Novel dimerization mode of the human Bcl-2 family protein Bak, a mitochondrial apoptosis regulator.
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 2.5A, 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-x(L). Therefore, the Bak dimer structure reported here may represent a pro-apoptotic mode under oxidized conditions.
Wang
Hongfei
H
Systems and Structural Biology Center, Yokohama Institute, RIKEN, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Japan.
Takemoto
Chie
C
Akasaka
Ryogo
R
Uchikubo-Kamo
Tomomi
T
Kishishita
Seiichiro
S
Murayama
Kazutaka
K
Terada
Takaho
T
Chen
Lirong
L
Liu
Zhi-Jie
ZJ
Wang
Bi-Cheng
BC
Sugano
Sumio
S
Tanaka
Akiko
A
Inoue
Makoto
M
Kigawa
Takanori
T
Shirouzu
Mikako
M
Yokoyama
Shigeyuki
S
D000595:Amino Acid Sequence; D003460:Crystallization; D018360:Crystallography, X-Ray; D003545:Cysteine / Q000737:chemistry; D003553:Cystine / Q000737:chemistry; D057927:Hydrophobic and Hydrophilic Interactions; D008027:Light; D008958:Models, Molecular; D008969:Molecular Sequence Data; D008970:Molecular Weight; D010084:Oxidation-Reduction; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry; D012542:Scattering, Radiation; D017386:Sequence Homology, Amino Acid; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000737:chemistry* / Q000235:genetics
C494772:BAK1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D050998:bcl-2 Homologous Antagonist-Killer Protein; D003553:Cystine; D003545:Cysteine