Heat shock protein coinducers with no effect on protein denaturation specifically modulate the membrane lipid phase.
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.
Török
Zsolt
Z
Institute of Biochemistry, Biological Research Centre, Hungarian Academy of Sciences, P.O. Box 521, H-6701 Szeged, Hungary.
Tsvetkova
Nelly M
NM
Balogh
Gábor
G
Horváth
Ibolya
I
Nagy
Enikö
E
Pénzes
Zoltán
Z
Hargitai
Judit
J
Bensaude
Olivier
O
Csermely
Péter
P
Crowe
John H
JH
Maresca
Bruno
B
Vigh
László
L
D016475:3T3 Cells; D000818:Animals; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D007094:Imides / Q000494:pharmacology*; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D008560:Membrane Fluidity / Q000187:drug effects; D008563:Membrane Lipids / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D011489:Protein Denaturation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D007094:Imides; D008563:Membrane Lipids; D011725:Pyridines; C108730:bimoclomol