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J. Biol. Chem., Vol. 282, Issue 22, 16256-16266, June 1, 2007

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Unique Dimeric Structure of BNip3 Transmembrane Domain Suggests Membrane Permeabilization as a Cell Death Trigger^*

Eduard V. Bocharov¹, Yulia E. Pustovalova, Konstantin V. Pavlov, Pavel E. Volynsky, Marina V. Goncharuk^¶, Yaroslav S. Ermolyuk^¶, Dmitry V. Karpunin^||, Alexey A. Schulga^¶, Michail P. Kirpichnikov^¶, Roman G. Efremov, Innokenty V. Maslennikov, and Alexander S. Arseniev²

From the Laboratories of Structural Biology, ^¶Protein Engineering, and ^||Neuroreceptors and Neuroregulators, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya, 16/10, Moscow 117997 and Laboratory of Bioelectrochemistry, Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences, Leninsky Prospect 31, Moscow 119991, Russia

BNip3 is a prominent representative of apoptotic Bcl-2 proteins with rather unique properties initiating an atypical programmed cell death pathway resembling both necrosis and apoptosis. Many Bcl-2 family proteins modulate the permeability state of the outer mitochondrial membrane by forming homo- and hetero-oligomers. The structure and dynamics of the homodimeric transmembrane domain of BNip3 were investigated with the aid of solution NMR in lipid bicelles and molecular dynamics energy relaxation in an explicit lipid bilayer. The right-handed parallel helix-helix structure of the domain with a hydrogen bond-rich His-Ser node in the middle of the membrane, accessibility of the node for water, and continuous hydrophilic track across the membrane suggest that the domain can provide an ion-conducting pathway through the membrane. Incorporation of the BNip3 transmembrane domain into an artificial lipid bilayer resulted in pH-dependent conductivity increase. A possible biological implication of the findings in relation to triggering necrosis-like cell death by BNip3 is discussed.

Received for publication, February 28, 2007 , and in revised form, March 28, 2007.

^* This work was supported by the Programme RAS MCB, by Russian Founds Investment Group, by the Russian Foundation for Basic Research, and by the Russian Federation Federal Agency for Science and Innovations ("The leading scientific schools" 4728.2006.4 and MK-5657.2006.4). 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.

The atomic coordinates and structure factors (code 2j5D) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

The chemical shift assignments of the BNip3tm dimer have been deposited at BioMagResBank (www.bmrb.wisc.edu) under accession code BMRB 7288.

The on-line version of this article (available at http://www.jbc.org) contains supplemental data and supplemental Figs. S1–S5.

¹ To whom correspondence may be addressed. Tel.: 7(495)3307483; Fax: 7(495)3355033; E-mail: bon{at}nmr.ru. ² To whom correspondence may be addressed. Tel.: 7(495)3305929; Fax: 7(495)3355033; E-mail: aars{at}nmr.ru.

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