Significance of Sterol Structural Specificity

Abstract

Desmosterol is an immediate precursor of cholesterol in the Bloch pathway of sterol synthesis and an abundant membrane lipid in specific cell types. The significance of the difference between the two sterols, an additional double bond at position C24 in the tail of desmosterol, is not known. Here, we provide evidence that the biophysical and functional characteristics of the two sterols differ and that this is because the double bond at C24 significantly weakens the sterol ordering potential. In model membranes, desmosterol was significantly weaker than cholesterol in promoting the formation or stability of ordered domains, and in mammalian cell membranes, desmosterol associated less avidly than cholesterol with detergent-resistant membranes. Atomic scale molecular dynamics simulations showed that the double bond gives rise to additional stress in the tail, creating a rigid structure between C24 and C27 and favoring tilting of desmosterol distinct from cholesterol. Functional effects of desmosterol in cell membranes were assessed upon acutely exchanging ∼70% of cholesterol to desmosterol. This led to impaired raft-dependent signaling via the insulin receptor, whereas non-raft-dependent protein secretion was not affected. We suggest that the choice of cholesterol synthesis route may provide a physiological mechanism to modulate raft-dependent functions in cells. Desmosterol is an immediate precursor of cholesterol in the Bloch pathway of sterol synthesis and an abundant membrane lipid in specific cell types. The significance of the difference between the two sterols, an additional double bond at position C24 in the tail of desmosterol, is not known. Here, we provide evidence that the biophysical and functional characteristics of the two sterols differ and that this is because the double bond at C24 significantly weakens the sterol ordering potential. In model membranes, desmosterol was significantly weaker than cholesterol in promoting the formation or stability of ordered domains, and in mammalian cell membranes, desmosterol associated less avidly than cholesterol with detergent-resistant membranes. Atomic scale molecular dynamics simulations showed that the double bond gives rise to additional stress in the tail, creating a rigid structure between C24 and C27 and favoring tilting of desmosterol distinct from cholesterol. Functional effects of desmosterol in cell membranes were assessed upon acutely exchanging ∼70% of cholesterol to desmosterol. This led to impaired raft-dependent signaling via the insulin receptor, whereas non-raft-dependent protein secretion was not affected. We suggest that the choice of cholesterol synthesis route may provide a physiological mechanism to modulate raft-dependent functions in cells. In model membranes, cholesterol associates preferentially with long, saturated acyl chains, such as those in sphingolipids, thus reducing the area per lipid molecule (1Sankaram M.B. Thompson T.E. Biochemistry. 1990; 29: 10670-10675Crossref PubMed Scopus (291) Google Scholar, 2Smaby J.M. Momsen M. Kulkarni V.S. Brown R.E. Biochemistry. 1996; 35: 5696-5704Crossref PubMed Scopus (92) Google Scholar). There is substantial evidence to suggest that ordered lipid domains (rafts) composed of sterol and saturated lipids also exist in eukaryotic cell membranes and play important roles in numerous biological processes (3Edidin M. Annu. Rev. Biophys. Biomol. Struct. 2003; 32: 257-283Crossref PubMed Scopus (1126) Google Scholar, 4Simons K. Ikonen E. Nature. 1997; 387: 569-572Crossref PubMed Scopus (7948) Google Scholar). Lipid rafts are considered to exist in a liquid-ordered (Lo) 2The abbreviations used are: Loliquid-orderedLdliquid-disorderedDMRdetergent-resistant membraneDOPCdioleylphosphatidylcholineDPPCdipalmitoylphosphatidylcholineDPH1,6-diphenyl-1,3,5-hexatrieneHPLChigh performance liquid chromatographyIRinsulin receptorMβCDmethyl-β-cyclodextrinPCphosphatidylcholinePOPCpalmitoyloleylphosphatidylcholine12-SLPC1-palmitoyl-2-(12-doxyl)-stearoylphosphatidylcholineTmtransition temperaturePBSphosphate-buffered salinePC-CHOLmixture of DPPC and cholesterolPC-DESMOmixture of DPPC and desmosterol.2The abbreviations used are: Loliquid-orderedLdliquid-disorderedDMRdetergent-resistant membraneDOPCdioleylphosphatidylcholineDPPCdipalmitoylphosphatidylcholineDPH1,6-diphenyl-1,3,5-hexatrieneHPLChigh performance liquid chromatographyIRinsulin receptorMβCDmethyl-β-cyclodextrinPCphosphatidylcholinePOPCpalmitoyloleylphosphatidylcholine12-SLPC1-palmitoyl-2-(12-doxyl)-stearoylphosphatidylcholineTmtransition temperaturePBSphosphate-buffered salinePC-CHOLmixture of DPPC and cholesterolPC-DESMOmixture of DPPC and desmosterol. state characterized by tight ordering but relatively high lateral mobility of lipids and operationally often defined as detergent-resistant membranes (DRMs) (5Brown D.A. London E. Biochem. Biophys. Res. Commun. 1997; 240: 1-7Crossref PubMed Scopus (457) Google Scholar, 6Brown D.A. Rose J.K. Cell. 1992; 68: 533-544Abstract Full Text PDF PubMed Scopus (2588) Google Scholar). Instead, unsaturated phospholipids are loosely packed, forming a liquid-disordered (Ld) membrane that is solubilized upon the addition of mild detergents. At least in model membranes, cholesterol is able to promote the separation of Lo and Ld domains (7Ahmed S.N. Brown D.A. London E. Biochemistry. 1997; 36: 10944-10953Crossref PubMed Scopus (604) Google Scholar, 8Baumgart T. Hess S.T. Webb W.W. Nature. 2003; 425: 821-824Crossref PubMed Scopus (1251) Google Scholar, 9Silvius J.R. del Giudice D. Lafleur M. Biochemistry. 1996; 35: 15198-15208Crossref PubMed Scopus (194) Google Scholar). In cells, cholesterol levels influence the domain partitioning and biological activity of proteins that co-isolate in detergent-resistant membranes (DRMs) (10Friedrichson T. Kurzchalia T.V. Nature. 1998; 394: 802-805Crossref PubMed Scopus (475) Google Scholar, 11Varma R. Mayor S. Nature. 1998; 394: 798-801Crossref PubMed Scopus (1017) Google Scholar). liquid-ordered liquid-disordered detergent-resistant membrane dioleylphosphatidylcholine dipalmitoylphosphatidylcholine 1,6-diphenyl-1,3,5-hexatriene high performance liquid chromatography insulin receptor methyl-β-cyclodextrin phosphatidylcholine palmitoyloleylphosphatidylcholine 1-palmitoyl-2-(12-doxyl)-stearoylphosphatidylcholine transition temperature phosphate-buffered saline mixture of DPPC and cholesterol mixture of DPPC and desmosterol. liquid-ordered liquid-disordered detergent-resistant membrane dioleylphosphatidylcholine dipalmitoylphosphatidylcholine 1,6-diphenyl-1,3,5-hexatriene high performance liquid chromatography insulin receptor methyl-β-cyclodextrin phosphatidylcholine palmitoyloleylphosphatidylcholine 1-palmitoyl-2-(12-doxyl)-stearoylphosphatidylcholine transition temperature phosphate-buffered saline mixture of DPPC and cholesterol mixture of DPPC and desmosterol. Taking the postulated critical role for cholesterol in raft formation and the diversity of sterols in biological materials, the sterol structural requirements for promoting ordered domain formation are highly relevant. Until now, the effects of sterol/steroid structure have mostly been addressed in model membranes. Slight modifications of the cholesterol structure (e.g. a shift of the double bond in the sterol ring or alteration of the 3-OH group) change the domain-forming properties of the molecule (12Bacia K. Schwille P. Kurzchalia T. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 3272-3277Crossref PubMed Scopus (320) Google Scholar, 13Wang J. Megha London E. Biochemistry. 2004; 43: 1010-1018Crossref PubMed Scopus (142) Google Scholar, 14Zuckermann M.J. Ipsen J.H. Miao L. Mouritsen O.G. Nielsen M. Polson J. Thewalt J. Vattulainen I. Zhu H. Methods Enzymol. 2004; 383: 198-229Crossref PubMed Scopus (23) Google Scholar). Among the structurally closest relatives of cholesterol are its immediate biosynthetic precursors. The only difference between cholesterol and its immediate precursor desmosterol is an additional double bond between carbon atoms 24 and 25 in the tail of desmosterol (Fig. 1). Recently, the influence of desmosterol on lipid order was found to be similar to that of cholesterol (15Huster D. Scheidt H.A. Arnold K. Herrmann A. Muller P. Biophys. J. 2005; 88: 1838-1844Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar). Cholesterol biosynthesis can proceed from lanosterol via two intersecting routes, the Kandutsch-Russell or Bloch pathways. The choice of pathway is determined by the stage at which the double bond at position C24 in the sterol side chain is reduced. If this double bond is retained until the last reaction, cholesterol synthesis proceeds via desmosterol (Bloch pathway), whereas early reduction leads to the formation of lathosterol and 7-dehydrocholesterol (Kandutsch-Russell pathway). The biological significance of this complexity remains enigmatic. We have shown that in cellular membranes, lathosterol associated with DRMs at least as efficiently as cholesterol (16Lusa S. Heino S. Ikonen E. J. Biol. Chem. 2003; 278: 19844-19851Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar). Accordingly, also in model membranes, lathosterol formed rafts that were at least as detergent-resistant as, and even more thermally stable than, cholesterol-containing rafts (13Wang J. Megha London E. Biochemistry. 2004; 43: 1010-1018Crossref PubMed Scopus (142) Google Scholar). Moreover, 7-dehydrocholesterol was found to be more strongly domain-promoting than cholesterol (17Xu X. Bittman R. Duportail G. Heissler D. Vilcheze C. London E. J. Biol. Chem. 2001; 276: 33540-33546Abstract Full Text Full Text PDF PubMed Scopus (453) Google Scholar). In contrast to many relatives of cholesterol, desmosterol is an abundant structural membrane component in mammalian cells, such as spermatozoa and astrocytes (18Lin D.S. Connor W.E. Wolf D.P. Neuringer M. Hachey D.L. J. Lipid Res. 1993; 34: 491-499Abstract Full Text PDF PubMed Google Scholar, 19Mutka A.L. Lusa S. Linder M.D. Jokitalo E. Kopra O. M. Ikonen E. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). to desmosterol to cholesterol of functional leads to the J. P. J. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). This is characterized by and M.J. K. J. 1998; PubMed Scopus Google Scholar). Instead, a and A. A. M. M. H. G. S. I. O. E. R. P. A. I. E. 2003; PubMed Scopus Google Scholar). In the we the roles of desmosterol and cholesterol in membrane by in model membranes and in model and cell membranes. In we addressed the functional effects of exchanging the of membrane cholesterol to desmosterol in cells, by raft-dependent and We found that the biophysical and functional properties of desmosterol differ from those of cholesterol. were by simulations to on the of which from the tail in the two were from for desmosterol and cholesterol lipid were from 1). were cholesterol, desmosterol, or that were by also 1,6-diphenyl-1,3,5-hexatriene were and in of and for at high the lipids were in the of of the the were at for which was for The were for at least at the temperature of used in the lipid in a were as in X. Bittman R. Duportail G. Heissler D. Vilcheze C. London E. J. Biol. Chem. 2001; 276: 33540-33546Abstract Full Text Full Text PDF PubMed Scopus (453) Google that the were at of at an and were a with a The were and were in in which the were by and the temperature the was was the from to and to with a of The and were the of in a 1-palmitoyl-2-(12-doxyl)-stearoylphosphatidylcholine mixture to the in the lipid was by dioleylphosphatidylcholine The of dipalmitoylphosphatidylcholine domain formation is by the difference between the in the and that not lipid domains domain transition and formation temperature were by a Biochemistry. 2003; PubMed Scopus Google Scholar). The is by the of the and the domain formation by the difference in the of domain formation and domain This was by the of the from the were in as in Brown Methods Enzymol. PubMed Scopus Google to and in of the were at between and The were in and in of with and at 25 The were by a which the were by for at of was with of and to a The was with a of and for 24 at at were and used for sterol or used for is an of G. M. Brown D.A. J. Biol. Chem. Full Text PDF PubMed Google were at was to the to a of by a on The were to by in to a and with of and of for at the DRMs at the between the and were from the solubilized membranes in the sterols were as in S. Lusa S. P. C. Ikonen E. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google lipids were to and J. Biochem. PubMed Scopus Google Scholar). The sterol was by and by high performance liquid chromatography were on to the cellular cholesterol, the were for on a at in the of methyl-β-cyclodextrin the were with and and in the of or for at as in H. Chem. PubMed Scopus Google of used in a of of the were with and to were the and was as and insulin was to the for the were for activity or in the of as S. I. M. Jokitalo E. P. Ikonen E. Biochem. J. 2005; PubMed Scopus Google Scholar, S. Heino S. P. E. O. Ikonen E. PubMed Scopus Google Scholar). and the were for at in 25 and sterol The were and to The proteins in the were by and the of was by The were with the of cellular protein in the were on the sterol and in the of activity and or insulin for The were and in and in the was with as the in was from the and as of was as S. Heino S. P. E. O. Ikonen E. PubMed Scopus Google Scholar). of cellular protein or from were used for used were from and of and of were as S. I. M. Jokitalo E. P. Ikonen E. Biochem. J. 2005; PubMed Scopus Google Scholar, S. Heino S. P. E. O. Ikonen E. PubMed Scopus Google Scholar). on were to the sterol with with and with and were with an with a and similar were used for of the Atomic composed of lipid and with The The and with cholesterol and desmosterol The simulations were the E. Hess D. J. 2001; Google Scholar). The for and for DPPC were from a for a DPPC O. O. Biophys. 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DRMs were from the between and The of cellular cholesterol and desmosterol was from the DRMs and membranes by We found that the was in the membranes than in DRMs (Fig. suggest that the desmosterol in the membranes as cholesterol but DRMs less efficiently than cholesterol. of Cholesterol with Desmosterol in of cholesterol by desmosterol functional effects on we a to acutely the of cellular cholesterol with desmosterol in cells. We used in which we have raft-dependent signaling S. Heino S. P. E. O. Ikonen E. PubMed Scopus Google Scholar). cholesterol as the structural with desmosterol (Fig. ∼70% of cholesterol was in (Fig. the were with desmosterol or cholesterol from a of sterols that upon cholesterol or desmosterol the sterol to the (Fig. Accordingly, of the with the sterol a reduction in upon cholesterol and of the and upon sterol (Fig. The structural and functional of the been to be on cholesterol levels S. M. S. K. 2005; PubMed Scopus Google Scholar, E. A. E. D. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). We found that in the cells, the of the was as by the more the of was upon sterol (Fig. the of the was by the sterol secretion from was the We have shown that of the is from in (16Lusa S. Heino S. Ikonen E. J. Biol. Chem. 2003; 278: 19844-19851Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar). of proteins from the showed that similar of were from and (Fig. At the of the the sterol levels were to of the desmosterol was to cholesterol the The of cholesterol was but the of cellular sterol was desmosterol cholesterol, This that the of on secretion was not to the of desmosterol but that secretion was not to the structural difference between the two the that the desmosterol was in cells. are to biosynthetic of cholesterol efficiently to the (16Lusa S. Heino S. Ikonen E. J. Biol. Chem. 2003; 278: 19844-19851Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of Cholesterol with Desmosterol on and have shown that in cells, insulin signaling in The was but upon insulin the receptor was Cholesterol insulin signaling and impaired the of the and upon cholesterol raft was S. Heino S. P. E. O. Ikonen E. PubMed Scopus Google Scholar). that the and are and we insulin signaling in cells. was as and S. I. M. Jokitalo E. P. Ikonen E. Biochem. J. 2005; PubMed Scopus Google Scholar, S. Heino S. P. E. O. Ikonen E. PubMed Scopus Google Scholar). We found in contrast to was in with (Fig. This was with that upon cholesterol S. Heino S. P. E. O. Ikonen E. PubMed Scopus Google Scholar). the levels were and insulin was cholesterol and desmosterol as assessed by and (Fig. and desmosterol with the of the with we or with the in and the in an as S. Heino S. P. E. O. Ikonen E. PubMed Scopus Google Scholar). In this DRMs are at the of the in We found in contrast to cholesterol, desmosterol to the of the as by the of the receptor from the of the (Fig. of the showed a significantly of the in DRMs in with of in that desmosterol cholesterol in This may be to the weaker properties of desmosterol as by the of the with DRMs in the of cholesterol. Atomic the biophysical and functional properties of desmosterol in membranes differ from those of cholesterol, we scale molecular dynamics We the properties of and at a sterol of in the and with those of a DPPC are to as mixture of DPPC and and mixture of DPPC and scale of are not the ordering of lipid chains, we determined the molecular order often in of the order for the chain of DPPC in and are shown in sterols were found to the order of the chain with the cholesterol was more in this The of membrane order is associated with in the of in acyl and in the of with to the membrane to cholesterol was found to be more than desmosterol in ordering the that the of DPPC on to the in the of cholesterol, whereas the of desmosterol is less can be from the structural properties the cholesterol the area per DPPC and membrane more than desmosterol We also determined the of the sterols in the by the between the sterol ring between carbon atoms and and the The of cholesterol and desmosterol were found to be for cholesterol and for desmosterol of sterols on properties The molecular order is an the order of the and chains, in the chains, to ordering in a The chain is the and as defined in T. K. R. A. M. J. Lipid Res. 2004; Full Text Full Text PDF PubMed Scopus (59) Google for the of per acyl the of and the membrane M. M. E. P. Vattulainen I. Biophys. J. 2003; Full Text Full Text PDF PubMed Scopus Google of and are The area was determined by the area of the by the of DPPC by in that are in and in and of in a The that with desmosterol are more than those cholesterol. the molecular for the of the two sterols, we on the of the sterol and with the of the DPPC The molecular order of the tail of the two sterols are shown in the cholesterol tail is strongly in the membrane the ordering of the desmosterol tail is significantly and strongly the of the This is associated with the of the two in the chain the and the for of the the bond are shown in the double bond in the tail of desmosterol gives rise to a difference with cholesterol and the and of the of the the last atoms on a and a rigid the of the desmosterol tail with the of the be from those of cholesterol. the of the double bond on the of atoms in the and we a similar as and T. M. Biophys. Chem. 2004; PubMed Scopus Google Scholar). We that of the last atoms of the tail with DPPC are in the of desmosterol than cholesterol. At the of the tail, to the ring the was found to be Here, the of DPPC the of the cholesterol tail and thus more with this of cholesterol than desmosterol. In the of was shown to in the than that of cholesterol T. M. Biophys. J. 2003; Full Text Full Text PDF PubMed Google Scholar). We the of the sterol as as its with DPPC at the of between cholesterol and desmosterol at the the simulations that the double bond in the tail of desmosterol gives rise to an additional stress in the tail, thus its at the of the tail with cholesterol. This difference for structural properties of the in the evidence to suggest that the biophysical and functional characteristics of membranes differ from those of cholesterol membranes. from model membranes suggest that the of desmosterol to promote the formation and of ordered domains is weaker than that of cholesterol. in cell membranes that desmosterol for DRMs and to the and of the raft-dependent signaling receptor, as as cholesterol. simulations in model membranes the that properties of the differ in a cholesterol-containing cholesterol is in ordering reducing the of in acyl and reducing the area by The simulations suggest that the difference in sterol is for the weaker effects of desmosterol on The of the ring with to DPPC membrane was found to be for desmosterol and for cholesterol. The the of desmosterol is distinct from cholesterol in the tail of the two In desmosterol, the double bond in the tail its with cholesterol, the membrane structure and tilting desmosterol. the structural and of desmosterol and cholesterol molecular dynamics of the the of the desmosterol tail and the of desmosterol to be more than cholesterol with to membrane an of the can also be associated with ordering of sterol as in the of in a the for cholesterol is and in is that the double bond in the tail of desmosterol not play a role in a of or unsaturated but its effects are more to domains of saturated The between desmosterol and cholesterol are to be in ordered This may cholesterol and desmosterol were found to the order of in a similar (15Huster D. Scheidt H.A. Arnold K. Herrmann A. Muller P. Biophys. J. 2005; 88: 1838-1844Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar). the lateral of desmosterol in a DPPC was found to be than that of cholesterol, in with H.A. D. K. Biophys. J. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). by insulin signaling as a that desmosterol not the role for cholesterol in raft-dependent that the precursor of cholesterol, was found to be more strongly domain-promoting than cholesterol (17Xu X. Bittman R. Duportail G. Heissler D. Vilcheze C. London E. J. Biol. Chem. 2001; 276: 33540-33546Abstract Full Text Full Text PDF PubMed Scopus (453) Google a the Kandutsch-Russell pathway via and the Bloch pathway via less sterols to cholesterol. is evidence for of the for In cholesterol is preferentially via the desmosterol in via the lathosterol pathway D. A. E. D. M. K. K. G. J. Lipid Res. 43: Full Text Full Text PDF PubMed Scopus Google Scholar). of the sterol by of the be to raft-dependent for by for We for The for and the at the of are for