Novel dimerization mode of the human Bcl-2 family protein Bak, a mitochondrial apoptosis regulator

Hongfei Wang, Chie Takemoto, Ryogo Akasaka, Tomomi Uchikubo-Kamo, Seiichiro Kishishita, Kazutaka Murayama, Takaho Terada, Lirong Chen, Zhi Jie Liu, Bi Cheng Wang, Sumio Sugano, Akiko Tanaka, Makoto Inoue, Takanori Kigawa, Mikako Shirouzu, Shigeyuki Yokoyama

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36 Citations (Scopus)

Abstract

Interactions of Bcl-2 family proteins play a regulatory role in mitochondrial apoptosis. The pro-apoptotic protein Bak resides in the outer mitochondrial membrane, and the formation of Bak homo- or heterodimers is involved in the regulation of apoptosis. The previously reported structure of the human Bak protein (residues Glu16-Gly186) revealed that a zinc ion was coordinated with two pairs of Asp160 and His164 residues from the symmetry-related molecules. This zinc-dependent homodimer was regarded as an anti-apoptotic dimer. In the present study, we determined the crystal structure of the human Bak residues Ser23-Asn185 at 2.5 Å, and found a distinct type of homodimerization through Cys166 disulfide bridging between the symmetry-related molecules. In the two modes of homodimerization, the molecular interfaces are completely different. In the membrane-targeted model of the S-S bridged dimer, the BH3 motifs are too close to the membrane to interact directly with the anti-apoptotic relatives, such as Bcl-xL. Therefore, the Bak dimer structure reported here may represent a pro-apoptotic mode under oxidized conditions.

Original languageEnglish
Pages (from-to)32-37
Number of pages6
JournalJournal of Structural Biology
Volume166
Issue number1
DOIs
Publication statusPublished - 2009 Apr 1

Keywords

  • Apoptosis regulator
  • Bak
  • Bcl-2 family protein
  • Crystal structure
  • Disulfide bridge
  • Homodimer

ASJC Scopus subject areas

  • Structural Biology

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  • Cite this

    Wang, H., Takemoto, C., Akasaka, R., Uchikubo-Kamo, T., Kishishita, S., Murayama, K., Terada, T., Chen, L., Liu, Z. J., Wang, B. C., Sugano, S., Tanaka, A., Inoue, M., Kigawa, T., Shirouzu, M., & Yokoyama, S. (2009). Novel dimerization mode of the human Bcl-2 family protein Bak, a mitochondrial apoptosis regulator. Journal of Structural Biology, 166(1), 32-37. https://doi.org/10.1016/j.jsb.2008.12.003