2XA0

Crystal structure of BCL-2 in complex with a BAX BH3 peptide

Summary for 2XA0

• Entry DOI: 10.2210/pdb2xa0/pdb
• Related: 1G5M 1GJH 1YSW 2W3L
• Descriptor: APOPTOSIS REGULATOR BCL-2, APOPTOSIS REGULATOR BAX (3 entities in total)
• Functional Keywords: apoptosis, cell death
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Mitochondrion outer membrane; Single-pass membrane protein: P10415; Isoform Alpha: Mitochondrion outer membrane; Single-pass membrane protein (By similarity). Isoform Beta: Cytoplasm (By similarity). Isoform Gamma: Cytoplasm (By similarity): Q07813
• Total number of polymer chains: 4
• Total formula weight: 52867.50

Authors

Ku, B.,Oh, B.H. (deposition date: 2010-03-25, release date: 2010-11-24, Last modification date: 2023-12-20)

Primary citation

Ku, B.,Liang, C.,Jung, J.U.,Oh, B.H.
Evidence that Inhibition of Bax Activation by Bcl- 2 Involves its Tight and Preferential Interaction with the Bh3 Domain of Bax.
Cell Res., 21:627-, 2011

PubMed Abstract: Interactions between the BCL-2 family proteins determine the cell's fate to live or die. How they interact with each other to regulate apoptosis remains as an unsettled central issue. So far, the antiapoptotic BCL-2 proteins are thought to interact with BAX weakly, but the physiological significance of this interaction has been vague. Herein, we show that recombinant BCL-2 and BCL-w interact potently with a BCL-2 homology (BH) 3 domain-containing peptide derived from BAX, exhibiting the dissociation constants of 15 and 23 nM, respectively. To clarify the basis for this strong interaction, we determined the three-dimensional structure of a complex of BCL-2 with a BAX peptide spanning its BH3 domain. It revealed that their interactions extended beyond the canonical BH3 domain and involved three nonconserved charged residues of BAX. A novel BAX variant, containing the alanine substitution of these three residues, had greatly impaired affinity for BCL-2 and BCL-w, but was otherwise indistinguishable from wild-type BAX. Critically, the apoptotic activity of the BAX variant could not be restrained by BCL-2 and BCL-w, pointing that the observed tight interactions are critical for regulating BAX activation. We also comprehensively quantified the binding affinities between the three BCL-2 subfamily proteins. Collectively, the data show that due to the high affinity of BAX for BCL-2, BCL-w and A1, and of BAK for BCL-X(L), MCL-1 and A1, only a subset of BH3-only proteins, commonly including BIM, BID and PUMA, could be expected to free BAX or BAK from the antiapoptotic BCL-2 proteins to elicit apoptosis.

PubMed: 21060336
DOI: 10.1038/CR.2010.149

Experimental method

X-RAY DIFFRACTION (2.7 Å)