Apoptosome

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3D structure of the human apoptosome-CARD complex. blue: apoptosome platform; magenta: CARD disk Human apoptosome-CARD complex.jpg
3D structure of the human apoptosome-CARD complex. blue: apoptosome platform; magenta: CARD disk

The apoptosome is a large quaternary protein structure formed in the process of apoptosis. Its formation is triggered by the release of cytochrome c from the mitochondria in response to an internal (intrinsic) or external (extrinsic) cell death stimulus. Stimuli can vary from DNA damage and viral infection to developmental cues such as those leading to the degradation of a tadpole's tail.

Contents

In mammalian cells, once cytochrome c is released, it binds to the cytosolic protein Apaf-1 to facilitate the formation of an apoptosome. An early biochemical study suggests a two-to-one ratio of cytochrome c to apaf-1 for apoptosome formation. However, recent structural studies suggest the cytochrome c to apaf-1 ratio is one-to-one. It has also been shown that the nucleotide dATP as third component binds to apaf-1, however its exact role is still debated. The mammalian apoptosome had never been crystallized, but a human APAF-1/cytochrome-c apoptosome has been imaged at lower (2 nm) resolution by cryogenic transmission electron microscopy in 2002, [2] revealing a heptameric wheel-like particle with 7-fold symmetry. Recently, a medium resolution (9.5 Ångström) structure of human apoptosome was also solved by cryo-electron microscopy, which allows unambiguous inference for positions of all the APAF-1 domains (CARD, NBARC and WD40) and cytochrome c. There is also now a crystal structure of the monomeric, inactive Apaf-1 subunit (PDB 3SFZ). [1] [3]

Once formed, the apoptosome can then recruit and activate the inactive pro-caspase-9. Once activated, this initiator caspase can then activate effector caspases and trigger a cascade of events leading to apoptosis.

History

The term Apoptosome was first introduced in Yoshihide Tsujimoto's 1998 paper "Role of Bcl-2 family proteins in apoptosis: apoptosomes or mitochondria?". [4] However, the Apoptosome was known before this time as a ternary complex. This complex involved caspase-9 and Bcl-XL which each bound a specific Apaf-1 domain. The formation of this complex was then believed to play a regulatory role in mammalian cell death. [5] In December of the same year, a further article was released in The Journal of Biological Chemistry stating that Apaf-1 is the regulator of apoptosis, through activation of procaspase-9. [6]

The criteria for an apoptosome were laid out in 1999. Firstly, it must be a large complex (greater than 1.3 million daltons). Secondly its formation requires the hydrolysis of a high energy bond of ATP or dATP. And lastly it must activate procaspase-9 in its functional form. The formation of this complex is the point of no return, and apoptosis will occur. The stable APAF-1 and cytochrome multimeric complex fit this description, and is now called the apoptosome. [7]

The apoptosome was thought to be a multimeric complex for two reasons. Firstly, to bring multiple procaspase-9 molecules close together for cleavage. And secondly, to raise the threshold for apoptosis, therefore nonspecific leakage of cytochrome c would not result in apoptosis. [7]

Once the apoptosome was established as the procaspase-9 activator, mutations within this pathway became an important research area. Some examples include human leukemia cells, ovarian cancer and viral infections. [8] [9] [10] Current research areas for this pathway will be discussed in further detail. There are hidden routes for cell death as well, which are independent of APAF-1 and therefore the apoptosome. These routes are also independent of caspase-3 and 9. These hidden pathways for apoptosis are slower, but may prove useful with further research. [11]

Pseudo atomic structure of the human apoptosome (Yuan et al. 2010, Structure of an apoptosome-procaspase-9 CARD complex Apop atomic model.jpg
Pseudo atomic structure of the human apoptosome

(Yuan et al. 2010, Structure of an apoptosome-procaspase-9 CARD complex

Structure

The apoptosome is a multimolecular holoenzyme complex assembled around the adaptor protein Apaf1 (apoptotic protease activating factor 1) upon mitochondria-mediated apoptosis which must be stimulated by some type of stress signal. The formation of the apoptosome requires the presence of ATP/dATP and cytochrome c in the cytosol. [12] A stress stimulus can trigger the release of cytochrome c into the cytoplasm which will then bind to the C-terminus of Apaf-1 within a region containing multiple WD-40 repeats. [2] The oligomerization of Apaf-1 appears to be accompanied by synchronized recruitment of procaspase-9 to the CARD motif at the Apaf-1 N-terminus. [2] The apoptosome triggers the activation of caspases in the intrinsic pathway of apoptosis. [12]

The wheel-shaped heptameric complex with sevenfold symmetry structure of the apoptosome was first revealed at 27 Å resolution by electron cryomicroscopy techniques and has a calculated mass of about 1 MDa (Acehan et al. 2002). [2] This wheel-like particle has seven spokes and a central hub. The distal region of the spoke has a pronounced Y shape. [12] The hub domain is connected to the Y domain by a bent arm. Each Y domain comprises two lobes (a large one and a small one) between which cytochrome c binding sites. [12] Because the resolution of the apoptosome structure was relatively low, two controversial models for apoptosome assembly were proposed. One model suggests NOD domains form the central hub and the CARD domains form a freer ring at the top of the NOD region. [2] Another model proposes that Apaf-1 is organized in an extended fashion such that both the N-terminal CARD and the nucleotide binding region form the central hub of the apoptosome, whereas the 13 WD-40 repeats constitute the two lobes. [12] The large lobe is formed by seven repeats and the small lobe is formed by six repeats. [12] Each caspase- 9 molecule binds a CARD domain at the central hub, forming a dome-shaped structure. [12] This controversy has been resolved by a recent high resolution structure of the human apoptosome-procaspase-9 CARD complex. [1] This structure clearly demonstrated that only the NOD regions form the central hub of the apoptosome (see pictures), while CARD is flexibly linked to the platform of apoptosome and becomes disordered in the ground state apoptosome. [1] Once apoptosome binds to procaspase-9, the Apaf-1 CARDs and procaspase-9 CARDs form a flexible disk-like structure sitting above the platform. [1] The number of WD-40 repeats has also been proved to be 15 instead of 13, [1] and it is composed of a 7-bladed beta-propeller and an 8-bladed beta-propeller. [1]

Rendering of apoptosome showing clear central-hub Apoptosome surface rendering.png
Rendering of apoptosome showing clear central-hub

Evidence from Wang and colleagues indicates that the stoichiometric ratio of procaspase-9 to Apaf-1 within the complex is approximately 1:1 . [7] This was further proved by quantitative mass spectrometry analysis. [13] The stoichiometry of cytochrome c to Apaf-1 within the complex is proved to be 1:1. [1] There are some debates about whether stable incorporation of cytochrome c into the apoptosome is required following oligomerization, but recent structural data favor the idea that cytochrome c stabilizes the oligomeric human apoptosome. [1] However, cytochrome c may be not required for the assembly of apoptosome in non-mammalian species, such as worms and fruit flies. [14] In addition, several other molecules, most notably caspase-3, have been reported to co-purify with the apoptosome [7] and caspase-3 has been proved to be able to bind the apoptosome-procaspase-9 complex. [13]

Apaf-1 forms the backbone of the apoptosome. It has three distinct regions: the N-terminal caspase-recruitment domain (CARD, residues 1–90), a central nucleotide-binding and oligomerization region (NB-ARC/NOD, 128–586) and a C-terminal WD40 region (613–1248) making up a protein about 140 KDa. [2]

  • The CARD domain of Apaf-1 interacts with procaspase-9 and involved with recruitment within the apoptosome. [2]
  • The NB-ARC/NOD region exhibits significant sequence similarity to the C. elegans Ced-4 protein. [2]
  • The C-terminal WD40 region of Apaf1 contains 15 WD-40 repeats structured into two b-propeller-shaped domains. [1] WD-40 repeats are sequences around 40 amino acids long which end in Trp-Asp and are typically involved in protein–protein interaction. [2]

A short linker and nucleotide binding a/b domains (NBD) that contain conserved Walker boxes A (p-loop 155-161) and B (239-243) follow the N-terminal CARD domain. [2] The Walker boxes A/B are critical for dATP/ATP and Mg2+ binding. [1] [2] Following the NBD is a small helical domain (HD1), a second linker and a conserved winged helix domain (WHD). [2] The NOD region comprises NBD, HD1 and WHD, creating an ATPase domain that is part of the AAA+ family of ATPases. [1] [2] There is a super helical domain (HD2) present in the junction between the NOD and the WD-40 repeats. [1] The WD40 repeats are in groups of eight and seven with linkers connecting them. [1]

Human, fruit fly, & nematode apoptosomes 177-Apoptosomes apoptosomes.png
Human, fruit fly, & nematode apoptosomes

Apoptosomes in other organisms

The above descriptions are for the human apoptosome. Apoptosome complex structures from other organisms have many similarities, but are of quite different sizes and numbers of subunits, as shown in the figure. The fruit-fly system, called Dark, has a ring of 8 subunits (PDB 4V4L). [14] The nematode apoptosome, called CED-4, is octameric but much smaller (PDB 3LQQ), and it does not include the regions that would bind cytochrome C. [15]

Mechanism of Action

Initiation

The initiation of apoptosome action corresponds with the first steps in the programmed cell death (PCD) pathway. In animals, apoptosis can be catalyzed in one of two ways; the extrinsic pathway involves binding of extracellular ligands to transmembrane receptors, while the intrinsic pathway take place in the mitochondria. [16] This intrinsic pathway involves the release of cytochrome C from the mitochondria and subsequent binding to the cytosolic protein Apaf-1. [16] [17] Cytochrome c release is thus necessary for the initiation of apoptosome action; this release is regulated in a number of ways, most importantly by detection of calcium ion levels. [16]

Cytochrome c Release

Cytochrome c release is proposed to take place in one of two ways. Firstly, the permeability transition pore (PTP) when the mitochondria receives a death inducing signal, and releases intermembrane space proteins (12). The PTP is composed of the voltage-dependent anion channel (VDAC), the inner membrane protein adenine nucleotide translocator (AdNT) and the matrix protein cyclophilin D (CyD) (12). This pore causes the mitochondria to swell and the outer mitochondrial membrane to rupture (Diamond & McCabe, 2007). With this change in permeability, proteins such as cytochrome c are released into the cytosol (12). This change likely causes the mitochondrial permeability transition (MPT), where the mitochondrial transmembrane potential collapses, and ATP production ceases (12). The inhibition of this method by the pharmaceutical agent cyclosporine A (CsA), lead to the discovery of the second pathway (13). The second method of cytochrome c release is independent of the PTP and involves only the VDAC. Members of the Bcl-2 family of pro-apoptotic proteins can induce the opening of the VDAC (12). This will cause the same release of intermembrane space proteins, including cytochrome c, and the subsequent MPT to occur (12).

Apaf-1

a. Absence of Cytochrome c

In the absence of cytochrome c, Apaf-1 exists in its monomeric form; it is thought that the WD-40 domain remain folded back onto the protein, keeping Apaf-1 in an auto inhibited state. [16] In addition, several areas are so tightly bound that the protein is unable to bind to anything else. [16] It has been determined through mass spectrometry that in the autoinhibited, or "locked" state, ADP is bound to the ATPase domain of Apaf-1. [16] In this state, this protein is singular, and incapable of activating any caspases.

b. Presence of Cytochrome c

Cytochrome c binds to the WD-40 domain of Apaf-1. [16] This allows for the "lock" to be released, meaning this domain is no longer autoinhibited. [1] [16] However, the CARD and NB-ARC domains remain in autoinhibited state. [16] The CARD domain will only be released from this lock when Apaf-1 is bound to (d) ATP/ATP; when ATP binds, the CARD domain will then be allowed to bind to Caspase-9. [1] [16] When ADP is in the ATPase domain, oligomerization is inhibited. Thus, the binding of ATP also allows for the oligomerization of Apaf-1 into the heptagonal structure necessary for downstream caspase activation. [1] [7] [16] Mutations in the ATPase domain render the protein inactive; however, the method of controlling this ADP-ATP exchange is unclear. [1] [7] [16] Oligomerization can thus only occur in the presence of 7 cytochrome c molecules, 7 Apaf-1 proteins and sufficient (d) ATP/ATP . [7] The ATPase domain belongs to the AAA+ family of ATPases; this family is known for its ability to link to other ATPase domains and form hexa- or heptamers. [16] The apoptosome is then considered active when there are seven Apaf-1 molecules arranged in a wheel structure, oriented such that the NB-ARC domains rest in the centre. [1] [16]

Active Apoptosome Action

This functional apoptosome then can provide a platform activation of caspase 9. [1] [16] Caspase 9 exists as a zymogen in the cytosol and is thought to be found at 20 nM in cells. [16] Though it is known that the zymogen does not need to be cleaved in order to become active, [16] the activity of procaspase-9 may increase significantly once cleaved. [13] The first hypothesis is that the apoptosome provides a location for the dimerization of two caspase 9 molecules before cleavage; this hypothesis was favoured by Reidl & Salvasen in 2007. The second is that cleavage takes place while caspase 9 is still in its monomeric form. [13] [16] In each case, caspase 9 activation leads to the activation of a full caspase cascade and subsequent cell death. It has been suggested that the evolutionary reason for the multimeric protein complex activating the caspase cascade is to ensure trace amounts of cytochrome c do not accidentally cause apoptosis. [7]

Research Areas

What happens when mutations occur?

While apoptosis is required for natural body function, mutations of the apoptosome pathway cause catastrophic effects and changes in the body. Mutations of the cell pathway can either promote cell death or disallow cell death creating a huge amount of disease in the body. Mutated apoptosis pathways causing disease are plentiful and have a wide range from cancer, due to lack of apoptosome activity, Alzheimer's disease due to too much apoptosome activity, and many other neurodegenerative diseases such as Parkinson's disease and Huntington's disease. [18] Neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's are all age-related diseases and involve increased apoptosis where cells die that are still able to function or that contribute to support function of tissue. Apaf-1-ALT is an Apaf-1 mutant found in prostate cancer, which does not have residues 339-1248. Recent structural studies of apoptosome prove that Apaf-1-ALT cannot form apoptosome as it misses key structural components for assembly. [1]

Repression of Apoptosis causing cancer

Genetic and biochemical abnormalities within a cell normally trigger programmed cell death to rid the body of irregular cell function and development; however, cancer cells have acquired mutations that allow them to repress apoptosis and survive. Chemotherapies like ionizing radiation have been developed to activate these repressed PCD pathways by hyper-stimulation to promote normal PCD. [19]

P53 mutations in Apoptosis

P53 functions as a tumor suppressor that is involved in preventing cancer and occurs naturally in apoptotic pathways. P53 causes cells to enter apoptosis and disrupt further cell division therefore preventing that cell from becoming cancerous (16). In the majority of cancers it is the p53 pathway that has become mutated resulting in lack of ability to terminate dysfunctional cells. P53 function can also be responsible for a limited life span where mutations of the p53 gene causes expression of dominant-negative forms producing long lived animals. For example in an experiment using C. elegans, the increased life span of p53 mutants was found to depend on increased autophagy. [19] In another experiment using Drosophila the p53 mutation had both positive and negative effects on the adult life span, which concluded a link between sexual differentiation, PCD and aging. [19] Determining how p53 are affecting life span will be an important area for future research.

Targeting the Apoptosome for Cancer therapy

The inhibition of apoptosis is one of the key features of cancer so finding ways to manipulate and overcome this inhibition to form the apoptosome and activate caspases are important in the development of new cancer treatments. [20] The ability to directly cause apoptosome activation is valuable in cancer therapies because the infected cancerous genes are unable to be destroyed causing a continuation of the cancer to form. By activating the apoptosome by an outside stimulus apoptosis can occur and get rid of the mutated cells. Numerous approaches to achieve this are currently being pursued including recombinant biomolecules, antisense strategies, gene therapy and classic organic combinatorial chemistry to target specific apoptotic regulators in the approach to correct excessive or deficient cell death in human diseases. [18]

In general the up regulation of anti-apoptotic proteins leads to the prevention of apoptosis which can be solved by inhibitors and the down regulation of anti-apoptotic proteins leads to the induction of apoptosis which is reversed by activators that are able to bind and modify their activity. An important target molecule in apoptosis based therapies is Bcl-2 for drug design. [18] Bcl-2 was the first oncogene found to cause cancer-inhibiting apoptosis. It is over expressed in tumors and is resistant to chemotherapy. [18] Scientists have found that binding depressors to Bcl-2 anti-apoptotic proteins inhibits them and leaves direct activators free to interact with Bax and Bak. [18]

Another targeted molecule for cancer therapy involves the caspase family and their regulators. The inhibition of caspase activity blocks cell death in human disease including neurodegenerative disorders, stroke, heart attack and liver injury. Therefore, caspase inhibitors are a promising pharmacological tool providing treatments for stroke and other human diseases. There are several caspase inhibitors that are currently in the preclinical stage that have shown promising evidence of reversing effects of some neurodegenerative diseases. In a recent study researchers developed a reversible caspase-3 inhibitor called M-826 and tested it in a mouse model where it blocked brain tissue damage. Furthermore, it was tested on a mouse with Huntington's disease and the inhibitor prevented striated neuron death revealing promising effects for further study of this caspase inhibitor. [18]

Apoptosome complex has revealed new potential targets for molecular therapy

The Apaf1/caspase-9 apoptosome formation is a crucial event in the apoptotic cascade. The identification of new potential drugs that prevent or stabilize the formation of active apoptosome complex is the ideal strategy for the treatment of disease characterized by excessive or insufficient apoptosis. [18] Recently taurine has been found to prevent ischemia-induced apoptosis in cardiomyocytes through its ability to inhibit Apaf1/caspase-9 apoptosome formation without preventing mitochondrial dysfunction. The possible mechanism by which taurine inhibits the apoptosome formation was identified as being capable of reducing the expression of caspase-9, a fundamental component of apoptosome. However, there are studies that show Apaf1 and caspase-9 have independent roles other than the apoptosome so altering their levels could alter cell function as well. So despite encouraging experimental data several problems remain unsolved and limit the use of experimental drugs in clinical practice. [18]

The discovery of apoptosome inhibitors will provide a new therapeutical tool for the treatment of apoptosis mediated disease. Of particular importance are those new compounds able to inhibit apoptosome stability and activity, by acting on intracellular protein–protein interactions without altering the transcriptional levels of the apoptosome components. [18] Recent structural studies of apoptosome may provide valuable tools for designing apoptosome-based therapies. [1] [13]

See also

Related Research Articles

<span class="mw-page-title-main">Apoptosis</span> Programmed cell death in multicellular organisms

Apoptosis is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemical events lead to characteristic cell changes (morphology) and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, DNA fragmentation, and mRNA decay. The average adult human loses 50 to 70 billion cells each day due to apoptosis. For the average human child between 8 and 14 years old, each day the approximate loss is 20 to 30 billion cells.

<span class="mw-page-title-main">Hsp70</span> Family of heat shock proteins

The 70 kilodalton heat shock proteins are a family of conserved ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms. Intracellularly localized Hsp70s are an important part of the cell's machinery for protein folding, performing chaperoning functions, and helping to protect cells from the adverse effects of physiological stresses. Additionally, membrane-bound Hsp70s have been identified as a potential target for cancer therapies and their extracellularly localized counterparts have been identified as having both membrane-bound and membrane-free structures.

<span class="mw-page-title-main">Death effector domain</span> InterPro Domain

The death-effector domain (DED) is a protein interaction domain found only in eukaryotes that regulates a variety of cellular signalling pathways. The DED domain is found in inactive procaspases and proteins that regulate caspase activation in the apoptosis cascade such as FAS-associating death domain-containing protein (FADD). FADD recruits procaspase 8 and procaspase 10 into a death induced signaling complex (DISC). This recruitment is mediated by a homotypic interaction between the procaspase DED and a second DED that is death effector domain in an adaptor protein that is directly associated with activated TNF receptors. Complex formation allows proteolytic activation of procaspase into the active caspase form which results in the initiation of apoptosis. Structurally the DED domain are a subclass of protein motif known as the death fold and contains 6 alpha helices, that closely resemble the structure of the Death domain (DD).

<span class="mw-page-title-main">Apoptosis regulator BAX</span> Mammalian protein found in Homo sapiens

Apoptosis regulator BAX, also known as bcl-2-like protein 4, is a protein that in humans is encoded by the BAX gene. BAX is a member of the Bcl-2 gene family. BCL2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. This protein forms a heterodimer with BCL2, and functions as an apoptotic activator. This protein is reported to interact with, and increase the opening of, the mitochondrial voltage-dependent anion channel (VDAC), which leads to the loss in membrane potential and the release of cytochrome c. The expression of this gene is regulated by the tumor suppressor P53 and has been shown to be involved in P53-mediated apoptosis.

<span class="mw-page-title-main">BH3 interacting-domain death agonist</span> Protein-coding gene in the species Homo sapiens

The BH3 interacting-domain death agonist, or BID, gene is a pro-apoptotic member of the Bcl-2 protein family. Bcl-2 family members share one or more of the four characteristic domains of homology entitled the Bcl-2 homology (BH) domains, and can form hetero- or homodimers. Bcl-2 proteins act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities.

p53 upregulated modulator of apoptosis Protein-coding gene in the species Homo sapiens

The p53 upregulated modulator of apoptosis (PUMA) also known as Bcl-2-binding component 3 (BBC3), is a pro-apoptotic protein, member of the Bcl-2 protein family. In humans, the Bcl-2-binding component 3 protein is encoded by the BBC3 gene. The expression of PUMA is regulated by the tumor suppressor p53. PUMA is involved in p53-dependent and -independent apoptosis induced by a variety of signals, and is regulated by transcription factors, not by post-translational modifications. After activation, PUMA interacts with antiapoptotic Bcl-2 family members, thus freeing Bax and/or Bak which are then able to signal apoptosis to the mitochondria. Following mitochondrial dysfunction, the caspase cascade is activated ultimately leading to cell death.

<span class="mw-page-title-main">Bcl-2 homologous antagonist killer</span> Protein-coding gene in the species Homo sapiens

Bcl-2 homologous antagonist/killer is a protein that in humans is encoded by the BAK1 gene on chromosome 6. The protein encoded by this gene belongs to the BCL2 protein family. BCL2 family members form oligomers or heterodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. This protein localizes to mitochondria, and functions to induce apoptosis. It interacts with and accelerates the opening of the mitochondrial voltage-dependent anion channel, which leads to a loss in membrane potential and the release of cytochrome c. This protein also interacts with the tumor suppressor P53 after exposure to cell stress.

<span class="mw-page-title-main">Bcl-2-associated death promoter</span> Mammalian protein found in Homo sapiens

The BCL2 associated agonist of cell death (BAD) protein is a pro-apoptotic member of the Bcl-2 gene family which is involved in initiating apoptosis. BAD is a member of the BH3-only family, a subfamily of the Bcl-2 family. It does not contain a C-terminal transmembrane domain for outer mitochondrial membrane and nuclear envelope targeting, unlike most other members of the Bcl-2 family. After activation, it is able to form a heterodimer with anti-apoptotic proteins and prevent them from stopping apoptosis.

<span class="mw-page-title-main">Caspase-9</span> Protein-coding gene in the species Homo sapiens

Caspase-9 is an enzyme that in humans is encoded by the CASP9 gene. It is an initiator caspase, critical to the apoptotic pathway found in many tissues. Caspase-9 homologs have been identified in all mammals for which they are known to exist, such as Mus musculus and Pan troglodytes.

<span class="mw-page-title-main">Bcl-xL</span> Transmembrane molecule in the mitochondria

B-cell lymphoma-extra large (Bcl-xL), encoded by the BCL2-like 1 gene, is a transmembrane molecule in the mitochondria. It is a member of the Bcl-2 family of proteins, and acts as an anti-apoptotic protein by preventing the release of mitochondrial contents such as cytochrome c, which leads to caspase activation and ultimately, programmed cell death.

Inhibitors of apoptosis are a group of proteins that mainly act on the intrinsic pathway that block programmed cell death, which can frequently lead to cancer or other effects for the cell if mutated or improperly regulated. Many of these inhibitors act to block caspases, a family of cysteine proteases that play an integral role in apoptosis. Some of these inhibitors include the Bcl-2 family, viral inhibitor crmA, and IAP's.

Xiaodong Wang is a Chinese-American biochemist best known for his work with apoptosis, one of the ways through which cells kill themselves.

<span class="mw-page-title-main">Diablo homolog</span> Protein-coding gene in the species Homo sapiens

Diablo homolog (DIABLO) is a mitochondrial protein that in humans is encoded by the DIABLO gene on chromosome 12. DIABLO is also referred to as second mitochondria-derived activator of caspases or SMAC. This protein binds inhibitor of apoptosis proteins (IAPs), thus freeing caspases to activate apoptosis. Due to its proapoptotic function, SMAC is implicated in a broad spectrum of tumors, and small molecule SMAC mimetics have been developed to enhance current cancer treatments.

<span class="mw-page-title-main">APAF1</span> Mammalian protein found in Homo sapiens

Apoptotic protease activating factor 1, also known as APAF1, is a human homolog of C. elegans CED-4 gene.

<span class="mw-page-title-main">BCL2L10</span> Protein-coding gene in the species Homo sapiens

Bcl-2-like protein 10 is a protein that in humans is encoded by the BCL2L10 gene.

Cell death abnormality gene 9 (CED-9), also known as apoptosis regulator CED-9, is a gene found in Caenorhabditis elegans that inhibits/represses programmed cell death (apoptosis). The gene was discovered while searching for mutations in the apoptotic pathway after the discovery of the apoptosis promoting genes CED-3 and CED-4. The gene gives rise to the apoptosis regulator CED-9 protein found as an Integral membrane protein in the mitochondrial membrane. The protein is homologous to the human apoptotic regulator Bcl-2 as well as all other proteins in the Bcl-2 protein family. CED-9 is involved in the inhibition of CED-4 which is the activator of the CED-3 caspase. Because of the pathway homology with humans as well as the specific protein homology, CED-9 has been used to represent the human cell apoptosis interactions of Bcl-2 in research.

<span class="mw-page-title-main">Bcl-2 family</span>

The Bcl-2 family consists of a number of evolutionarily-conserved proteins that share Bcl-2 homology (BH) domains. The Bcl-2 family is most notable for their regulation of apoptosis, a form of programmed cell death, at the mitochondrion. The Bcl-2 family proteins consists of members that either promote or inhibit apoptosis, and control apoptosis by governing mitochondrial outer membrane permeabilization (MOMP), which is a key step in the intrinsic pathway of apoptosis. A total of 25 genes in the Bcl-2 family were identified by 2008.

Anticancer genes exhibit a preferential ability to kill cancer cells while leaving healthy cells unharmed. This phenomenon is achieved through various processes such as apoptosis following a mitotic catastrophe, necrosis, and autophagy. In the late 1990s, extensive research in the field of cancer cells led to the discovery of anticancer genes. Mutations in these genes due to base substitutions leading to insertions, deletions, or alterations in missense amino acids can cause frameshifts, thereby altering the protein. A change in gene copy number or rearrangements is also essential for deregulating these genes. The loss or alteration of these anticancer genes due to mutations or rearrangements may lead to the development of cancer.

<span class="mw-page-title-main">Necroptosis</span> Programmed form of necrosis, or inflammatory cell death

Necroptosis is a programmed form of necrosis, or inflammatory cell death. Conventionally, necrosis is associated with unprogrammed cell death resulting from cellular damage or infiltration by pathogens, in contrast to orderly, programmed cell death via apoptosis. The discovery of necroptosis showed that cells can execute necrosis in a programmed fashion and that apoptosis is not always the preferred form of cell death. Furthermore, the immunogenic nature of necroptosis favors its participation in certain circumstances, such as aiding in defence against pathogens by the immune system. Necroptosis is well defined as a viral defense mechanism, allowing the cell to undergo "cellular suicide" in a caspase-independent fashion in the presence of viral caspase inhibitors to restrict virus replication. In addition to being a response to disease, necroptosis has also been characterized as a component of inflammatory diseases such as Crohn's disease, pancreatitis, and myocardial infarction.

<span class="mw-page-title-main">Death regulator Nedd2-like caspase</span> Type of cysteine protease

Death regulator Nedd2-like caspase was firstly identified and characterised in Drosophila in 1999 as a cysteine protease containing an amino-terminal caspase recruitment domain. At first, it was thought of as an effector caspase involved in apoptosis, but subsequent findings have proved that it is, in fact, an initiator caspase with a crucial role in said type of programmed cell death.

References

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  5. ↑ Pan, G.; O'Rourke, K.; Dixit, V. M. (1998). "Caspase-9, Bcl-XL, and Apaf-1 Form a Ternary Complex". Journal of Biological Chemistry. 273 (10): 5841–845. doi: 10.1074/jbc.273.10.5841 . PMID   9488720.
  6. ↑ Hu, Ding; Spencer; Nunez (1998). "WD-40 Repeat Region Regulates Apaf-1 Self-association and Procaspase-9 Activation". Journal of Biological Chemistry. 273 (50): 33489–3494. doi: 10.1074/jbc.273.50.33489 . PMID   9837928.
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  8. ↑ Jia L, Srinivasula SM, Liu FT, Newland AC, Fernandes-Alnemri T, Alnemri ES, Kelsey SM (July 2001). "Apaf-1 protein deficiency confers resistance to cytochrome c-dependent apoptosis in human leukemic cells". Blood. 98 (2): 414–21. doi: 10.1182/blood.v98.2.414 . PMID   11435311.
  9. ↑ Bitzer M, Armeanu S, Prinz F, Ungerechts G, Wybranietz W, Spiegel M, Bernlöhr C, Cecconi F, Gregor M, Neubert WJ, Schulze-Osthoff K, Lauer UM (August 2002). "Caspase-8 and Apaf-1-independent caspase-9 activation in Sendai virus-infected cells". The Journal of Biological Chemistry. 277 (33): 29817–9824. doi: 10.1074/jbc.M111898200 . PMID   12021264.
  10. ↑ Wolf BB, Schuler M, Li W, Eggers-Sedlet B, Lee W, Tailor P, Fitzgerald P, Mills GB, Green DR (September 2001). "Defective cytochrome c-dependent caspase activation in ovarian cancer cell lines due to diminished or absent apoptotic protease activating factor-1 activity". The Journal of Biological Chemistry. 276 (36): 34244–51. doi: 10.1074/jbc.M011778200 . PMID   11429402.
  11. ↑ Belmokhtar CA, Hillion J, Dudognon C, Fiorentino S, Flexor M, Lanotte M, Ségal-Bendirdjian E (August 2003). "Apoptosome-independent pathway for apoptosis. Biochemical analysis of APAF-1 defects and biological outcomes". The Journal of Biological Chemistry. 278 (32): 29571–80. doi: 10.1074/jbc.M302924200 . PMID   12773531.
  12. 1 2 3 4 5 6 7 Ceconi F, Ferraro E, Fuoco C, Strappazzon F (2010). Apoptosome Structure and Regulation. pp. 27–39. doi:10.1007/978-90-481-3415-1_2. ISBN   978-90-481-3414-4.{{cite book}}: |journal= ignored (help)
  13. 1 2 3 4 5 Yuan S, Yu X, Asara JM, Heuser JE, Ludtke SJ and Akey CW. "The Holo-Apoptosome: Activation of Procaspase-9 and Interactions with Caspase-3." Structure. 2011 August;19(8):1084-1096.
  14. 1 2 Yuan S, Yu X, Topf M, Dorstyn L, Kumar S, Ludtke SJ and Akey CW. "Structure of the Drosophila Apoptosome at 6.9 Å Resolution." Structure. 2011 January;19(1):128-140.
  15. ↑ S. Qi; Y. Pang; Q. Hu; Q. Liu; H. Li; Y. Zhou; T. He; Q. Liang; Y. Liu; X. Yuan; G. Luo; H. Li; J. Wang; N. Yan; Y. Shi (2010). "Crystal structure of the Caenorhabditis elegans apoptosome reveals an octameric assembly of CED-4". Cell. 141 (3): 446–457. doi: 10.1016/j.cell.2010.03.017 . PMID   20434985.
  16. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Riedl SJ, Salvesen GS (May 2007). "The apoptosome: signalling platform of cell death". Nature Reviews. Molecular Cell Biology. 8 (5): 405–13. doi:10.1038/nrm2153. PMID   17377525. S2CID   3064077.
  17. ↑ Diamond & McCabe (2007). The mitochondrion and plant programmed cell death. In: Logan DC (Ed.), Plant mitochondria. Annual Plant Review 2007, 31:308–334.
  18. 1 2 3 4 5 6 7 8 9 D'Amelio M, Tino E, Cecconi F (April 2008). "The apoptosome: emerging insights and new potential targets for drug design". Pharmaceutical Research. 25 (4): 740–51. doi:10.1007/s11095-007-9396-z. PMC   2279152 . PMID   17674158.
  19. 1 2 3 Shen J, Tower J (December 2009). "Programmed cell death and apoptosis in aging and life span regulation". Discovery Medicine. 8 (43): 223–6. PMID   20040274.
  20. ↑ Fischer U, Janssen K, Schulze-Osthoff K (2007). "Cutting-edge apoptosis-based therapeutics: a panacea for cancer?". BioDrugs. 21 (5): 273–97. doi:10.2165/00063030-200721050-00001. PMID   17896835. S2CID   36028755.
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