TAILIEUCHUNG - Báo cáo khoa học: Restriction of lipid motion in membranes triggered by b-sheet aggregation of the anti-apoptotic BH4 domain

The regulative BH4 domain of human Bcl-2 protein exerts its anti-apoptic activity via the mitochondrion. In the present study, we investigated the molecular interactions of this domain with negatively charged liposomes mimicking the outer mitochondrial membrane. | ỊFEBS Journal Restriction of lipid motion in membranes triggered by b-sheet aggregation of the anti-apoptotic BH4 domain Marc-Antoine Sani1 2 Sabine Castano1 Erick J. Dufourc1 and Gerhard Grobner2 1 UMR 5248 CBMN CNRS-Universite Bordeaux 1-ENITAB Pessac France 2 Department of Chemistry Umea University Sweden Keywords apoptosis BH4 domain membrane protein lipid interactions solid state NMR Correspondence G. Grobner Department of Chemistry Umea University 901 87 Umea Sweden Fax 46 907 86 7655 Tel 46 907 86 6346 E-mail E. J. Dufourc UMR 5248 CBMN CNRS-Universite Bordeaux 1-ENITAB IECB 2 rue Robert Escarpit 33607 Pessac France Fax 33 5 4000 2218 Tel 33 5 4000 2218 E-mail Received 21 October 2007 revised 28 November 2007 accepted 5 December 2007 The regulative BH4 domain of human Bcl-2 protein exerts its anti-apoptic activity via the mitochondrion. In the present study we investigated the molecular interactions of this domain with negatively charged liposomes mimicking the outer mitochondrial membrane. To model the overproduction of Bcl-2 found in cancer processes we studied the impact of elevated concentrations of its regulative BH4 segment on these mitochondrial membranes from the peptide and lipid perspective. Combined solid state 2H-NMR and differential scanning calorimetry revealed the coexistence of small sized fluid and rigid membrane domains over a large temperature range which is confirmed by 31P-NMR at 30 C. The latter are stabilized in a cholesterol-like manner by the presence of a BH4 peptide. In the same time scale the reduction of the headgroup order is seen in the static 14N and 31P-NMR spectra when BH4 inserts into the bilayers. Indeed attenuated total reflection spectroscopy indicated a dominant aggregated b-sheet secondary structure of BH4 with a 42 tilt relative to the membrane surface. These results are discussed in terms of membrane stabilization versus apoptotic mechanisms at the outer .

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