Trends in Biochemical Sciences
ReviewMany players in BCL-2 family affairs
Section snippets
BCL-2 family proteins drive apoptosis
The most common form of programmed cell death in biology and disease is the mitochondrial pathway of apoptosis [1]. During apoptosis, cellular stress signals converge at the mitochondria to induce MOMP: typically the ‘point of no return’ during controlled cellular self-destruction (Figure 1) [2]. Cellular stress may be extrinsic, initiated by the engagement of death receptors at the plasma membrane, or intrinsic, such as chemotherapy-induced DNA damage. Through release of cytochrome c (cyt c)
A unified model of BCL-2 family protein–protein interactions
The mammalian BCL-2 protein family contains both pro-apoptotic and anti-apoptotic members. The family members BCL-2 antagonist killer 1 (BAK), BCL-2-associated X protein (BAX), and possibly BCL-2-related ovarian killer (BOK) – termed ‘effectors’ – mediate MOMP, and the anti-apoptotic family members BCL-2, BCL-xL, BCL-w, myeloid cell leukemia 1 (MCL-1), and BCL-2-related gene A1 (A1) inhibit it. The subfamily of BH3-only proteins [sharing only the third BCL-2 homology (BH) domain] function to
Plasticity of BCL-2 family proteins
An emerging feature of protein–protein interactions between BCL-2 family members is the functional role of structural plasticity, which may be categorized into ‘canonical’ and ‘non-canonical’ interactions based on the engagement or lack thereof of the BH3 and C terminus-binding (BC) groove. This is a conserved, hydrophobic groove on the surface of the BCL-2 core, demarcated on one face of the globular domain by the BH1–BH3 regions (Box 1). Canonical interactions at the BC groove involve binding
Canonical BC groove mechanisms
Anti-apoptotic and effector BCL-2 family proteins canonically bind the BH3 regions of pro-apoptotic proteins at the BC groove, as originally illustrated for the anti-apoptotic complex of BCL-xL and a BAK BH3 peptide [14] (Box 1), and recently for the pro-apoptotic complexes of BAK [15] or BAX [16] and a BID BH3 peptide. The similarities and differences in the BC grooves and their interactions with BH3 ligands correlate with the biological functions of BCL-2 family proteins. Structural features
Molecular basis of BH3 specificity for the BC groove
Structure–function studies have elucidated the molecular basis for recognition of BH3 regions of pro-apoptotic proteins by the BCL-2 core of anti-apoptotic 6, 47 and effector BCL-2 family proteins 15, 16. The minimal (4–5 helix turns) and extended (>6 helix turns) BH3 region binds similarly to the BC groove of BCL-2 family proteins for all tested pairs. Both hydrophobic and hydrophilic/electrostatic contacts define the selectivity and specificity of BH3–BC groove complexes (Figure 3). This mode
SAHBed in the BAX
The initial steps of BAX activation implicate a transient ‘hit-and-run’ mechanism originally proposed by the Korsmeyer laboratory studying the BID–BAK axis [24]. Based on observations that oligomeric BAK did not remain associated with activator BID, this hit-and-run model postulated that BID dissociates after inducing the active BAK conformation. At the molecular level, interactions by activator BH3 domains occur first at a non-canonical site 18, 52, 53 and then at the BC groove [16]. In BAX,
BC groove drugs
Since the early 2000s, significant progress has been made toward the pharmaceutical targeting of BCL-2 family proteins 9, 76. Small-molecule BH3-mimetic inhibitors of anti-apoptotic family members, including BCL-2, BCL-xL, and BCL-w 77, 78, 79, were designed to prevent anti-apoptotic BCL-2 proteins from sequestering pro-apoptotic family members, thereby acting as mimetics of derepressors/sensitizers (Figure 5). The original BH3 mimetic ABT-737 was generated based on screening and binding
Concluding remarks
Most of the key members of the mammalian BCL-2 family proteins, including the effectors BAK and BAX, the promiscuous direct activators BID and BIM, the anti-apoptotic BCL-2, BCL-xL, and MCL-1, and the classical derepressor/sensitizer BAD as reviewed here, are now well understood genetically, biochemically, and structurally. Remaining unknowns in this regard include elucidating the definitive function of BH3-only proteins claimed to act as borderline direct activators, including PUMA, Noxa, and
Acknowledgments
This work was supported by National Institutes of Health (NIH) grants R01CA082491 and 1R01GM083159 (to R.W.K), NIH grant GM096208 (to D.R.G), and a National Cancer Institute Cancer Center Support Grant P30CA21765 (at St. Jude Children's Research Hospital), and the American Lebanese Syrian Associated Charities.
References (105)
Apoptotic pathways: ten minutes to dead
Cell
(2005)The BCL-2 family reunion
Mol. Cell
(2010)- et al.
How do BCL-2 proteins induce mitochondrial outer membrane permeabilization?
Trends Cell Biol.
(2008) Solution structure of BID, an intracellular amplifier of apoptotic signaling
Cell
(1999)A unified model of mammalian BCL-2 protein family interactions at the mitochondria
Mol. Cell
(2011)Bax crystal structures reveal how BH3 domains activate Bax and nucleate its oligomerization to induce apoptosis
Cell
(2013)Bcl-xL retrotranslocates Bax from the mitochondria into the cytosol
Cell
(2011)The X-ray structure of a BAK homodimer reveals an inhibitory zinc binding site
Mol. Cell
(2006)Stepwise activation of BAX and BAK by tBID, BIM, and PUMA initiates mitochondrial apoptosis
Mol. Cell
(2009)Evaluation of the BH3-only protein Puma as a direct Bak activator
J. Biol. Chem.
(2014)
BH3 domains other than Bim and Bid can directly activate Bax/Bak
J. Biol. Chem.
To trigger apoptosis, Bak exposes its BH3 domain and homodimerizes via BH3:groove interactions
Mol. Cell
Nonionic detergents induce dimerization among members of the Bcl-2 family
J. Biol. Chem.
Molecular details of Bax activation, oligomerization, and membrane insertion
J. Biol. Chem.
Conformational changes in BAK, a pore-forming proapoptotic Bcl-2 family member, upon membrane insertion and direct evidence for the existence of BH3-BH3 contact interface in BAK homo-oligomers
J. Biol. Chem.
Bak activation for apoptosis involves oligomerization of dimers via their alpha6 helices
Mol. Cell
Assembly of the Bak apoptotic pore: a critical role for the Bak alpha6 helix in the multimerization of homodimers during apoptosis
J. Biol. Chem.
Heterodimerization of BAK and MCL-1 activated by detergent micelles
J. Biol. Chem.
Defining the p53 DNA-binding domain/Bcl-x(L)-binding interface using NMR
FEBS Lett.
Structure of the BH3 domains from the p53-inducible BH3-only proteins Noxa and Puma in complex with Mcl-1
J. Mol. Biol.
Apoptotic regulation by MCL-1 through heterodimerization
J. Biol. Chem.
The first alpha helix of Bax plays a necessary role in its ligand-induced activation by the BH3-only proteins Bid and PUMA
Mol. Cell
Structure of Bax: coregulation of dimer formation and intracellular localization
Cell
BH3-triggered structural reorganization drives the activation of proapoptotic BAX
Mol. Cell
Multimodal interaction with BCL-2 family proteins underlies the proapoptotic activity of PUMA BH3
Chem. Biol.
Comparative biophysical characterization of p53 with the pro-apoptotic BAK and the anti-apoptotic BCL-xL
J. Biol. Chem.
Oligomerization of BAK by p53 utilizes conserved residues of the p53 DNA binding domain
J. Biol. Chem.
Pharmacologic activation of p53 elicits Bax-dependent apoptosis in the absence of transcription
Cancer Cell
Transcription, apoptosis and p53: catch-22
Trends Genet.
Bcl-xL changes conformation upon binding to wild-type but not mutant p53 DNA binding domain
J. Biol. Chem.
Structural biology of the Bcl-2 family of proteins
Biochim. Biophys. Acta
WT p53, but not tumor-derived mutants, bind to Bcl-2 via the DNA binding domain and induce mitochondrial permeabilization
J. Biol. Chem.
Dual-site interactions of p53 protein transactivation domain with anti-apoptotic Bcl-2 family proteins reveal a highly convergent mechanism of divergent p53 pathways
J. Biol. Chem.
The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized
Cancer Cell
Targeting BCL-2 with the BH3 mimetic ABT-199 in estrogen receptor-positive breast cancer
Cancer Cell
Discovery of a potent and selective Bcl-2 inhibitor using SAR by NMR
Bioorg. Med. Chem. Lett.
Mitochondria: gatekeepers of response to chemotherapy
Trends Cell Biol.
Targeting post-mitochondrial effectors of apoptosis for neuroprotection
Biochim. Biophys. Acta
Protein–protein interactions as druggable targets: recent technological advances
Curr. Opin. Pharmacol.
Shedding light on apoptosis at subcellular membranes
Cell
Cell death
N. Engl. J. Med.
Cytochrome c-mediated apoptosis
Annu. Rev. Biochem.
A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD
Nature
Xk-related protein 8 and CED-8 promote phosphatidylserine exposure in apoptotic cells
Science
BCL-2 family members and the mitochondria in apoptosis
Genes Dev.
The BCL-2 protein family: opposing activities that mediate cell death
Nat. Rev. Mol. Cell Biol.
BCL-2 family antagonists for cancer therapy
Nat. Rev. Drug Discov.
Bim, Bad and Bmf: intrinsically unstructured BH3-only proteins that undergo a localized conformational change upon binding to prosurvival Bcl-2 targets
Cell Death Differ.
Structure of Bcl-xL–Bak peptide complex: recognition between regulators of apoptosis
Science
BID-induced structural changes in BAK promote apoptosis
Nat. Struct. Mol. Biol.
Cited by (342)
Bidirectional effects of geniposide in liver injury: Preclinical evidence construction based on meta-analysis
2024, Journal of EthnopharmacologySOHO State of the Art Updates and Next Questions: Understanding and Overcoming Venetoclax Resistance in Hematologic Malignancies
2024, Clinical Lymphoma, Myeloma and LeukemiaCell death classification: A new insight based on molecular mechanisms
2023, Experimental Cell ResearchMechanism of the anti-liver fibrosis effect of Periplaneta americana extracts that promote apoptosis of HSC-T6 cells through the Bcl-2/Bax signaling pathway
2023, Journal of Asia-Pacific Entomology