Introduction
Proteolytic enzymes, includes the cell's
degrading machine preoteasome, caplains, and integral membrane
proteases (such as γ-secretase and rhomboid); participate in
several intracellular signaling processes. Caspases are one of the protein
families in the body which are the only constitute a formal multistep pathway
able to transmit intracellular signals by proteolysis and the name of this
family is an abbreviation of cysteine-dependent
aspartate-directed proteases, with a cysteine in their active site, as catalytic
nucleophile, that cleave on the C-terminal side of aspartate residues.
The first discovery by Robert Horvitz and
his colleagues who found that the ced-3 gene was required for the cell to die
that take place during the development of the nematode, which called c.elegans. They found in 1993 that the protein, which encoded
by ced-3 gene, was a cystiene protease with similar properties to the mammalian
interleukiene-1-beta converting enzyme (ICE, or IL-1β), in which at this
time is the only known caspase, named caspase-1. Other caspases have
been discovered and numbered in the order in which they have been identified.
The human body contains cells with
different life expectancies. Some (white blood cells, skin) are programmed to
rapidly die and be replaced. Others (nerve cells) are programmed to survive the
lifetime of the individual and are seldom replaced. There is a central role of
enzymatic pathways play in the life and death of cells. When death pathways
slowing down in cells that are normally programmed to die, cancer results.
Conversely, when death pathways become overactive in cells that are programmed
to survive, a degenerative disease occurs. So there is must be a balance
between cell survival and programmed cell death (apoptosis) and that balance is
managed by a family of proteases called caspases.
Some of them are essential for apoptosis
(which mean the falling of leaves in Greek), others are required in the immune
system for the maturation of cytokines, and also they have a role in necrosis
and inflammation.
Basic properties
Nowadays there are many caspases have been
discovered in many species, currently there are 11 members from human, 4 from
c.elegans and 7 from Drosophila with obvious conservation in evolution.
¨
The General structure
Caspases are regulated at post-translational
level, ensuring that they can be activated rapidly. They are
first synthesized as inactive single chain polypeptide precursor, called zymogens
or pro-caspases, in each caspase zymogen an N-terminal peptide
(prodomain) is followed by sequences comprising first a large and then a small subunit
[Fig. 1 and 2 ]. Pro-caspases have an intrinsic proteolytic activity. This
unusual property is essential for triggering the proteolytic pathways that lead
to complete their functions as in apoptosis.
Initiator caspases have a longer
N-terminal prodomain (>90 amino acids) than the effector caspases, which their prodomain is very
small (20-30 residues). The prodomain of the initiator caspases contain
domains such as CARD or DED, which enables caspases to interact
with other molecules that regulate their activation by responding to the
stimuli that cause the clustering of the initiator caspases. This allowing them
to be auto-activated via auto-catalytic intra-chain cleavage and then they can
proceed to activate the effector caspases by intra-chain cleavage.
¨ The Specificity
Caspases recognizing at least 4 contiguous amino
acids, named P4-P3-P2-P1, and cleaving after the C-terminal residue (P1), it is
usually an Asp or D. Although the P1
residue was thought to be exclusively Asp, recent studies indicate that some
caspases can also cleave after Glu (Hawkins et
al., 2000; Srinivasula et al., 2001).
Interestingly, the preferred P3 position is
invariantly Glu or E for all mammalian caspases examined (Thornberry et
al., 1997). Thus the preferred specificity can be described as X-Glu-X-Asp. All
caspases contain a conserved QACXG (where X is R, Q or G) pentapeptide active-site
motif [Table 1].
Table 1, shows the different human caspases with their different
names and with their common and different active sites.
Figure 2, Proenzyme
organization of the caspases: Caspases are synthesized as
proenzymes, with an N-terminal peptide or prodomain (PRO), and two subunits
sometimes separated by a linker peptide (black box). Based on caspase-1 and
caspase-3, active enzymes are heterotetramers of two large (~20
KDa) & and two small (~ 10 KDa)
subunits. The proenzymes are cleaved at specific Asp residues (Dn, where
n is the position in the protein). The numbers at the right-hand side
are the numbers of amino acids in the protein. a Exact cleavage site
not known. b the cleavage site of caspase-3 may be at Asp-9 or
Asp-28. ccaspase-9 is cleaved preferentially at Asp-330 by caspase-3
and at Asp-315 by granzyme B. Caspase-2 cleavage sites are based on equivalent
sites being present in Nedd2.FADD (in the white box) represents the domains of caspase-8 and caspase-10 that
are homologous to the DED of FADD/MORT1.
¨ The Activation of
caspases
Conversion of each caspase zymogen [dormant state of the enzyme] to the mature enzyme requires a minimum
of 2 cleavages, one separating the prodomain from the large subunit and another
is separating the large and small subunits [Fig. 3]. All of these cleavages
involve Asp-X bond. This process eventually yields a heterodimeric enzyme with
both fragments contributing to the formation of the catalytic machinery.
It is believed now that the functional caspase unit is a homodimer
[which referred to as "homodimer of heterodimer"],
with each monomer comprising a large (20KDa, named p20.) and a small (10 KDa,
named p10.) subunit, according to the structural characterization of the
caspase-1 which reveals the homodimeric structure. In addition to caspase-1,
structural information is available for caspase-3, -7, -8 and -9. The overall
architecture of them is similar and consists of 2 heterodimers composed of
large and small subunits. The subunits of each heterodimer are folded into a
compact cylinder that is dominated by a central six-stranded β-sheet and five
α-helices that are distributed on opposing sides of the plane that is formed by
the β-sheet. This so-called caspase-fold is a unique quaternary structure among
proteases and has only been described for caspases [Fig. 4].
Figure 3, Schematic
diagram of the mammalian caspases: except caspase-11 and 12 (mouse),
caspase-13 (bovine), all listed caspases are of human origin.
Their phylogenetic relationship (left) appears to correlate with their function
in apoptosis or inflammation. The initiator and effector caspases are labeled
in purple and red, respectively. The
position of the cleavage (between the large and small subunits) is highlighted
with a large arrow while additional sites of cleavage are represented by medium
and small arrows.
The four surface loops (L1-L4) that shape the catalytic groove are
indicated. The catalytic residue Cys is
shown as a red line at the beginning of loop L2.
Homodimerization [Fig. 4a] is
mediated by hydrophobic interactions, with 6 β-strands
(5 are parallel and one anti-parallel) from each catalytic subunit forming a
single contiguous 12-stranded β-sheets. Several α-helices (six helices) and
short β-strands (βI, II, III, IV and V) are located on either side
of the central β-sheet, giving rise to globular fold. The active sites, formed
by 4 protruding loops form the scaffold, are located at 2 opposite ends
of the β-sheet.
Crystallographic analysis has demonstrated that the
active caspase is a tetramer composed of two such heterodimers. As
first appreciated in the structure of caspase-1, this general rule is valid
also for caspases, since the catalytic residue His-237 is located in the loop
that connects β-strand (β3) to the "front" helix (α3), while the
neighbouring strand (β1) is followed by
the "back" helix (α1) (‘back’ and ‘front’ refer to the standard
caspase orientation shown in [Fig. 4a]). The β1-α1 loop has one of the
residues that determine the characteristic P1 specificity, Arg-179.
The entire active center of
caspases, consisting of the S4-S3-S2-S1 specificity sub-sites binding
P4-P3-P2-P1 residues of the substrate, respectively, is formed by a flexible
loops (L1– L4, Fig. 5). Loop L1 and a
portion of L2, which contains the catalytic Cys-285 residue, are a part of the
large subunit, whereas L3 and L4 come from the small subunit. The activation-mediated
cleavage of caspases occurs in the loop L2; liberating the C-terminus of the
large (L2) and the N-terminus of the small subunits (L2\).
[Fig. 6] is an example of caspases activation by proteolysis.
Figure 4, Structure of active caspases: (a) the crystal structure
of human caspase-8 exemplifies the fundamental caspase fold, and is shown bound
to the tetrapeptide aldehyde inhibitor acetyl-Ile-Glu-Thr-Asp-CHO (PDB entry
1QTN), which represents the highest-resolution structure of a caspase reported
to date. Note the three-layer structure of a twisted, 12-stranded β-sheet that is sandwiched by α-helices. Most of the interdomain contact area is
built by the central small subunits, with additional interactions (the
characteristic ‘loop bundle’) tying together the C- and N-termini of large and
small subunits from neighbouring domains. The bound inhibitor is represented
with a ball-and-stick model, as are dithiane diol molecules trapped in the
cleft between the two monomers (termed the central cavity, for obvious
reasons).
(b) Simplified topological
diagram of the caspase structure, following the CATCH definition of secondary
structure elements for 1QTN. An additional N-terminal α-helix of variable length (α0; not shown) is present in caspases-1, -2 and -9,
and closes the ‘bottom’ of the α/β barrel. Also not depicted is an additional α-helix found solely in the long 179-loop of caspase-8.
The positions of catalytic dyad residues His-237 and Cys-285 (red), along with those of the
specificity-determining arginine residues (Arg-179 and Arg-341), are indicated.
The location of loops that contain important functional elements is indicated
in blue
text using the numbering convention designated throughout this review, along
with an alternative designation.
Figure 5, The Generalized distribution of
caspase catalytic center loops (L1– L4) on small and large subunits: Loops
are shown in blue. Position of the activating cleavage processing is shown
by arrows. Numbers represent the order of the activation cleavages. The active
site Cys is shown by a red asterisk.
Processing occurs in L2. The resulting large subunit portion of the L2 loop of
one monomer and small subunit portion of the L2 loop of another monomer (L2\).
On the right is Schematic
diagram of the substrate-binding groove: L1 and L4 constitute two parallel sides of the groove
while L3 serves as the base. L2, harboring the catalytic residue Cys, is
positioned at one end of the groove, poised for catalysis. L2\ plays a critical role by stabilizing the conformation of
the L2 and L4 loops.
Figure
6, Mechanism of
activation for effector caspases as exemplified by caspase-7: A schematic diagram of
procaspase-7 activation is shown here. The active-site loops before and after
the proteolytic processing is shown in orange/cyan
and magenta/green, respectively. The detailed
conformational changes at the active site are depicted in the middle panel, in
which the four surface loops, L1-L4, and the L2\ loop are
labeled.
Role
of caspases in Apoptosis
Apoptosis is a physiological cell
suicide program (one of the main types of PCD) that is critical for the
development and maintenance of healthy tissues. Regulation of PCD allows the organism
to control the cell number and the tissue size, and to protect itself from
rogue cells that threaten homeostasis. The changed activity of numerous genes
influences switching of cells to a self-destruction program. Apoptosis requires
co-ordinate action and fine tuning of a set of proteins that are either
regulators or executors of the process. Cancer, autoimmune diseases,
immunodeficiency disease, reperfusion injury and neurodegenerative disorders
are characterized by unregulated apoptosis. Modulation of the expression and
activation of the key molecular components of the apoptotic process has emerged
as an attractive therapeutic strategy for many diseases.
There are two distinct types of cell
death, death by injury and death by suicide. Cells that are damaged by injury,
such as mechanical damage or exposure to toxic chemicals, undergo a series of
changes characterized by swelling of cells and their organelles, leakage of
cell content and inflammation of the surrounding tissues. In other words, cells
die by necrosis. In contrast, apoptosis is an organized, genetically
directed process, which leads to cell death. Cells dying by apoptosis share
unique morphological features, distinct from autolytic, degenerative cell
changes observed during necrosis [Fig. 7].
m MORPHOLOGY
OF APOPTOSIS
Morphological changes of an
apoptotic cell might be easily detected under the microscope. Some of these
changes can be seen even by light microscopy using specific dyes, while other
can be detected only by electron microscopy. The dying cell starts to show
protrusion from the plasma membrane, referred to as bleb [Fig. 8]. Staining
DNA with certain dyes allows observation of the condensation of the cell
nucleus, which usually starts as a condensed ring along the nuclear envelope.
The condensed nucleus can disassemble into several fragments. The entire cell
condenses and is re-organized into apoptotic bodies [Fig. 8], which
are membrane-bound vesicles varying in size and composition, containing the
entire cell content in various combinations, such as cytosolic elements,
organelles or parts of condensed nuclei. Additional changes have been described
by electron microscopy. Condensation or swelling of mitochondria, dilatation of
endoplasmic reticulum (ER), vacuolisation of cytoplasm and loss of plasma membrane
microvilli have been observed. At a certain point, apoptosis affects all
compartments and organelles in a dying cell.
Apoptosis includes cellular shrinking, chromatin condensation and margination at the nuclear periphery with the eventual formation of membrane-bound apoptotic bodies that contain organelles, cytosol and nuclear fragments and are phagocytosed without triggering inflammatory processes.The necrotic cell swells, becomes leaky and finally is disrupted and releases its contents into the surrounding tissue resulting in inflammation. Modified from [Van Cruchten, 2002].
Figure
7, Schematic diagram of differences between
apoptosis and necrosis: (A) Apoptosis
includes cellular shrinking, chromatin condensation and margination at the
nuclear periphery with the eventual formation of membrane-bound apoptotic
bodies that contain organelles, cytosol and nuclear fragments and are phagocytosed
without triggering inflammatory processes (B). The necrotic cell swells,
becomes leaky and finally is disrupted and releases its contents into the
surrounding tissue resulting in inflammation.
Figure
8, Schematic diagram of morphological changes in the cell during apoptosis.
Molecular mechanism
of apoptosis
Apoptosis can be triggered by various stimuli from outside
or inside the cell, as by ligation of cell surface receptors, DNA damage as a cause of defects in DNA repair
mechanisms, treatment with cytotoxic drugs or irradiation, a lack of survival
signals, contradictory cell cycle signaling or by developmental death signals.
Death signals of such diverse origin nevertheless appear to eventually activate
common cell death machinery leading to the characteristic features of apoptotic
cell death [Fig. 9].The
apoptosis process can be divided into at least three functionally distinct
phases: initiation, effector and degradation. During
the initiation phase, cells receive
death-inducing signals: as lack of obligatory survival factors, shortage of
metabolite supply, ligation of death-signal transmitting receptors, sub-necrotic
damage by toxins, heat or irradiation.
During
the effector phase, these signals are
translated into metabolic reactions and the decision to die is taken. The
ultimate fate of the cell is subject to regulatory events. Beyond this stage,
during the degradation phase, an increase in the overall entropy,
including activation of catabolic enzymes, precludes further regulatory
effects. During the late phase, DNA fragmentation and massive protein degradation
becomes apparent. Subsequently, fragments are encapsulated into ‘apoptotic
bodies’.
Figure 9, Apoptosis may occur
through 2 main signaling pathways: The intrinsic pathway may be triggered by DNA damage and other
types of severe cell stress. It may involve the release of intracellular
pro-apoptotic proteins that activate caspases, a network of proteases that
ultimately destroy critical structural proteins in the cell and stimulate
fragmentation of the chromosomal DNA, resulting in cell death. The extrinsic
pathway may be triggered in response to external pro-apoptotic signals, such as
endogenous Apo2L/TRAIL. Binding of this molecule to pro-apoptotic cell surface
transmembrane receptors DR4 and DR5 may lead to apoptosis by initiating a
signaling cascade, which results in the activation of the caspase system. The
intrinsic and extrinsic apoptosis pathways converge via the activated caspases
that ultimately trigger cell death.
Caspases in apoptosis
Caspases are the family which can be
classified into 3 subgroups according to their function:
I-Initiator caspases [caspase-2, -8, -9 and
-10]
II-Executioner caspases [caspase-3, -6 and -7]
Both (I) and (II) have either direct or
indirect role in the processing, propagation and amplification of apoptotic signals,
which result in the destruction of the cellular structure.
III-Inflammatory caspases, which involved
in the maturation of pro-inflammatory cytokines [caspase-1, -4, -5, -11, -12, -13
and -14]
At the molecular level, two
principal pathways of apoptotic cell
death have been described (Twomey and McCarthy, 2005). The pathway
of apoptosis often referred to as:
A) Extrinsic
apoptosis (Receptor-mediated apoptosis or type
1 apoptosis).
B) Intrinsic apoptosis (mitochondria-independent
apoptosis and or type
2 apoptosis) [Fig. 10].
Many of the proteins involved
utilize at least two types of sequence
motifs. One motif is
known as DD and the other motif as
DED [The
instigators include the long prodomain, DED containing caspases 8 and 10, and
the CARD containing caspase-9].
Figure 10, Basic two principal pathways: the receptor and the mitochondria-mediated
apoptosis.
A)
Extrinsic
apoptosis:
Extrinsic
apoptosis signalling is mediated by the activation of so called “death
receptors” which are cell surface receptors that transmit apoptotic signals
after ligation with specific ligands. DRs belong to (TNFR) gene superfamily,
including TNFR-1, Fas/CD95, and the TRAIL receptors DR-4 and
DR-5 [Fig. 11 B and 12 and table 2]. All members of the TNFR family consist
of cysteine rich extracellular sub-domains which allow
them to recognize their
ligands with specificity, resulting in the trimerization and activation of the
respective death receptor. Subsequent signalling is mediated by the cytoplasmic
part of the DR which contains a conserved sequence termed the DD.
Adapter molecules like FADD or TRADD themselves possess their own DDs by which
they are recruited to the DDs of the activated DR, thereby forming the
so-called DISC [Fig. 12 A]. In addition to its DD, the adaptor FADD also
contains a DED which through homotypic DED-DED interaction sequesters
procaspase-8 to the DISC [Fig. 11 B]. The local concentration of several
procaspase-8 molecules at the DISC leads to their autocatalytic activation and
release of active caspase-8. Active caspase-8 then processes downstream
effector caspases which subsequently cleave specific substrates resulting in
cell death. The signal needs to be amplified via mitochondria-dependent
apoptotic pathways. The link between the caspase signalling cascade and the
mitochondria is provided by the Bcl-2 family member Bid. Bid is
cleaved by caspase-8 in to its truncated form (tBid), translocates to the
mitochondria where it acts in concert with the proapoptotic Bcl-2 family
members Bax and Bak to induce the release of cytochrome c (Apaf-2) and
other mitochondrial proapoptotic factors into the cytosol [Fig. 9, 10 and (11 A)].
Cytosolic cytochrome c is binding to monomeric Apaf-1 which then, in a
dATP-dependent conformational change, oligomerizes to assemble the apoptosome, a
complex of wheel-like structure with 7-fold symmetry, which triggers the
activation of the initiator procaspase-9. Activated caspase-9 subsequently
initiates a caspase cascade involving downstream effector caspases such as
caspase-3, caspase-7, and caspase-6, ultimately resulting in cell death.
Figure 11, (A)
Table 2, Shows many different
molecules and receptors involved in apoptosis.
Figure 11,(B)
B) Intrinsic apoptosis
Besides amplifying and mediating extrinsic apoptotic pathways,
mitochondria also play a central role in the integration and propagation of
death signals originating from inside the cell such as DNA damage, oxidative
stress, starvation, as well as those induced by chemotherapeutic drugs. Most
apoptosis-inducing conditions involve the disruption of normal mitochondrial
inner transmembrane potential (Δψ) [Fig. 13 A] as well as the so called
permeability transition (PT), a sudden increase of the inner mitochondrial
membrane permeability to solutes with a molecular mass below approximately 1.5
kDa. Concomitantly, osmotic mitochondrial swelling has been observed by
influx of water into the matrix with eventual rupture of the outer
mitochondrial membrane, resulting in the release of proapoptotic proteins from
the mitochondrial intermembrane space into the cytoplasm. Released proteins
include cytochrome c, which activates the apoptosome [Fig. 14] and therefore the caspase cascade [Fig. 11 A, B and Fig.
13 A], but also other factors such as the apoptosis-inducing factor (AIF), the
endonuclease (endoG), Smac/Diablo, and Htr/Omi. In addition to
the release of mitochondrial factors, the dissipation of Δψ and PT also cause a
loss of the biochemical homeostasis of the cell: ATP synthesis is stopped,
redox molecules such as NADH, NADPH, and glutathione are oxidized, and reactive
oxygen species (ROS) are increasingly generated.
Caspases and chromatin break down
One of the hallmarks of apoptosis is the cleavage of chromosomal
DNA into nucleosomal units. The caspases play an important role in this process
by activating DNases, inhibiting DNA repair enzymes and breaking down
structural proteins in the nucleus. The
role of the caspases in the breakdown of chromatin is illustrated in [Fig. 15].
1) Inactivation of enzymes involved in DNA repair: The enzyme poly (ADP-ribose) polymerase, or PARP, is an important
DNA repair enzyme and was one of the first proteins identified as a substrate
for caspases. The ability of PARP to repair DNA damage is prevented following
cleavage of PARP by caspase-3.
2) Breakdown of structural nuclear proteins: Lamins are intra-nuclear proteins that maintain the shape of the
nucleus and mediate interactions between chromatin and the nuclear membrane.
Degradation of lamins by caspase 6 results in the chromatin condensation and
nuclear fragmentation.
3) Fragmentation of DNA: The fragmentation of DNA into nucleosomal units is caused by an
enzyme known as CAD, or caspase activated DNase. Normally CAD exists as an
inactive complex with ICAD (inhibitor of CAD). During apoptosis, ICAD is
cleaved by caspases, such as caspase 3, to release CAD. Rapid fragmentation of
the nuclear DNA follows.
Caspases in inflammation
In mammles, there are 5 inflammatory
caspases that all have a CARD at their N-terminus. Human inflammatory caspases are clustered on chromosome 11q22 in following order from
the telomere: caspase-1, caspase-5, caspase-4, and finally the gene for
caspase-12 [Fig. 16].
The role of caspase-1 in the
maturation of IL-1β and IL- 18 renders it a key player in response to pathogenic
infection as well as in inflammatory and autoimmune disorders. IL-1β and IL-18 are
key cytokines in these conditions. Although they share certain proinflammatory
activities, they also have very important individual functions. For example,
IL-1β but not IL-18 is anorectic, pyrogenic, results in skin rashes and urticaria,
induces hepatic-acute phase proteins, up-regulates prostanoid synthesis, and is
involved in inflammatory pain hypersensitivity. IL-1β is also implicated in
destructive joint and bone disease, tumor angiogenesis and invasiveness, and
toxicity of insulin-producing pancreatic islets β-cells, and neurons in stroke
and neurodegeneration. IL-18, in contrast, was originally known for its ability
to stimulate IFN-γ production and to mediate T cell polarization. Now it is known
that it possesses many other functions including modulation of the heart
contractile force, upregulation of adhesion molecules and NO synthesis, and regulation
of energy intake and insulin sensitivity. Therefore, inhibition of caspase-1 is
an attractive therapeutic strategy aimed at blocking the effects of both
cytokines in inflammatory and autoimmune diseases. Although we know of many
biological effects of IL-1β and IL-18, we still lack information on the exact
mechanisms by which caspase-1 is activated, and by which these cytokines are
matured and secreted.
Our understanding of the
inflammatory caspases and their regulatory mechanisms has recently improved
substantially. Multiple new players have now been identified to modulate the function
of these enzymes. The discovery of the caspase-12 polymorphism and the
characterization of its function in sepsis and the host response to pathogenic
infection have emphasized the essential role of these caspases in innate
immunity. In parallel, the identification of the NLR family and its regulation
of the inflammatory caspases has provided an important step forward in our
knowledge of the tight and highly specific mechanisms of activation of these
enzymes.
Abbreviations
1. C.elegans: Caenorhabditis elegans, it is a type of nematodes.
2. Ced-3 gene: c.elegans
death gene or Cell Death Defective-3,
which is involved in the cell death.
3. CARD: caspase
recruitment domains, they are interaction motifs
found in a wide array in proteins, typically those involved in apoptosis and
inflammation.
4. DED: death
effector domain (DD is Death Domain),
which is a protein domain found in procaspases and proteins that regulate caspase
activation in apoptotic cascade such as FADD.
5. FADD: fas-associated
with death domain protein.
6. Glu or E: Glutamic acid.
7. Asp or D: Aspartic
acid.
8. X: any amino acid (aa\).
9. MORT-1: Mediator Of
Receptor-induced Toxicity-1, which is also
called FADD.
10. Nedd2: Neural
precursor cell Expressed Developmentally Down-regulated
2, it is a developmental regulated mouse gene that encodes a protein (mouse
homologue of ICH-1, ICE and Ced-3 Homolouge-1)
similar to the ced-3 gene protein and mammalian ICE. It is renamed as caspase-2
(Alnemri et al Human ICE/CED-3
protease nomenclature, 1996).
11. Cys or C:
Cysteine aa\.
12. PDB: Protein Data Bank. (http://www.rcsb.org/pdb/home/home.do)
13. P: Pocket.
14. PCD: Programmed Cell Death.
15. TNFR1: Tumor Necrosis
Factor Receptor-1
16. TRAIL-R1 or 2:
TNF-Related Apoptosis-Inducing
Ligand Receptor-1 or -2
17. p75-NGFR: p75-Nerve Growth
Factor Receptor.
18. TNF: Tumor Necrosis Factor.
19. Motif and domain appear to be used interchangeable.
20.
Initiator
caspases (º activator or apical or upstream or instigator caspases).
21. Effector caspases (º
Executioner or downstream or terminator caspases).
22.
DISC: Death Inducing
Signaling Complex.
23.
L: Ligand.
24.
TRADD: TNF Receptor-Associated
Death Domain.
25.
TRAF2: TNF Receptor-Associated Factor-2
26.
BH: Bcl-2 Homology (has 4
domains BH1, BH2, BH3 and BH4).
27.
DR: Death Receptor.
28.
APAF-1: Apoptotic Protease
Activating Factor-1, it is a protein contains three functional
regions: an N-terminal CARD domain that can bind to the zymogen form of caspase-9, a CED4
like region enabling self-oligomerization, and a regulatory C-terminus with
WD-40 repeats masking the CARD
and CED4
region. During apoptosis, cytochrome-C and dATP can relieve the inhibitory action of the WD-40
repeats and thus enable the oligomerization of APAF-1 and the subsequent
recruitment and activation of caspase-9 from its zymogen form.
29.
Smac: Second Mitochondria-Derived
Activator of Caspases.
30. DIABLO:
Direct Inhibitor of Apoptosis-Binding
Protein with LOw pI.
31. NLR: Nod-Like
Receptor.
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(***Note: The last update by me was in 2009. Therefore, if there any new updates, please do not hesitate to contact me.)
(***Note: The last update by me was in 2009. Therefore, if there any new updates, please do not hesitate to contact me.)
