Many players in BCL-2 family affairs

doi:10.1016/j.tibs.2013.12.006

Trends in Biochemical Sciences

Volume 39, Issue 3, March 2014, Pages 101-111

https://doi.org/10.1016/j.tibs.2013.12.006 Get rights and content

Highlights

•
Binding-induced conformational transitions within BCL-2 family proteins regulate apoptosis.
•
Canonical and non-canonical ligand binding occurs at the globular BCL-2 cores.
•
Allosteric activation of BCL-2 effectors initiates mitochondrial outer-membrane permeabilization (MOMP).
•
PUMA-induced unfolding of BCL-xL releases p53 to trigger BCL-2 effectors and MOMP.

During apoptotic cell death, cellular stress signals converge at the mitochondria to induce mitochondrial outer-membrane permeabilization (MOMP) through B cell lymphoma-2 (BCL-2) family proteins and their effectors. BCL-2 proteins function through protein–protein interactions, the mechanisms and structural aspects of which are only now being uncovered. Recently, the elucidation of the dynamic features underlying their function has highlighted their structural plasticity and the consequent complex thermodynamic landscape governing their protein–protein interactions. These studies show that canonical interactions involve a conserved, hydrophobic groove, whereas non-canonical interactions function allosterically outside the groove. We review the latest structural advances in understanding the interactions and functions of mammalian BCL-2 family members, and discuss new opportunities to modulate these proteins in health and disease.

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.

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Trends in Biochemical Sciences

ReviewMany players in BCL-2 family affairs

Highlights

Section snippets

BCL-2 family proteins drive apoptosis

A unified model of BCL-2 family protein–protein interactions

Plasticity of BCL-2 family proteins

Canonical BC groove mechanisms

Molecular basis of BH3 specificity for the BC groove

SAHBed in the BAX

BC groove drugs

Concluding remarks

Acknowledgments

Cell

Mol. Cell

Trends Cell Biol.

Cell

Mol. Cell

Cell

Cell

Mol. Cell

Mol. Cell

J. Biol. Chem.

J. Biol. Chem.

Mol. Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Mol. Cell

J. Biol. Chem.

J. Biol. Chem.

FEBS Lett.

J. Mol. Biol.

J. Biol. Chem.

Mol. Cell

Cell

Mol. Cell

Chem. Biol.

J. Biol. Chem.

J. Biol. Chem.

Cancer Cell

Trends Genet.

J. Biol. Chem.

Biochim. Biophys. Acta

J. Biol. Chem.

J. Biol. Chem.

Cancer Cell

Cancer Cell

Bioorg. Med. Chem. Lett.

Trends Cell Biol.

Biochim. Biophys. Acta

Curr. Opin. Pharmacol.

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.

Review
Many players in BCL-2 family affairs