Significance of sterol structural specificity: desmosterol cannot replace cholesterol in lipid rafts

Saara Vainio, Maurice Jansen, Mirkka Koivusalo, Tomasz Rog, Mikko Karttunen, Ilpo Vattulainen, Elina Ikonen

Research output: Contribution to journalArticleScientificpeer-review

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 similar to 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.
Original languageEnglish
JournalJournal of Biological Chemistry
Volume281
Issue number1
Pages (from-to)348-355
Number of pages8
ISSN0021-9258
DOIs
Publication statusPublished - 2006
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 114 Physical sciences

Cite this

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title = "Significance of sterol structural specificity: desmosterol cannot replace cholesterol in lipid rafts",
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 similar to 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.",
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author = "Saara Vainio and Maurice Jansen and Mirkka Koivusalo and Tomasz Rog and Mikko Karttunen and Ilpo Vattulainen and Elina Ikonen",
year = "2006",
doi = "10.1074/jbc.M509530200",
language = "English",
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pages = "348--355",
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Significance of sterol structural specificity : desmosterol cannot replace cholesterol in lipid rafts. / Vainio, Saara; Jansen, Maurice; Koivusalo, Mirkka; Rog, Tomasz; Karttunen, Mikko; Vattulainen, Ilpo; Ikonen, Elina.

In: Journal of Biological Chemistry, Vol. 281, No. 1, 2006, p. 348-355.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Significance of sterol structural specificity

T2 - desmosterol cannot replace cholesterol in lipid rafts

AU - Vainio, Saara

AU - Jansen, Maurice

AU - Koivusalo, Mirkka

AU - Rog, Tomasz

AU - Karttunen, Mikko

AU - Vattulainen, Ilpo

AU - Ikonen, Elina

PY - 2006

Y1 - 2006

N2 - 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 similar to 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.

AB - 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 similar to 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.

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