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Structural biology of the intrinsic cell death pathway: what do we know and what is missing?

Erinna F. Lee,W. Fairlie

Published 2012 in Computational and Structural Biotechnology Journal

ABSTRACT

Programmed cell death, or apoptosis, is essential for the proper development and maintenance of tissue homeostasis in metazoans. Cells that are damaged, dangerous or superfluous undergo apoptosis and are removed unobtrusively by professional phagocytes, such as macrophages and dendritic cells [1–3]. This is unlike other forms of cell death such as necrosis, which elicits an inflammatory response due to the release of noxious cellular contents from the dying cell. The apoptotic demise of the cell is executed by a group of proteases, known as caspases (cysteine-dependent asparate-specific proteases), which once activated, cleave vital cellular substrates. Upstream of caspase activation, a group of proteins that plays a vital role in the regulation of apoptosis signaling is the Bcl-2 family of proteins. These proteins are defined by the presence of at least one, and up to four, regions of sequence homology known as cl-2 omology (BH) domains and the family comprises three sub-classes, each distinguished by their functional role (Figure 1A, ​,B)B) [4]. The first of these sub-classes are the pro-survival Bcl-2 proteins (Bcl-2 itself, Bcl-xL, Bcl-w, Mcl-1 and Bfl-1) which are responsible for the protection of cells against various death stimuli such as cytokine withdrawal or DNA damage. The second sub-class contain the Bax/Bak proteins. These are multi-BH domain-containing proteins that are closely related to their pro-survival counterparts in their domain architecture. However, in contrast, Bax and Bak promote cell death and are critical mediators of apoptosis as evidenced by the severe phenotype of the bax-/-bak-/- mice, and the resistance of cells derived from these mice to most forms of stress-induced apoptosis, and the enforced expression of the BH3-only proteins [5]. These BH3-only proteins constitute the third sub-class of Bcl-2 family proteins and are the initiators of the apoptotic cascade. As suggested by their name, BH3-only proteins are related to each other, and to other members of the Bcl-2 family, by the presence of just the BH3 domain. The BH3-only proteins are upregulated transcriptionally and post-translationally upon receipt of a death stimulus. Figure 1 A) Schematic of the Bcl-2 regulated cell death in humans. B) Domain architecture of the Bcl-2 family of proteins. These proteins are characterized by the presence of up to 4 regions of sequence homology, known as Bcl-2 homology (BH) domains. C) The structure ... A number of models have been proposed for how BH3-only proteins activate Bax and Bak. In one model, known as “indirect activation”, Bax and Bak activation is spontaneous and their pro-apoptotic activities are exerted once released from pro-survival protein sequestration. This release occurs following binding of the BH3-only proteins to the pro-survival proteins [6, 7]. An alternate model, known as “direct activation”, suggests that a sub-group of the BH3-only proteins are able to bind directly to, and trigger the activation of Bax and Bak. Here, pro-survival proteins act to sequester these “activator” BH3-only proteins [8–11]. A third model, known as the “embedded together” model proposes that the pro-survival proteins are dominant-negative regulators of Bax and Bak and bind both the BH3-only proteins as well as Bax and Bak in the mitochondrial membrane, thereby inhibiting apoptosis [12, 13]. Very recently, a fourth “unified” model encompassing the major aspects of the above-mentioned models has been proposed [14]. Significantly, this model takes into account the differential efficiencies by which each model of cell death activation occurs. Regardless of the mechanism by which Bax/Bak activation occurs, the key point of no return in the apoptotic cascade is the permeabilization of the outer mitochondrial membrane (MOMP). MOMP occurs when Bax/Bak oligomerize on the outer mitochondrial membrane, forming pore-like structures through which apoptogenic factors such as cytochrome c are released into the cytosol from the space between the inner and outer mitochondrial membranes. Cytochrome c then binds to an adaptor protein known as Apaf-1, which leads to the formation of an oligomeric assembly known as the “apoptosome”. Formation of the apoptosome leads to the activation of the cellular demolitionists, the caspases and in turn this spells the inevitable death of the cell. It should be noted that alternative pathways independent of the Apaf-1-cytochrome c axis have been reported [15]. Given the importance of apoptosis in the maintenance of tissue homeostasis and the removal of rogue cells, it comes as no surprise that dysfunctional apoptosis signaling leads to disease manifestation. Deficient apoptosis leads to an accumulation of unwanted cells and the inability to respond normally to apoptotic stimuli. Diseases such as cancer and autoimmune disorders are characterized by this. In contrast, excessive apoptosis results in diseases in which cells are removed inappropriately. Examples of these include neurodegenerative disorders. The therapeutic targeting of the Bcl-2-regulated apoptotic pathway has therefore been an attractive avenue for the treatment of diseases characterized by such defects. As one would expect, a detailed molecular understanding of how these proteins interact functionally and structurally is essential to the development of safe and effective drugs. Since the initial discovery of the bcl-2 gene [16] and the subsequent characterization of the function of its gene product, Bcl-2 [17], more than 20 years ago, our understanding of how these proteins work together to regulate apoptosis has expanded enormously. In addition, a large body of structural studies has been undertaken that have provided us with a “family album” of the various components that make up the Bcl-2-regulated apoptotic pathway. Here, we will review the structural information available to us in this area, as well as discuss where structural information is still lacking.

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