Heat shock protein coinducers with no effect on protein denaturation specifically modulate the membrane lipid phase

被引:78
作者
Török, Z
Tsvetkova, NM
Balogh, G
Horváth, I
Nagy, E
Pénzes, Z
Hargitai, J
Bensaude, O
Csermely, P
Crowe, JH
Maresca, B
Vígh, L
机构
[1] Hungarian Acad Sci, Biol Res Ctr, Inst Biochem, H-6701 Szeged, Hungary
[2] Univ Calif Davis, Sect Mol & Cellular Biol, Davis, CA 95616 USA
[3] Biorex R&D Co, H-8201 Veszprem, Hungary
[4] Ecole Normale Super, Dept Mol Genet, F-75230 Paris, France
[5] Semmelweis Univ, Dept Med Chem, H-1088 Budapest, Hungary
[6] Univ Salerno, Dept Pharmaceut Sci, I-84084 Fisciano Salerno, Italy
关键词
D O I
10.1073/pnas.0438003100
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The hydroxylamine derivative bimoclomol (BM) has been shown to activate natural cytoprotective homeostatic responses by enhancing the capability of cells to cope with various pathophysiological conditions. It exerts its effect in synergy with low levels of stress to induce the synthesis of members of major stress protein families. We show here that the presence of BM does not influence protein denaturation in the cells. BM and its derivatives selectively interact with acidic lipids and modulate their thermal and dynamic properties. BM acts as a membrane fluidizer at normal temperature, but it is a highly efficient membrane stabilizer, inhibiting the bilayer-nonbilayer phase transitions during severe heat shock. We suggest that BM and the related compounds modify those domains of membrane lipids where the thermally or chemically induced perturbation of lipid phase is sensed and transduced into a cellular signal, leading to enhanced activation of heat shock genes. BM may be a prototype for clinically safe membrane-interacting drug candidates that rebalance the level and composition of heat shock proteins.
引用
收藏
页码:3131 / 3136
页数:6
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