Abstract
The StAR-related lipid transfer (START) domain is an evolutionary conserved protein module of approximately 210 amino acids. There are 15 mammalian proteins that possess a START domain. Whereas the functions and specific ligands are being elucidated, 5 of them have already been shown to bind specifically cholesterol. The most intensively studied member of this subclass is the steroidogenic acute regulatory protein (StAR) or STARD1. While its role in steroid hormone production has been demonstrated, much less is understood about how its START domain specifically recognizes cholesterol and how it releases it to be transferred inside the mitochondria of steroidogenic cell of the gonads and adrenal cortex. A major obstacle that is slowing down progress in this area is the lack of knowledge of the 3D structures of the START domain of StAR in both its free and complexed forms. However, 3D models of the START domain of StAR and mechanisms of binding have been proposed. In addition biophysical studies aimed at validating the models and mechanism have been published. What’s more, the crystal structures of the free forms of 3 START domains (STARD3, STARD4 and STARD5) known to specifically bind cholesterol have been elucidated so far. In this chapter, we will review and critically summarize existing data in order to provide the most current view and status of our understanding of the structure and reversible cholesterol binding mechanism of START domains.
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References
Alpy, F., Stoeckel, M.E., Dierich, A., Escola, J.M., Wendling, C., Chenard, M.P., Vanier, M.T., Gruenberg, J., Tomasetto, C. and Rio, M.C., 2001, The steroidogenic acute regulatory protein homolog MLN64, a late endosomal cholesterol-binding protein. J. Biol. Chem. 276: 4261–4269.
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.
Arakane, F., Kallen, C.B., Watari, H., Foster, J.A., Sepuri, N.B., Pain, D., Stayrook, S.E., Lewis, M., Gerton, G.L., and Strauss, J.F., 3rd., 1998, The mechanism of action of steroidogenic acute regulatory protein (StAR). StAR acts on the outside of mitochondria to stimulate steroidogenesis. J. Biol. Chem. 273: 16339–16345.
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.
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.
Bose, H.S., Sugawara, T., Strauss, J.F., 3rd, and Miller, W.L., 1996, The pathophysiology and genetics of congenital lipoid adrenal hyperplasia. International Congenital Lipoid Adrenal Hyperplasia Consortium. N. Engl. J. Med. 335: 1870–1878.
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.
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 congenital lipoid adrenal hyperplasia. J. Clin. Endocrinol. Metab. 85: 3636–3639.
Bose, H.S., Lingappa, V.R., and Miller, W.L., 2002, The steroidogenic acute regulatory protein, StAR, works only at the outer mitochondrial membrane. Endocr. Res. 28: 295–308.
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-lineprotein. Biochemistry 47: 2277–2288.
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.
DeLano, W.L., 2002, The PyMOL Molecular Graphics System. DeLano Scientific, Palo Alto, CA, USA.
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 43: 134–144.
Kudo, N., Kumagai, K., Tomishige, N., Yamaji, T., Wakatsuki, S., Nishijima, M., Hanada, K., and Kato R., 2008, Structural basis for specific lipid recognition by CERT responsible for nonvesicular trafficking of ceramide. Proc. Natl. Acad. Sci. USA 105: 488–493.
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.
Murcia, M., Faráldo-Gómez, 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.
Ptitsyn, O.B., 1995, Molten globule and protein folding. Adv. Protein Chem. 47: 83–229.
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.
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) containing a StAR-related lipid transfer domain. Proc. Natl. Acad. Sci. USA 99: 6949–6954.
Rone, M. B., Fan, J., and Papadopoulos V., 2009, Cholesterol transport in steroid biosynthesis: role of protein-protein interactions and implications in disease states. Biochim. Biophys. Acta 1791: 646–658.
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.
Roostaee, A., Barbar, E., Lavigne, P., and LeHoux, J.G., 2009, The mechanism of specific binding of free cholesterol by the Steroidogenic Acute Regulatory Protein : Evidence for a role of the C-terminal helix in the gating of the binding site. Biosci. Rep. 29: 89–101.
Schrick, K., Nguyen, D., Karlowski, W.M., and Mayer, K.F., 2004, START lipid/sterol-binding domains are amplified in plants and are predominantly associated with homeodomain transcription factors. Genome Biol. 5: R41.
Tsujishita, Y., and Hurley, J.H., 2000, Structure and lipid transport mechanism of a StAR-related domain. Nat. Struct. Biol. 7: 408–414.
Wang, X., Liu, Z., Eimerl, S., Timberg, R., Weiss, A.M., Orly, J., and Stocco, D.M., 1998, Effect of truncated forms of the steroidogenic acute regulatory protein on intramitochondrial cholesterol transfer. Endocrinology 139: 3903–3912.
Watari, H., Arakane, F., Moog-Lutz, C., Kallen, C.B., Tomasetto, C., Gerton, G.L., Rio, M.C., Baker, M.E., and Strauss, J.F., 3rd, 1997, MLN64 contains a domain with homology to the steroidogenic acute regulatory protein (StAR) that stimulates steroidogenesis. Proc. Natl. Acad. Sci. USA 94: 8462–8467.
Yaworsky, D.C., Baker, B.Y., Bose, H.S., Best, K.B., Jensen, L.B., Bell, J.D., Baldwin, M.A., and Miller, W.L., 2005, pH-dependent Interactions of the carboxyl-terminal helix of steroidogenic acute regulatory protein with synthetic membranes. J. Biol. Chem. 280: 2045–2054.
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Lavigne, P., Najmanivich, R., LeHoux, JG. (2010). Mammalian StAR-Related Lipid Transfer (START) Domains with Specificity for Cholesterol: Structural Conservation and Mechanism of Reversible Binding. In: Harris, J. (eds) Cholesterol Binding and Cholesterol Transport Proteins:. Subcellular Biochemistry, vol 51. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-8622-8_15
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DOI: https://doi.org/10.1007/978-90-481-8622-8_15
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