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J. Biol. Chem., Vol. 283, Issue 21, 14610-14618, May 23, 2008

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Cholesterol Substitution Increases the Structural Heterogeneity of Caveolae^*

Maurice Jansen¹, Vilja M. Pietiaïnen¹, Harri Pölönen, Laura Rasilainen^¶, Mirkka Koivusalo, Ulla Ruotsalainen, Eija Jokitalo^¶, and Elina Ikonen²

From the Institute of Biomedicine/Anatomy and the ^¶Institute of Biotechnology, University of Helsinki, Helsinki 00140 and the Institute of Signal Processing, Tampere University of Technology, Tampere 33101, Finland

Caveolin-1 binds cholesterol and caveola formation involves caveolin-1 oligomerization and cholesterol association. The role of cholesterol in caveolae has so far been addressed by methods that compromise membrane integrity and abolish caveolar invaginations. To study the importance of sterol specificity for the structure and function of caveolae, we replaced cholesterol in mammalian cells with its immediate precursor desmosterol by inhibiting 24-dehydrocholesterol reductase. Desmosterol could substitute for cholesterol in maintaining cell growth, membrane integrity, and preserving caveolar invaginations. However, in desmosterol cells the affinity of caveolin-1 for sterol and the stability of caveolin oligomers were decreased. Moreover, caveolar invaginations became more heterogeneous in dimensions and in the number of caveolin-1 molecules per caveola. Despite the altered caveolar structure, caveolar ligand uptake was only moderately inhibited. We found that in desmosterol cells, Src kinase phosphorylated Cav1 at Tyr¹⁴ more avidly than in cholesterol cells. Taken the role of Cav1 Tyr¹⁴ phosphorylation in caveolar endocytosis, this may help to preserve caveolar uptake in desmosterol cells. We conclude that a sterol C24 double bond interferes with caveolin-sterol interaction and perturbs caveolar morphology but facilitates Cav1 Src phosphorylation and allows caveolar endocytosis. More generally, substitution of cholesterol by a structurally closely related sterol provides a method to selectively modify membrane protein-sterol affinity, structure and function of cholesterol-dependent domains without compromising membrane integrity.

Received for publication, December 19, 2007 , and in revised form, March 5, 2008.

^* This work was supported by Academy of Finland Projects 213462, 117064, and 210969, the Sigrid Juselius Foundation, the Finnish Cultural Foundation, the Orion Pharma Foundation, the Paavo Nurmi Foundation, the Jenny and Antti Wihuri Foundation, and the Helsinki Biomedical Graduate School. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally.

² To whom correspondence should be addressed: Haartmaninkatu 8, FIN 00140 University of Helsinki, Finland. Tel.: 358-9-191-25277; Fax: 358-9-191-25261; E-mail: elina.ikonen{at}helsinki.fi.

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