook, S. E., Lewis, M., and Strauss, J. F. (1998) Steroidogenic acute regulatory protein (StAR) is a sterol transfer protein, J. Biol. Chem., 273, 26285–26288.

    Article  CAS  PubMed  Google Scholar 

  63. Petrescu, A. D., Gallegos, A. M., Okamura, Y., Strauss, J. F., and Schroeder, F. (2001) Steroidogenic acute regulatory protein binds cholesterol and modulates mitochondrial membrane sterol domain dynamics, J. Biol. Chem., 276, 36970–36982.

    Article  CAS  PubMed  Google Scholar 

  64. Korytowski, W., Wawak, K., Pabisz, P., Schmitt, J. C., Chadwick, A. C., Sahoo, D., and Girotti, A. W. (2015) Impairment of macrophage cholesterol efflux by choles–terol hydroperoxide trafficking implications for atherogen–esis under oxidative stress, Arterioscler. Thromb. Vasc. Biol., 35, 2104–2113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Baker, B. Y., Epand, R. F., Epand, R. M., and Miller, W. L. (2007) Cholesterol binding does not predict activity of the steroidogenic acute regulatory protein, StAR, J. Biol. Chem., 282, 10223–10232.

    Article  CAS  PubMed  Google Scholar 

  66. Clark, B. J., and Stocco, D. M. (1996) StAR–a tissue spe–cific acute mediator of steroidogenesis, Trends Endocrinol. Metab., 7, 227–233.

    Article  CAS  PubMed  Google Scholar 

  67. Tsujishita, Y., and Hurley, J. H. (2000) Structure and lipid transport mechanism of a StAR–related domain, Nat. Struct. Biol., 7, 408–414.

    Article  CAS  PubMed  Google Scholar 

  68. Horvath, M. P., George, E. W., Tran, Q. T., Baumgardner, K., Zharov, G., Lee, S., Sharifzadeh, H., Shihab, S., Mattinson, T., Li, B., and Bernstein, P. S. (2016) Structure of the lutein–binding domain of human StARD3 at 1.74 Å resolution and model of a complex with lutein, Acta Crystallogr. Sect. F Struct. Biol. Commun., 72, 609–618.

    Article  CAS  Google Scholar 

  69. Li, B., Vachali, P., Frederick, J. M., and Bernstein, P. S. (2011) Identification of StARD3 as a lutein–binding pro–tein in the macula of the primate retina, Biochemistry, 50, 2541–2549.

    Article  CAS  PubMed  Google Scholar 

  70. Vachali, P., Li, B., Nelson, K., and Bernstein, P. S. (2012) Surface plasmon resonance (SPR) studies on the interac–tions of carotenoids and their binding proteins, Arch. Biochem. Biophys., 519, 32–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Tuckey, R. C., Bose, H. S., Czerwionka, I., and Miller, W. L. (2004) Molten globule structure and steroidogenic activ–ity of N–218MLN64 in human placental mitochondria, Endocrinology, 145, 1700–1707.

    Article  CAS  PubMed  Google Scholar 

  72. Rodriguez–Agudo, D., Ren, S., Wong, E., Marques, D., Redford, K., Gil, G., Hylemon, P., and Pandak, W. M. (2008) Intracellular cholesterol transporter StarD4 binds free cholesterol and increases cholesteryl ester formation, J. Lipid Res., 49, 1409–1419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Korytowski, W., Rodriguez–Agudo, D., Pilat, A., and Girotti, A. W. (2010) StarD4–mediated translocation of 7–hydroperoxycholesterol to isolated mitochondria: deleteri–ous effects and implications for steroidogenesis under oxidative stress conditions, Biochem. Biophys. Res. Commun., 392, 58–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Romanowski, M. J., Soccio, R. E., Breslow, J. L., and Burley, S. K. (2002) Crystal structure of the Mus musculus cholesterol–regulated START protein 4 (StarD4 ) contain–ing a StAR–related lipid transfer domain, Proc. Natl. Acad. Sci. USA, 99, 6949–6954.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Rodriguez–Agudo, D., Calderon–Dominguez, M., Ren, S., Marques, D., Redford, K., Medina–Torres, M. A., Hylemon, P., Gil, G., and Pandak, W. M. (2011) Subcellular localization and regulation of StarD4 protein in macrophages and fibroblasts, Biochim. Biophys. Acta, 1811, 597–606.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Mesmin, B., Pipalia, N. H., Lund, F. W., Ramlall, T. F., Sokolov, A., Eliezer, D., and Maxfield, F. R. (2011) STARD4 abundance regulates sterol transport and sensing, Mol. Biol. Cell, 22, 4004–4015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Rodriguez–Agudo, D., Ren, S., Hylemon, P. B., Redford, K., Natarajan, R., Del Castillo, A., Gil, G., and Pandak, W. M. (2005) Human StarD5, a cytosolic StAR–related lipid binding protein, J. Lipid Res., 46, 1615–1623.

    Article  CAS  PubMed  Google Scholar 

  78. Letourneau, D., Lorin, A., Lefebvre, A., Frappier, V., Gaudreault, F., Najmanovich, R., Lavigne, P., and LeHoux, J.–G. (2012) StAR–related lipid transfer domain protein 5 binds primary bile acids, J. Lipid Res., 53, 2677–2689.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Soccio, R. E., Adams, R. M., Romanowski, M. J., Sehayek, E., Burley, S. K., and Breslow, J. L. (2002) The cholesterol–regulated StarD4 gene encodes a StAR–related lipid transfer protein with two closely related homologues, StarD5 and StarD6, Proc. Natl. Acad. Sci. USA, 99, 6943–6948.

    Article  CAS  PubMed  Google Scholar 

  80. Letourneau, D., Lorin, A., Lefebvre, A., Cabana, J., Lavigne, P., and Lehoux, J. G. (2013) Thermodynamic and solution state NMR characterization of the binding of sec–ondary and conjugated bile acids to STARD5, Biochim. Biophys. Acta Mol. Cell Biol. Lipids, 1831, 1589–1599.

    Article  CAS  Google Scholar 

  81. Letourneau, D., Lefebvre, A., Lavigne, P., and LeHoux, J. G. (2013) STARD5 specific ligand binding: comparison with STARD1 and STARD4 subfamilies, Mol. Cell. Endocrinol., 371, 20–25.

    Article  CAS  PubMed  Google Scholar 

  82. Letourneau, D., Lefebvre, A., Lavigne, P., and LeHoux, J. G. (2015) The binding site specificity of STARD4 subfam–ily: breaking the cholesterol paradigm, Mol. Cell. Endocrinol., 408, 53–61.

    Article  CAS  PubMed  Google Scholar 

  83. Letourneau, D., Bedard, M., Cabana, J., Lefebvre, A., LeHoux, J.–G., and Lavigne, P. (2016) STARD6 on steroids: solution structure, multiple timescale backbone dynamics and ligand binding mechanism, Sci. Rep., 6, 28486.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Bose, H. S., Whittal, R. M., Ran, Y., Bose, M., Baker, B. Y., and Miller, W. L. (2008) StAR–like activity and molten globule behavior of StARD6, a male germ–line protein, Biochemistry, 47, 2277–2288.

    Article  CAS  PubMed  Google Scholar 

  85. Chang, I. Y., Jeon, Y. J., Jung, S. M., Jang, Y. H., Ahn, J. B., Park, K. S., and Yoon, S. P. (2010) Does the StarD6 mark the same as the StAR in the nervous system? J. Chem. Neuroanat., 40, 239–242.

    Article  CAS  PubMed  Google Scholar 

  86. Calderon–Dominguez, M., Gil, G., Medina, M. A., Pandak, W. M., and Rodriguez–Agudo, D. (2014) The StarD4 subfamily of steroidogenic acute regulatory–related lipid transfer (START) domain proteins: new players in cholesterol metabolism, Int. J. Biochem. Cell Biol., 49, 64–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Kang, H. W., Wei, J., and Cohen, D. E. (2010) PC–TP/StARD2: of membranes and metabolism, Trends Endocrinol. Metab., 21, 449–456.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Horibata, Y., and Sugimoto, H. (2010) StarD7 mediates the intracellular trafficking of phosphatidylcholine to mito–chondria, J. Biol. Chem., 285, 7358–7365.

    Article  CAS  PubMed  Google Scholar 

  89. Cohen, D. E., Green, R. M., Wu, M. K., and Beier, D. R. (1999) Cloning, tissue–specific expression, gene structure and chromosomal localization of human phosphatidyl–choline transfer protein, Biochim. Biophys. Acta, 1447, 265–270.

    Article  CAS  PubMed  Google Scholar 

  90. De Brouwer, A. P. M., Westerman, J., Kleinnijenhuis, A., Bevers, L. E., Roelofsen, B., and Wirtz, K. W. A. (2002) Clofibrate–induced relocation of phosphatidylcholine transfer protein to mitochondria in endothelial cells, Exp. Cell Res., 274, 100–111.

    Article  CAS  PubMed  Google Scholar 

  91. Kanno, K., Wu, M. K., Scapa, E. F., Roderick, S. L., and Cohen, D. E. (2007) Structure and function of phos–phatidylcholine transfer protein (PC–TP)/StarD2, Biochim. Biophys. Acta Mol. Cell Biol. Lipids, 1771, 654–662.

    Article  CAS  Google Scholar 

  92. Flores–Martin, J., Rena, V., Angeletti, S., Panzetta–Dutari, G. M., and Genti–Raimondi, S. (2013) The lipid transfer protein StarD7: structure, function, and regula–tion, Int. J. Mol. Sci., 14, 6170–6186.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Olayioye, M. A., Vehring, S., Muller, P., Herrmann, A., Schiller, J., Thiele, C., Lindeman, G. J., Visvader, J. E., and Pomorski, T. (2005) StarD10, a START domain pro–tein overexpressed in breast cancer, functions as a phos–pholipid transfer protein, J. Biol. Chem., 280, 27436–27442.

    Article  CAS  PubMed  Google Scholar 

  94. Alpy, F., and Tomasetto, C. (2014) START ships lipids across interorganelle space, Biochimie, 96, 85–95.

    Article  CAS  PubMed  Google Scholar 

  95. Zhang, S., Chang, X., Ma, J., Chen, J., Zhi, Y., Li, Z., and Dai, D. (2018) Downregulation of STARD8 in gastric cancer and its involvement in gastric cancer progression, Onco. Targets. Ther., 11, 2955–2961.

    Article  PubMed  PubMed Central  Google Scholar 

  96. Naumann, H., Rathjen, T., Poy, M. N., and Spagnoli, F. M. (2018) The RhoGAP Stard13 controls insulin secretion through F–actin remodeling, Mol. Metab., 8, 96–105.

    Article  CAS  PubMed  Google Scholar 

  97. Basak, P., Leslie, H., Dillon, R. L., Muller, W. J., Raouf, A., and Mowat, M. R. A. (2018) In vivo evidence support–ing a metastasis suppressor role for Stard13 (Dlc2) in ErbB2 (Neu) oncogene induced mouse mammary tumors, Genes Chromosom. Cancer, 57, 182–191.

    Article  CAS  PubMed  Google Scholar 

  98. Adams, S. H., Chui, C., Schilbach, S. L., Yu, X. X., Goddard, A. D., Grimaldi, J. C., Lee, J., Dowd, P., Colman, S., and Lewin, D. A. (2001) BFIT, a unique acyl–CoA thioesterase induced in thermogenic brown adipose tissue: cloning, organization of the human gene and assessment of a potential link to obesity, Biochem. J., 360, 135–142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Han, S., and Cohen, D. E. (2012) Functional characteri–zation of thioesterase superfamily member 1/Acyl–CoA thioesterase 11: implications for metabolic regulation, J. Lipid Res., 53, 2620–2631.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Torres, J. Z., Summers, M. K., Peterson, D., Brauer, M. J., Lee, J., Senese, S., Gholkar, A. A., Lo, Y.–C., Lei, X., Jung, K., Anderson, D. C., Davis, D. P., Belmont, L., and Jackson, P. K. (2011) The STARD9/Kif16a kinesin associ–ates with mitotic microtubules and regulates spindle pole assembly, Cell, 147, 1309–1323.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Gatta, A. T., Wong, L. H., Sere, Y. Y., Calderon–Norena, D. M., Cockcroft, S., Menon, A. K., and Levine, T. P. (2015) A new family of StART domain proteins at mem–brane contact sites has a role in ER–PM sterol transport, Elife, 4, e07253.

    Google Scholar 

  102. Elbaz–Alon, Y., Eisenberg–Bord, M., Shinder, V., Stiller, S. B., Shimoni, E., Wiedemann, N., Geiger, T., and Schuldiner, M. (2015) Lam6 regulates the extent of con–tacts between organelles, Cell Rep., 12, 7–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Murley, A., Sarsam, R. D., Toulmay, A., Yamada, J., Prinz, W. A., and Nunnari, J. (2015) Ltc1 is an ER–local–ized sterol transporter and a component of ER–mito–chondria and ER–vacuole contacts, J. Cell Biol., 209, 539–548.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Murley, A., Yamada, J., Niles, B. J., Toulmay, A., Prinz, W. A., Powers, T., and Nunnari, J. (2017) Sterol transporters at membrane contact sites regulate TORC1 and TORC2 signaling, J. Cell Biol., 216, 2679–2689.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Jentsch, J. A., Kiburu, I., Pandey, K., Timme, M., Ramlall, T., Levkau, B., Wu, J., Eliezer, D., Boudker, O., and Menon, A. K. (2018) Structural basis of sterol binding and transport by a yeast StARkin domain, J. Biol. Chem., 293, 5522–5531.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Tong, J., Manik, M. K., and Im, Y. J. (2018) Structural basis of sterol recognition and nonvesicular transport by lipid transfer proteins anchored at membrane contact sites, Proc. Natl. Acad. Sci. USA, 115, E856–E865.

    Book  Google Scholar 

  107. Wong, L. H., and Levine, T. P. (2016) Lipid transfer pro–teins do their thing anchored at membrane contact sites… but what is their thing? Biochem. Soc. Trans., 44, 517–527.

    Article  CAS  PubMed  Google Scholar 

  108. Im, Y. J., Raychaudhuri, S., Prinz, W. A., and Hurley, J. H. (2005) Structural mechanism for sterol sensing and trans–port by OSBP–related proteins, Nature, 437, 154–158.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Schulz, T. A., and Prinz, W. A. (2007) Sterol transport in yeast and the oxysterol binding protein homologue (OSH) family, Biochim. Biophys. Acta, 1771, 769–780.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Thorsell, A.–G., Lee, W. H., Persson, C., Siponen, M. I., Nilsson, M., Busam, R. D., Kotenyova, T., Schuler, H., and Lehtio, L. (2011) Comparative structural analysis of lipid binding START domains, PLoS One, 6, e19521.

    Book  Google Scholar 

  111. Yang, J., Yan, R., Roy, A., Xu, D., Poisson, J., and Zhang, Y. (2015) The I–TASSER suite: protein structure and func–tion prediction, Nat. Methods, 12, 7–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Iyer, L. M., Koonin, E. V., and Aravind, L. (2001) Adaptations of the helix–grip fold for ligand binding and catalysis in the START domain superfamily, Proteins Struct. Funct. Genet., 43, 134–144.

    Article  CAS  PubMed  Google Scholar 

  113. Arakane, F., Sugawara, T., Nishino, H., Liu, Z., Holt, J. A., Pain, D., Stocco, D. M., Miller, W. L., and Strauss, J. F. (1996) Steroidogenic acute regulatory protein (StAR) retains activity in the absence of its mitochondrial import sequence: implications for the mechanism of StAR action, Proc. Natl. Acad. Sci. USA, 93, 13731–13736.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Sasaki, G., Ishii, T., Jeyasuria, P., Jo, Y., Bahat, A., Orly, J., Hasegawa, T., and Parker, K. L. (2008) Complex role of the mitochondrial targeting signal in the function of steroidogenic acute regulatory protein revealed by bacteri–al artificial chromosome transgenesis in vivo, Mol. Endocrinol., 22, 951–964.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Bose, H. S., Lingappa, V. R., and Miller, W. L. (2002) The steroidogenic acute regulatory protein, StAR, works only at the outer mitochondrial membrane, Endocrin. Res., 28, 295–308.

    CAS  Google Scholar 

  116. Bose, H. S., Whittal, R. M., Baldwin, M. A., and Miller, W. L. (1999) The active form of the steroidogenic acute regulatory protein, StAR, appears to be a molten globule, Proc. Natl. Acad. Sci. USA, 96, 7250–7255.

    Article  CAS  PubMed  Google Scholar 

  117. Sluchanko, N. N., Tugaeva, K. V., and Maksimov, E. G. (2017) Solution structure of human steroidogenic acute regulatory protein STARD1 studied by small–angle X–ray scattering, Biochem. Biophys. Res. Commun., 489, 445–450.

    Article  CAS  PubMed  Google Scholar 

  118. Murcia, M., Faraldo–Gomez, J. D., Maxfield, F. R., and Roux, B. (2006) Modeling the structure of the StART domains of MLN64 and StAR proteins in complex with cholesterol, J. Lipid Res., 47, 2614–2630.

    Article  CAS  PubMed  Google Scholar 

  119. Kumar, K. K., Devi, B. U., and Neeraja, P. (2018) Molecular activities and ligand–binding specificities of StAR–related lipid transfer domains: exploring integrated in silico methods and ensemble–docking approaches, SAR QSAR Environ. Res., 29, 483–501.

    Article  CAS  PubMed  Google Scholar 

  120. Mathieu, A. P., Fleury, A., Ducharme, L., Lavigne, P., and LeHoux, J. G. (2002) Insights into steroidogenic acute regulatory protein (StAR)–dependent cholesterol transfer in mitochondria: evidence from molecular modeling and structure–based thermodynamics supporting the existence of partially unfolded states of StAR, J. Mol. Endocrinol., 29, 327–345.

    Article  CAS  PubMed  Google Scholar 

  121. Tugaeva, K. V., Faletrov, Y. V., Allakhverdiev, E. S., Shkumatov, V. M., Maksimov, E. G., and Sluchanko, N. N. (2018) Effect of the NBD–group position on interac–tion of fluorescently–labeled cholesterol analogues with human steroidogenic acute regulatory protein STARD1, Biochem. Biophys. Res. Commun., 497, 58–64.

    Article  CAS  PubMed  Google Scholar 

  122. Haberland, M. E., and Reynolds, J. A. (1973) Self–associ–ation of cholesterol in aqueous solution, Proc. Natl. Acad. Sci. USA, 70, 2313–2316.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Baker, B. Y., Yaworsky, D. C., and Miller, W. L. (2005) A pH–dependent molten globule transition is required for activity of the steroidogenic acute regulatory protein, StAR, J. Biol. Chem., 280, 41753–41760.

    Article  CAS  PubMed  Google Scholar 

  124. Roostaee, A., Barbar, E., Lehoux, J.–G., and Lavigne, P. (2008) Cholesterol binding is a prerequisite for the activity of the steroidogenic acute regulatory protein (StAR), Biochem. J., 412, 553–562.

    Article  CAS  PubMed  Google Scholar 

  125. Faletrov, Y. V., Bialevich, K. I., Edimecheva, I. P., Kostsin, D. G., Rudaya, E. V., Slobozhanina, E. I., and Shkumatov, V. M. (2013) 22–NBD–cholesterol as a novel fluorescent substrate for cholesterol–converting oxidoreductases, J. Steroid Biochem. Mol. Biol., 134, 59–66.

    CAS  PubMed  Google Scholar 

  126. Robalo, J. R., Ramalho, J. P. P., and Loura, L. M. S. (2013) NBD–labeled cholesterol analogues in phospho–lipid bilayers: insights from molecular dynamics, J. Phys. Chem. B, 117, 13731–13742.

    Article  CAS  PubMed  Google Scholar 

  127. Roderick, S. L., Chan, W. W., Agate, D. S., Olsen, L. R., Vetting, M. W., Rajashankar, K. R., and Cohen, D. E. (2002) Structure of human phosphatidylcholine transfer protein in complex with its ligand, Nat. Struct. Biol., 9, 507–511.

    CAS  PubMed  Google Scholar 

  128. Roostaee, A., Barbar, E., Lavigne, P., and LeHoux, J.–G. (2009) The mechanism of specific binding of free choles–terol by the steroidogenic acute regulatory protein: evi–dence for a role of the C–terminal alpha–helix in the gating of the binding site, Biosci. Rep., 29, 89–101.

    Article  CAS  PubMed  Google Scholar 

  129. Kudo, N., Kumagai, K., Matsubara, R., Kobayashi, S., Hanada, K., Wakatsuki, S., and Kato, R. (2010) Crystal structures of the CERT START domain with inhibitors provide insights into the mechanism of ceramide transfer, J. Mol. Biol., 396, 245–251.

    Article  CAS  PubMed  Google Scholar 

  130. Iaea, D. B., Dikiy, I., Kiburu, I., Eliezer, D., and Maxfield, F. R. (2015) STARD4 membrane interactions and sterol binding, Biochemistry, 54, 4623–4636.

    Article  CAS  PubMed  Google Scholar 

  131. Artemenko, I. P., Zhao, D., Hales, D. B., Hales, K. H., and Jefcoate, C. R. (2001) Mitochondrial processing of newly synthesized steroidogenic acute regulatory protein (StAR), but not total StAR, mediates cholesterol transfer to cytochrome P450 side chain cleavage enzyme in adrenal cells, J. Biol. Chem., 276, 46583–46596.

    Article  CAS  PubMed  Google Scholar 

  132. Bahat, A., Perlberg, S., Melamed–Book, N., Lauria, I., Langer, T., and Orly, J. (2014) StAR enhances transcription of genes encoding the mitochondrial proteases involved in its own degradation, Mol. Endocrinol., 28, 208–224.

    Article  CAS  PubMed  Google Scholar 

  133. Rajapaksha, M., Kaur, J., Bose, M., Whittal, R. M., and Bose, H. S. (2013) Cholesterol–mediated conformational changes in the steroidogenic acute regulatory protein are essential for steroidogenesis, Biochemistry, 52, 7242–7253.

    Article  CAS  PubMed  Google Scholar 

  134. Prasad, M., Pawlak, K. J., Burak, W. E., Perry, E. E., Marshall, B., Whittal, R. M., and Bose, H. S. (2017) Mitochondrial metabolic regulation by GRP78, Sci. Adv., 3, e1602038.

    Book  Google Scholar 

  135. LaVoie, H. A., and King, S. R. (2009) Transcriptional reg–ulation of steroidogenic genes: STARD1, CYP11A1 and HSD3B, Exp. Biol. Med., 234, 880–907.

    Article  CAS  Google Scholar 

  136. Sasaki, G., Zubair, M., Ishii, T., Mitsui, T., Hasegawa, T., and Auchus, R. J. (2014) The contribution of serine 194 phosphorylation to steroidogenic acute regulatory protein function, Mol. Endocrinol., 28, 1088–1096.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Arakane, F., King, S. R., Du, Y., Kallen, C. B., Walsh, L. P., Watari, H., Stocco, D. M., and Strauss, J. F. (1997) Phosphorylation of steroidogenic acute regulatory protein (StAR) modulates its steroidogenic activity, J. Biol. Chem., 272, 32656–32662.

    Article  CAS  PubMed  Google Scholar 

  138. Duarte, A., Castillo, A. F., Podesta, E. J., and Poderoso, C. (2014) Mitochondrial fusion and ERK activity regulate steroidogenic acute regulatory protein localization in mitochondria, PLoS One, 9, e100387.

    Book  Google Scholar 

  139. Christenson, L. K., and Strauss, J. F. (2001) Steroidogenic acute regulatory protein: an update on its regulation and mechanism of action, Arch. Med. Res., 32, 576–586.

    Article  CAS  PubMed  Google Scholar 

  140. Clark, B. J., and Stocco, D. M. (2014) The steroidogenic acute regulatory protein (StAR), in Cholesterol Transporters of the START Domain Protein Family in Health and Disease: START Proteins–Structure and Function (Clark, . J., and Stocco, D. M., eds.) Springer Science+Business Media, New York, pp. 15–48.

    Google Scholar 

  141. Men, Y., Fan, Y., Shen, Y., Lu, L., and Kallen, A. N. (2017) The steroidogenic acute regulatory protein (StAR) is regulated by the H19/let–7 axis, Endocrinology, 158, 402–409.

    Article  PubMed  Google Scholar 

  142. Paz, C., Cornejo Maciel, F., Gorostizaga, A., Castillo, A. F., Mori Sequeiros Garcia, M. M., Maloberti, P. M., Orlando, U. D., Mele, P. G., Poderoso, C., and Podesta, E. J. (2016) Role of protein phosphorylation and tyrosine phosphatases in the adrenal regulation of steroid synthesis and mitochondrial function, Front. Endocrinol. (Lausanne), 7, 60.

    Article  Google Scholar 

  143. Fleury, A., Mathieu, A. P., Ducharme, L., Hales, D. B., and Lehoux, J. G. (2004) Phosphorylation and function of the hamster adrenal steroidogenic acute regulatory protein (StAR), J. Steroid Biochem. Mol. Biol., 91, 259–271.

    Article  CAS  PubMed  Google Scholar 

  144. Colell, A., Garcia–Ruiz, C., Lluis, J. M., Coll, O., Mari, M., and Fernandez–Checa, J. C. (2003) Cholesterol impairs the adenine nucleotide translocator–mediated mitochondrial permeability transition through altered membrane fluidity, J. Biol. Chem., 278, 33928–33935.

    Article  CAS  PubMed  Google Scholar 

  145. Clark, B. J., and Hudson, E. A. (2015) StAR protein sta–bility in Y1 and Kin–8 mouse adrenocortical cells, Biology (Basel), 4, 200–215.

    CAS  Google Scholar 

  146. Granot, Z., Geiss–Friedlander, R., Melamed–Book, N., Eimerl, S., Timberg, R., Weiss, A. M., Hales, K. H., Hales, D. B., Stocco, D. M., and Orly, J. (2003) Proteolysis of normal and mutated steroidogenic acute regulatory proteins in the mitochondria: the fate of unwanted proteins, Mol. Endocrinol., 17, 2461–2476.

    Article  CAS  PubMed  Google Scholar 

  147. Bahat, A., Perlberg, S., Melamed–Book, N., Isaac, S., Eden, A., Lauria, I., Langer, T., and Orly, J. (2015) Transcriptional activation of LON Gene by a new form of mitochondrial stress: a role for the nuclear respiratory fac–tor 2 in StAR overload response (SOR), Mol. Cell. Endocrinol., 408, 62–72.

    Article  CAS  PubMed  Google Scholar 

  148. Lee, J., Tong, T., Duan, H., Foong, Y. H., Musaitif, I., Yamazaki, T., and Jefcoate, C. (2016) Regulation of StAR by the N–terminal domain and coinduction of SIK1 and TIS11b/Znf36l1 in single cells, Front. Endocrinol. (Lausanne), 7, 107.

    Article  Google Scholar 

  149. Granot, Z., Kobiler, O., Melamed–Book, N., Eimerl, S., Bahat, A., Lu, B., Braun, S., Maurizi, M. R., Suzuki, C. K., Oppenheim, A. B., Orly, J., and Star, L. (2007) Turnover of mitochondrial steroidogenic acute regulatory (StAR) protein by Lon protease: the unexpected effect of proteasome inhibitors, Mol. Endocrinol., 21, 2164–2177.

    Article  CAS  PubMed  Google Scholar 

  150. Rone, M. B., Midzak, A. S., Issop, L., Rammouz, G., Jagannathan, S., Fan, J., Ye, X., Blonder, J., Veenstra, T., and Papadopoulos, V. (2012) Identification of a dynamic mitochondrial protein complex driving cholesterol import, trafficking, and metabolism to steroid hormones, Mol. Endocrinol., 26, 1868–1882.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Caron, K. M., Soo, S. C., Wetsel, W. C., Stocco, D. M., Clark, B. J., and Parker, K. L. (1997) Targeted disruption of the mouse gene encoding steroidogenic acute regulato–ry protein provides insights into congenital lipoid adrenal hyperplasia, Proc. Natl. Acad. Sci. USA, 94, 11540–11545.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Papadopoulos, V., Amri, H., Li, H., Boujrad, N., Vidic, B., and Garnier, M. (1997) Targeted disruption of the peripheral–type benzodiazepine receptor gene inhibits steroidogenesis in the R2C Leydig tumor cell line, J. Biol. Chem., 272, 32129–32135.

    Article  CAS  PubMed  Google Scholar 

  153. Li, H., Degenhardt, B., Tobin, D., Yao, Z.–X., Tasken, K., and Papadopoulos, V. (2001) Identification, localization, and function in steroidogenesis of PAP7: a peripheral–type benzodiazepine receptor–and PKA (RIα)–associated pro–tein, Mol. Endocrinol., 15, 2211–2228.

    CAS  PubMed  Google Scholar 

  154. Morohaku, K., Pelton, S. H., Daugherty, D. J., Butler, W. R., Deng, W., and Selvaraj, V. (2014) Translocator pro–tein/peripheral benzodiazepine receptor is not required for steroid hormone biosynthesis, Endocrinology, 155, 89–97.

    Article  CAS  PubMed  Google Scholar 

  155. Papadopoulos, V., Aghazadeh, Y., Fan, J., Campioli, E., Zirkin, B., and Midzak, A. (2015) Translocator protein–mediated pharmacology of cholesterol transport and steroidogenesis, Mol. Cell. Endocrinol., 408, 90–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Rone, M. B., Fan, J., and Papadopoulos, V. (2009) Cholesterol transport in steroid biosynthesis: role of pro–tein–protein interactions and implications in disease states, Biochim. Biophys. Acta, 1791, 646–658.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Liu, J., Rone, M., and Papadopoulos, V. (2006) Protein–protein interactions mediate mitochondrial cho–lesterol transport and steroid biosynthesis, J. Biol. Chem., 281, 38879–38893.

    Article  CAS  PubMed  Google Scholar 

  158. Bose, M., Whittal, R. M., Miller, W. L., and Bose, H. S. (2008) Steroidogenic activity of StAR requires contact with mitochondrial VDAC1 and phosphate carrier protein, J. Biol. Chem., 283, 8837–8845.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Prasad, M., Kaur, J., Pawlak, K. J., Bose, M., Whittal, R. M., and Bose, H. S. (2015) Mitochondria–associ–ated endoplasmic reticulum membrane (MAM) regulates steroidogenic activity via steroidogenic acute regulatory protein (StAR)–voltage–dependent anion channel 2 (VDAC2) interaction, J. Biol. Chem., 290, 2604–2616.

    Article  CAS  PubMed  Google Scholar 

  160. Obsil, T., and Obsilova, V. (2011) Structural basis of 14–3–3 protein functions, Semin. Cell Dev. Biol., 22, 663–672.

    Article  CAS  PubMed  Google Scholar 

  161. Sluchanko, N. N., and Gusev, N. B. (2012) Oligomeric structure of 14–3–3 protein: what do we know about monomers? FEBS Lett., 586, 4249–4256.

    Article  CAS  PubMed  Google Scholar 

  162. Van Hemert, M. J., Steensma, H. Y., and van Heusden, G. P. (2001) 14–3–3 proteins: key regulators of cell division, signalling and apoptosis, BioEssays, 23, 936–946.

    Google Scholar 

  163. Aghazadeh, Y., Rone, M. B., Blonder, J., Ye, X., Veenstra, T. D., Hales, D. B., Culty, M., and Papadopoulos, V. (2012) Hormone–induced 14–3–3γ adaptor protein regulates steroido–genic acute regulatory protein activity and steroid biosynthesis in MA–10Leydig cells, J. Biol. Chem., 287, 15380–15394.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Wilker, E. W., Grant, R. A., Artim, S. C., and Yaffe, M. B. (2005) A structural basis for 14–3–3σ functional specificity, J. Biol. Chem., 280, 18891–18898.

    Article  CAS  PubMed  Google Scholar 

  165. Hachiya, N., Komiya, T., Alam, R., Iwahashi, J., Sakaguchi, M., Omura, T., and Mihara, K. (1994) MSF, a novel cytoplasmic chaperone which functions in pre–cursor targeting to mitochondria, EMBO J., 13, 5146–5154.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Aghazadeh, Y., Ye, X., Blonder, J., and Papadopoulos, V. (2014) Protein modifications regulate the role of 14–3–3γ adaptor protein in cAMP–induced steroidogenesis in MA–10Leydig cells, J. Biol. Chem., 289, 26542–26553.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Aghazadeh, Y., and Papadopoulos, V. (2016) The role of the 14–3–3 protein family in health, disease, and drug development, Drug Discov. Today, 21, 278–287.

    Article  CAS  PubMed  Google Scholar 

  168. Aghazadeh, Y., Martinez–Arguelles, D. B., Fan, J., Culty, M., and Papadopoulos, V. (2014) Induction of androgen formation in the male by a TAT–VDAC1 fusion peptide blocking 14–3–3ε protein adaptor and mitochondrial VDAC1 interactions, Mol. Ther., 22, 1779–1791.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Sluchanko, N. N. (2018) Association of multiple phospho–rylated proteins with the 14–3–3 regulatory hubs: problems and perspectives, J. Mol. Biol., 430, 20–26.

    Article  CAS  PubMed  Google Scholar 

  170. Liapis, A., Chen, F. W., Davies, J. P., Wang, R., and Ioannou, Y. A. (2012) MLN64 transport to the late endo–some is regulated by binding to 14–3–3 via a non–canonical binding site, PLoS One, 7, e34424.

    Google Scholar 

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  1. Bach Institute of Biochemistry, Federal Research Center of Biotechnology, Russian Academy of Sciences, 119071, Moscow, Russia

    K. V. Tugaeva & N. N. Sluchanko

  2. Department of Biochemistry, Lomonosov Moscow State University, Biological Faculty, 119234, Moscow, Russia

    K. V. Tugaeva

  3. Department of Biophysics, Lomonosov Moscow State University, Biological Faculty, 119991, Moscow, Russia

    N. N. Sluchanko

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Russian Text © K. V. Tugaeva, N. N. Sluchanko, 2019, published in Uspekhi Biologicheskoi Khimii, 2019, Vol. 59, pp. 473–512.

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Tugaeva, K.V., Sluchanko, N.N. Steroidogenic Acute Regulatory Protein: Structure, Functioning, and Regulation. Biochemistry Moscow 84 (Suppl 1), 233–253 (2019). https://doi.org/10.1134/S0006297919140141

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