B cell CLL/lymphoma-2 (Bcl-2) and related proteins comprise the Bcl-2 family. Bcl-2 proteins are central regulators of caspase activation, and play a key role in cell death by regulating the integrity of the mitochondrial and endoplasmic reticulum (ER) membranes []. Though originally characterised with respect to their roles in controlling outer mitochondrial membrane integrity and apoptosis, the members of the Bcl-2 family are involved in numerous cellular pathways [].Bcl-2 and its relatives are functionally classified as either antiapoptoticor proapoptotic. All members contain at least one of four conserved motifs, termed Bcl-2 Homology (BH) domains. Antiapoptotic BCL-2 proteins contain four Bcl-2 homology domains (BH1-4). The major antiapoptotic proteins are Bcl-2-related gene A1 (A1), Bcl-2, Bcl-2-related gene, long isoform (Bcl-xL), Bcl-w, and myeloid cell leukemia 1 (MCL-1). They preserve outer mitochondrial membrane (OMM) integrity by directly inhibiting the proapoptotic Bcl-2 proteins [].The proapoptotic Bcl-2 members are divided into the effector proteins and the BH3-only proteins. The effector proteins Bcl-2 antagonist killer 1 (BAK) and Bcl-2-associated x protein (BAX) were originally described to contain only BH1-3; however, structure-based alignments revealed a conserved BH4 motif []. Upon activation BAK and BAX homo-oligomerise into proteolipid pores within the OMM to promote MOMP (mitochondrial outer membrane permeabilisation). The BH3-only proteins function in distinct cellular stress scenarios and are subdivided based on their ability to interact with the antiapoptotic or both the antiapoptotic and the effector proteins [].Bcl-2-associated x protein (BAX) is a proapoptotic member of the Bcl-2 family. It accelerates programmed cell death by binding to, and antagonising the apoptosis repressor Bcl2 [, ].
Bax inhibitor-1 (BI-1) []is a suppressor of apoptosis that interacts with BCL2 and BCL-X. Human Bax BI-1 is an evolutionarily conserved integral membrane protein containing multiple membrane-spanning segments localised to the ER membrane. It has 6-7 membrane-spanning domains. The C termini of the mammalian BI-1 proteins are comprised of basic amino acids resembling some nuclear targeting sequences, but otherwise the predicted proteins lack motifs that suggest this function. BI-1 also regulates cell death triggered by ER stress [, , ]. BI-1 appears to exert its effect through an interaction with calmodulin []. Crystal structure of a bacterial member reveals that these proteins mediate a calcium leak across the membrane in a pH-dependent manner. Calcium homoeostasis balances passive calcium leak with active calcium uptake. The structure exists in a pore-closed and pore-open conformation, at pHs of 8 and 6 respectively [, ].This entry represents BI-1 and related sequences, including lifeguard proteins, which resemble BI-1 and also act as apoptotic regulators [].
Bax inhibitor-1 (BI-1) (gene TEGT) []is a suppressor of apoptosis that interacts with BCL2 and BCL-X. These are proteins of about 25kDa which seem to contain seven transmembrane domains. Homologues are found in plants and bacteria.This entry corresponds to a conserved region that starts with the beginning of the third transmembrane domain and endsin the middle of the fourth one.
Bcl-2-interacting killer promotes cell death in a manner similar to the death-promoting members of the Bcl-2 family, Bax and Bak. Its death-promoting activity can be suppressed by coexpression of Bcl-2, Bcl-XL, EBV-BHRF1 and E1B-19kDa proteins, suggesting that it may be a common target for both cellular and viral anti-apoptotic proteins [].
The poxvirus F1 family members are related to Vaccinia virus protein F1L, which interacts with and inhibits NLR-mediated interleukin-1 beta/IL1B production in infected cells. F1L suppresses mitochondrial-dependent apoptosis by binding to the BH3 domain of host BAK and prevents BAK from binding active BAX [, ].
Humanin (HN) and humanin-like proteins are found exclusively in humans. Humanin is a short anti-apoptotic peptide that inhibits the activation of Bax (Bcl-2-associated X protein), which is involved in apoptosis []. Humanin suppresses neuronal cell death caused by Alzheimer's disease (AD)-specific insults []. Humanin also interacts with the insulin-like growth factor-binding protein-3 (IGFBP-3), which is essential in the regulation of cell survival []. This entry represents the humanin family, and also matches some uncharacterised non-human proteins, mainly from chimpanzee.
GHITM (also known as MICS1) appears to be ubiquitiously expressed in mammalian cells and expression has also been observed in various cancer cell lines []. It is involved in maintenance of mitochondrial morphology and apoptotic release of cytochrome c []. It is closely related to the BAX inhibitor (BI)-1 like family of small transmembrane proteins, which have been shown to have an anti-apoptotic effect [, , ].
This family consists of adenovirus E1B 19kDa protein or small t-antigen. The E1B 19kDa protein inhibits E1A induced apoptosis and hence prolongs the viability of the host cell []. It can also inhibit apoptosis mediated by tumour necrosis factor alpha and Fas antigen []. E1B 19kDa blocks apoptosis by interacting with and inhibiting the p53-inducible and death-promoting Bax protein []. The E1B region of adenovirus encodes two proteins E1B 19kDa the small t-antigen as found in this family and E1B 55kDa thelarge t-antigen which is not found in this family; bothof these proteins inhibit E1A induced apoptosis [].
Endophilin-B2 is a cytoplasmic protein that colocalizes to the cytoplasmic compartment of the cell together with Bax and is excluded from the nucleus []. It is overexpressed in prostate cancer metastasis and has been identified as a cancer antigen with potential utility in immunotherapy []. Endophilins play roles in synaptic vesicle formation, virus budding, mitochondrial morphology maintenance, receptor-mediated endocytosis inhibition and endosomal sorting. They contain an N-terminal N-BAR domain (BAR domain with an additional N-terminal amphipathic helix), followed by a variable region containing proline clusters, and a C-terminal SH3 domain. Endophilin-B2 forms homo- and heterodimers (with endophilin-B1) through its BAR domain []. This entry represents the SH3 domain of endophilin-B2.
This entry includes the poxvirus families F1 and C10. C10 proteins are apoptosis regulators, which function to modulate the apoptotic cascades and thereby favour productive viral replication. One of these, M11L inhibits mitochondrial-dependent apoptosis by mimicking and competing with host proteins for the binding and blocking of Bak and Bax, two executioner proteins []. The poxvirus F1 family members are related to Vaccinia virus protein F1L, which interacts with and inhibits NLR-mediated interleukin-1 beta/IL1B production in infected cells. F1L suppresses mitochondrial-dependent apoptosis by binding to the BH3 domain of host BAK and prevents BAK from binding active BAX [, ].
PUMA (p53 upregulated modulator of apoptosis), also known as Bbc3 (Bcl-2-binding component 3), is a critical mediator of p53-dependent and -independent apoptosis []. PUMA transduces death signals primarily to the mitochondria. It is induced in cells after p53 activation. It binds to Bcl-2, localises to the mitochondria to induce cytochrome c release, and activates the rapid induction of apoptosis []. PUMA is capable of inhibiting all the five major anti-apoptotic Bcl-2-like proteins (Mcl-1, Bcl-2, Bcl-XL, Bcl-W and A1) []. The binding of PUMA to the inhibitory members of the Bcl-2 family via its BH3 domain results in the displacement of the proteins Bax and/or Bak, and seems to be a critical regulatory step in the induction of apoptosis [].
Members of the ING (inhibitor of growth protein) family of tumour suppressors regulate cell cycle progression, apoptosis, and DNA repair as important cofactors of p53. Inhibitor of growth protein 1 (ING1) is the best characterised member of this family of five genes (ING1-5) with conserved plant homeodomains (PHDs) [].ING1 interacts with proliferating cell nuclear antigen (PCNA) and PCNA-interacting protein p15 (PAF) [, ]. p53 and ING1 have been shown to functionally cooperate in the activation of apoptosis []. ING1 could also induce apoptosis by translocation from the nucleus to the mitochondria where interaction with BAX stabilises this protein, promoting its pro-apoptotic function []. ING1 functions in DNA demethylation []and has a role in the early steps of multiple DNA repair pathways [].
Apoptosis, or programmed cell death (PCD), is a common and evolutionarily conserved property of all metazoans []. In many biological processes, apoptosis is required to eliminate supernumerary or dangerous (such as pre-cancerous) cells and to promote normal development. Dysregulation of apoptosis can, therefore, contribute to the development of many major diseases including cancer, autoimmunity and neurodegenerative disorders. In most cases, proteins of the caspase family execute the genetic programme that leads to cell death.Bcl-2 proteins are central regulators of caspase activation, and play a key role in cell death by regulating the integrity of the mitochondrial and endoplasmic reticulum (ER) membranes []. At least 20 Bcl-2 proteins have been reported in mammals, and several others have been identified in viruses. Bcl-2 family proteins fall roughly into three subtypes, which either promote cell survival (anti-apoptotic) or trigger cell death (pro-apoptotic). All members contain at least one of four conserved motifs, termed Bcl-2 Homology (BH) domains. Bcl-2 subfamily proteins, which contain at least BH1 and BH2, promote cell survival by inhibiting the adapters needed for the activation of caspases.Pro-apoptotic members potentially exert their effects by displacing the adapters from the pro-survival proteins; these proteins belong either to the Bax subfamily, which contain BH1-BH3, or to the BH3 subfamily, which mostly only feature BH3 []. Thus, the balance between antagonistic family members is believed to play a role in determining cell fate. Members of the wider Bcl-2 family, which also includes Bcl-x, Bcl-w and Mcl-1, are described by their similarity to Bcl-2 protein, a member of the pro-survival Bcl-2 subfamily []. Full-length Bcl-2 proteins feature all four BH domains, seven α-helices, and a C-terminal hydrophobic motif that targets the protein to the outer mitochondrial membrane, ER and nuclear envelope. Bcl-X is a dominant regulator of programmed cell death in mammalian cells.The long form (Bcl-X(L)) displays cell death repressor activity, but the short isoform(Bcl-X(S)) and the b-isoform (Bcl-Xb) promote cell death. Bcl-X(L), Bcl-X(S) and Bcl-Xb are three isoforms derived by alternative RNA splicing. Bcl-X(S)forms heterodimers with Bcl-2. Homologues of Bcl-X include the rat Bax and mouse Bak proteins which also influenceapoptosis.In healthy cells, Bcl-x resides in the cytoplasm and becomes membrane-associated in response to cytotoxic insults. Its 3D structure comprises a bundle of five amphipathic alpha- helices surrounding two central hydrophobic helical regions. A hydro- phobic groove, formed by residues from BH1-BH3, is capable of binding the BH3 α-helix from a pro-apoptotic BH3-only family member [].
B cell CLL/lymphoma-2 (Bcl-2) and related proteins comprise the Bcl-2 family. Bcl-2 proteins are central regulators of caspase activation, and play a key role in cell death by regulating the integrity of the mitochondrial and endoplasmic reticulum (ER) membranes []. Though originally characterised with respect to their roles in controlling outer mitochondrial membrane integrity and apoptosis, the members of the Bcl-2 family are involved in numerous cellular pathways [].Bcl-2 and its relatives are functionally classified as either antiapoptoticor proapoptotic. All members contain at least one of four conserved motifs, termed Bcl-2 Homology (BH) domains. Antiapoptotic BCL-2 proteins contain four Bcl-2 homology domains (BH1-4). The major antiapoptotic proteins are Bcl-2-related gene A1 (A1), Bcl-2, Bcl-2-related gene, long isoform (Bcl-xL), Bcl-w, and myeloid cell leukemia 1 (MCL-1). They preserve outer mitochondrial membrane (OMM) integrity by directly inhibiting the proapoptotic Bcl-2 proteins [].The proapoptotic Bcl-2 members are divided into the effector proteins and the BH3-only proteins. The effector proteins Bcl-2 antagonist killer 1 (BAK) and Bcl-2-associated x protein (BAX) were originally described to contain only BH1-3; however, structure-based alignments revealed a conserved BH4 motif []. Upon activation BAK and BAX homo-oligomerise into proteolipid pores within the OMM to promote MOMP (mitochondrial outer membrane permeabilisation). The BH3-only proteins function in distinct cellular stress scenarios and are subdivided based on their ability to interact with the antiapoptotic or both the antiapoptotic and the effector proteins [].
B cell CLL/lymphoma-2 (Bcl-2) and related proteins comprise the Bcl-2 family. Bcl-2 proteins are central regulators of caspase activation, and play a key role in cell death by regulating the integrity of the mitochondrial and endoplasmic reticulum (ER) membranes []. Though originally characterised with respect to their roles in controlling outer mitochondrial membrane integrity and apoptosis, the members of the Bcl-2 family are involved in numerous cellular pathways [].Bcl-2 and its relatives are functionally classified as either antiapoptoticor proapoptotic. All members contain at least one of four conserved motifs, termed Bcl-2 Homology (BH) domains. Antiapoptotic BCL-2 proteins contain four Bcl-2 homology domains (BH1-4). The major antiapoptotic proteins are Bcl-2-related gene A1 (A1), Bcl-2, Bcl-2-related gene, long isoform (Bcl-xL), Bcl-w, and myeloid cell leukemia 1 (MCL-1). They preserve outer mitochondrial membrane (OMM) integrity by directly inhibiting the proapoptotic Bcl-2 proteins [].The proapoptotic Bcl-2 members are divided into the effector proteins and the BH3-only proteins. The effector proteins Bcl-2 antagonist killer 1 (BAK) and Bcl-2-associated x protein (BAX) were originally described to contain only BH1-3; however, structure-based alignments revealed a conserved BH4 motif []. Upon activation BAK and BAX homo-oligomerise into proteolipid pores within the OMM to promote MOMP (mitochondrial outer membrane permeabilisation). The BH3-only proteins function in distinct cellular stress scenarios and are subdivided based on their ability to interact with the antiapoptotic or both the antiapoptotic and the effector proteins [].This entry covers the Bcl-2 homology regions 1, 2 and 3 (BH1-3).
B cell CLL/lymphoma-2 (Bcl-2) and related proteins comprise the Bcl-2 family. Bcl-2 proteins are central regulators of caspase activation, and play a key role in cell death by regulating the integrity of the mitochondrial and endoplasmic reticulum (ER) membranes []. Though originally characterised with respect to their roles in controlling outer mitochondrial membrane integrity and apoptosis, the members of the Bcl-2 family are involved in numerous cellular pathways [].Bcl-2 and its relatives are functionally classified as either antiapoptoticor proapoptotic. All members contain at least one of four conserved motifs, termed Bcl-2 Homology (BH) domains. Antiapoptotic BCL-2 proteins contain four Bcl-2 homology domains (BH1-4). The major antiapoptotic proteins are Bcl-2-related gene A1 (A1), Bcl-2, Bcl-2-related gene, long isoform (Bcl-xL), Bcl-w, and myeloid cell leukemia 1 (MCL-1). They preserve outer mitochondrial membrane (OMM) integrity by directly inhibiting the proapoptotic Bcl-2 proteins [].The proapoptotic Bcl-2 members are divided into the effector proteins and the BH3-only proteins. The effector proteins Bcl-2 antagonist killer 1 (BAK) and Bcl-2-associated x protein (BAX) were originally described to contain only BH1-3; however, structure-based alignments revealed a conserved BH4 motif []. Upon activation BAK and BAX homo-oligomerise into proteolipid pores within the OMM to promote MOMP (mitochondrial outer membrane permeabilisation). The BH3-only proteins function in distinct cellular stress scenarios and are subdivided based on their ability to interact with the antiapoptotic or both the antiapoptotic and the effector proteins [].
The DnaJ proteins, also known as heat shock protein 40 (Hsp40 or Hsc40), are proteins originally identified in Escherichia coli that act as cochaperones to the molecular chaperone DnaK (Hsp70), which is responsible for several cellular processes such as rescuing misfolded proteins, folding polypeptide chains, transport of polypeptides through membranes, assembly and disassembly of protein complexes, and control of regulatory proteins [].Structurally, the DnaJ protein consists of an N-terminal conserved domain (called 'J' domain) of about 70 amino acids, a glycine-rich region ('G' domain') of about 30 residues, a central domain containing four repeats of a CXXCXGXG motif ('CRR' domain) and a C-terminal region of 120 to 170 residues.This entry represents a group of DnaJ domain containing proteins, including DNJA1/2/4 from humans, Scj1/Mas5/Xdj1/Apj1 from budding yeasts, and DNAJ2/3/19 from Arabidopsis. [].In humans, DNAJA1, DNAJA2 and HSC70 have been shown to play key roles in both the folding and degradation of wild-type and mutant CFTR (cystic fibrosis transmembrane conductance regulator) [, ]. They also function as co-chaperone for HSPA1B and negatively regulates the translocation of BAX from the cytosol to mitochondria in response to cellular stress, thereby protecting cells against apoptosis [].
VDAC-1 (outer mitochondrial membrane protein porin 1) is a voltage dependent anion channel that mediates the flow of metabolites and ions across the outer mitochondrial membrane. VDAC-1 appeares to be a pro-apoptotic protein through oligomerisation []. It is implicated in cell death induction for its ability to interact with BAX, a protein belonging to the BCL-2 protein family. BAX plays a role in apoptosis and mitochondrial function regulation via multiple protein-protein interactions with BCL-2, BAK, BID or other members of the family [, ]. Voltage dependent anion channels (VDACs) or porins by analogy with bacterial porins, are pore-forming proteins associated with mitochondria, although they are also present in the endoplasmic reticulum (ER) []and plasma membrane []. In mammals, three VDAC isoforms have been identified: VDAC1 to 3. They have a very similar predicted structure, consisting of a 19 amphipathic β-strands barrel with an N-terminal α-helix in the central pore [, ]. The channel opening faces both the cytosol and mitochondrial intermembrane space [, ]. They play a major role in cellular energetic metabolism due to its ability to allow the exchange of molecules between the cytosol and the mitochondrial intermembrane space. They may also play a role in cell death. However, several mouse gene knock out studies show that VDACs are dispensable for both MPT (mitochondrial permeability transition) and Bcl-2 family member-driven cell death [, ].
Apoptosis, or programmed cell death (PCD), is a common and evolutionarily conserved property of all metazoans []. In many biological processes, apoptosis is required to eliminate supernumerary or dangerous (such as pre-cancerous) cells and to promote normal development. Dysregulation of apoptosis can, therefore, contribute to the development of many major diseases including cancer, autoimmunity and neurodegenerative disorders. In most cases, proteins of the caspase family execute the genetic programme that leads to cell death.Bcl-2 proteins are central regulators of caspase activation, and play a key role in cell death by regulating the integrity of the mitochondrial and endoplasmic reticulum (ER) membranes []. At least 20 Bcl-2 proteins have been reported in mammals, and several others have been identified in viruses. Bcl-2 family proteins fall roughly into three subtypes, which either promote cell survival (anti-apoptotic) or trigger cell death (pro-apoptotic). All members contain at least one of four conserved motifs, termed Bcl-2 Homology (BH) domains. Bcl-2 subfamily proteins, which contain at least BH1 and BH2, promote cell survival by inhibiting the adapters needed for the activation of caspases.Pro-apoptotic members potentially exert their effects by displacing the adapters from the pro-survival proteins; these proteins belong either to the Bax subfamily, which contain BH1-BH3, or to the BH3 subfamily, which mostly only feature BH3 []. Thus, the balance between antagonistic family members is believed to play a role in determining cell fate. Members of the wider Bcl-2 family, which also includes Bcl-x, Bcl-w and Mcl-1, are described by their similarity to Bcl-2 protein, a member of the pro-survival Bcl-2 subfamily []. Full-length Bcl-2 proteins feature all four BH domains, seven α-helices, and a C-terminal hydrophobic motif that targets the protein to the outer mitochondrial membrane, ER and nuclear envelope. Active cell suicide (apoptosis) is induced by events such as growth factor withdrawal and toxins. It is controlled by regulators, which have either an inhibitory effect on programmed cell death (anti-apoptotic) or block the protective effect of inhibitors (pro-apoptotic) [,]. Many viruses have found a way of countering defensive apoptosis by encoding their own anti-apoptosis genes preventing their target-cells from dying too soon. All proteins belonging to the Bcl-2 family []contain either a BH1, BH2, BH3, or BH4 domain. All anti-apoptoticproteins contain BH1 and BH2 domains, some of them contain an additional N-terminal BH4 domain (Bcl-2, Bcl-x(L), Bcl-w), which is never seen in pro-apoptotic proteins, except for Bcl-x(S). On the other hand, all pro-apoptotic proteins contain a BH3 domain (except for Bad) necessary fordimerisation with other proteins of Bcl-2 family and crucial for their killing activity, some of them also contain BH1 and BH2 domains (Bax, Bak). The BH3 domain is also present in some anti-apoptotic protein, such as Bcl-2 or Bcl-x(L). Proteins that are known to contain these domains include vertebrateBcl-2 (alpha and beta isoforms) and Bcl-x (isoforms (Bcl-x(L) and Bcl-x(S)); mammalian proteins Bax and Bak; mouse protein Bid; Xenopus laevis proteins Xr1 and Xr11; human induced myeloid leukemia celldifferentiation protein MCL1 and Caenorhabditis elegans protein ced-9.
Apoptosis, or programmed cell death (PCD), is a common and evolutionarily conserved property of all metazoans []. In many biological processes, apoptosis is required to eliminate supernumerary or dangerous (such as pre-cancerous) cells and to promote normal development. Dysregulation of apoptosis can, therefore, contribute to the development of many major diseases including cancer, autoimmunity and neurodegenerative disorders. In most cases, proteins of the caspase family execute the genetic programme that leads to cell death.Bcl-2 proteins are central regulators of caspase activation, and play a key role in cell death by regulating the integrity of the mitochondrial and endoplasmic reticulum (ER) membranes []. At least 20 Bcl-2 proteins have been reported in mammals, and several others have been identified in viruses. Bcl-2 family proteins fall roughly into three subtypes, which either promote cell survival (anti-apoptotic) or trigger cell death (pro-apoptotic). All members contain at least one of four conserved motifs, termed Bcl-2 Homology (BH) domains. Bcl-2 subfamily proteins, which contain at least BH1 and BH2, promote cell survival by inhibiting the adapters needed for the activation of caspases.Pro-apoptotic members potentially exert their effects by displacing the adapters from the pro-survival proteins; these proteins belong either to the Bax subfamily, which contain BH1-BH3, or to the BH3 subfamily, which mostly only feature BH3 []. Thus, the balance between antagonistic family members is believed to play a role in determining cell fate. Members of the wider Bcl-2 family, which also includes Bcl-x, Bcl-w and Mcl-1, are described by their similarity to Bcl-2 protein, a member of the pro-survival Bcl-2 subfamily []. Full-length Bcl-2 proteins feature all four BH domains, seven α-helices, and a C-terminal hydrophobic motif that targets the protein to the outer mitochondrial membrane, ER and nuclear envelope.
Apoptosis, or programmed cell death (PCD), is a common and evolutionarily conserved property of all metazoans []. In many biological processes, apoptosis is required to eliminate supernumerary or dangerous (such as pre-cancerous) cells and to promote normal development. Dysregulation of apoptosis can, therefore, contribute to the development of many major diseases including cancer, autoimmunity and neurodegenerative disorders. In most cases, proteins of the caspase family execute the genetic programme that leads to cell death.Bcl-2 proteins are central regulators of caspase activation, and play a key role in cell death by regulating the integrity of the mitochondrial and endoplasmic reticulum (ER) membranes []. At least 20 Bcl-2 proteins have been reported in mammals, and several others have been identified in viruses. Bcl-2 family proteins fall roughly into three subtypes, which either promote cell survival (anti-apoptotic) or trigger cell death (pro-apoptotic). All members contain at least one of four conserved motifs, termed Bcl-2 Homology (BH) domains. Bcl-2 subfamily proteins, which contain at least BH1 and BH2, promote cell survival by inhibiting the adapters needed for the activation of caspases.Pro-apoptotic members potentially exert their effects by displacing the adapters from the pro-survival proteins; these proteins belong either to the Bax subfamily, which contain BH1-BH3, or to the BH3 subfamily, which mostly only feature BH3 []. Thus, the balance between antagonistic family members is believed to play a role in determining cell fate. Members of the wider Bcl-2 family, which also includes Bcl-x, Bcl-w and Mcl-1, are described by their similarity to Bcl-2 protein, a member of the pro-survival Bcl-2 subfamily []. Full-length Bcl-2 proteins feature all four BH domains, seven α-helices, and a C-terminal hydrophobic motif that targets the protein to the outer mitochondrial membrane, ER and nuclear envelope.
B cell CLL/lymphoma-2 (Bcl-2) and related proteins comprise the Bcl-2 family. Bcl-2 proteins are central regulators of caspase activation, and play a key role in cell death by regulating the integrity of the mitochondrial and endoplasmic reticulum (ER) membranes []. Though originally characterised with respect to their roles in controlling outer mitochondrial membrane integrity and apoptosis, the members of the Bcl-2 family are involved in numerous cellular pathways [].Bcl-2 and its relatives are functionally classified as either antiapoptoticor proapoptotic. All members contain at least one of four conserved motifs, termed Bcl-2 Homology (BH) domains. Antiapoptotic BCL-2 proteins contain four Bcl-2 homology domains (BH1-4). The major antiapoptotic proteins are Bcl-2-related gene A1 (A1), Bcl-2, Bcl-2-related gene, long isoform (Bcl-xL), Bcl-w, and myeloid cell leukemia 1 (MCL-1). They preserve outer mitochondrial membrane (OMM) integrity by directly inhibiting the proapoptotic Bcl-2 proteins [].The proapoptotic Bcl-2 members are divided into the effector proteins and the BH3-only proteins. The effector proteins Bcl-2 antagonist killer 1 (BAK) and Bcl-2-associated x protein (BAX) were originally described to contain only BH1-3; however, structure-based alignments revealed a conserved BH4 motif []. Upon activation BAK and BAX homo-oligomerise into proteolipid pores within the OMM to promote MOMP (mitochondrial outer membrane permeabilisation). The BH3-only proteins function in distinct cellular stress scenarios and are subdivided based on their ability to interact with the antiapoptotic or both the antiapoptotic and the effector proteins [].Bcl-2-related ovarian killer protein (BOK) is a member of the Bcl-2 family that may play a role in apoptosis []. It is a potential proapoptotic effector protein, but there is no evidence to support a function akin to BAK or BAX.
B cell CLL/lymphoma-2 (Bcl-2) and related proteins comprise the Bcl-2 family. Bcl-2 proteins are central regulators of caspase activation, and play a key role in cell death by regulating the integrity of the mitochondrial and endoplasmic reticulum (ER) membranes []. Though originally characterised with respect to their roles in controlling outer mitochondrial membrane integrity and apoptosis, the members of the Bcl-2 family are involved in numerous cellular pathways [].Bcl-2 and its relatives are functionally classified as either antiapoptoticor proapoptotic. All members contain at least one of four conserved motifs, termed Bcl-2 Homology (BH) domains. Antiapoptotic BCL-2 proteins contain four Bcl-2 homology domains (BH1-4). The major antiapoptotic proteins are Bcl-2-related gene A1 (A1), Bcl-2, Bcl-2-related gene, long isoform (Bcl-xL), Bcl-w, and myeloid cell leukemia 1 (MCL-1). They preserve outer mitochondrial membrane (OMM) integrity by directly inhibiting the proapoptotic Bcl-2 proteins [].The proapoptotic Bcl-2 members are divided into the effector proteins and the BH3-only proteins. The effector proteins Bcl-2 antagonist killer 1 (BAK) and Bcl-2-associated x protein (BAX) were originally described to contain only BH1-3;however, structure-based alignments revealed a conserved BH4 motif []. Upon activation BAK and BAX homo-oligomerise into proteolipid pores within the OMM to promote MOMP (mitochondrial outer membrane permeabilisation). The BH3-only proteins function in distinct cellular stress scenarios and are subdivided based on their ability to interact with the antiapoptotic or both the antiapoptotic and the effector proteins [].Bcl-2 homologue antagonist/killer (BAK) is a proapoptotic member of the Bcl-2 family. In the presence of an appropriate stimulus, accelerates programmed cell death by binding to, and antagonizing the anti-apoptotic action of Bcl2 or its adenovirus homologue E1B 19k protein. Low micromolar levels of zinc ions inhibit the promotion of apoptosis [, ].
Apoptosis, or programmed cell death (PCD), is a common and evolutionarily conserved property of all metazoans []. In many biological processes, apoptosis is required to eliminate supernumerary or dangerous (such as pre-cancerous) cells and to promote normal development. Dysregulation of apoptosis can, therefore, contribute to the development of many major diseases including cancer, autoimmunity and neurodegenerative disorders. In most cases, proteins of the caspase family execute the genetic programme that leads to cell death.Bcl-2 proteins are central regulators of caspase activation, and play a key role in cell death by regulating the integrity of the mitochondrial and endoplasmic reticulum (ER) membranes []. At least 20 Bcl-2 proteins have been reported in mammals, and several others have been identified in viruses. Bcl-2 family proteins fall roughly into three subtypes, which either promote cell survival (anti-apoptotic) or trigger cell death (pro-apoptotic). All members contain at least one of four conserved motifs, termed Bcl-2 Homology (BH) domains. Bcl-2 subfamily proteins, which contain at least BH1 and BH2, promote cell survival by inhibiting the adapters needed for the activation of caspases.Pro-apoptotic members potentially exert their effects by displacing the adapters from the pro-survival proteins; these proteins belong either to the Bax subfamily, which contain BH1-BH3, or to the BH3 subfamily, which mostly only feature BH3 []. Thus, the balance between antagonistic family members is believed to play a role in determining cell fate. Members of the wider Bcl-2 family, which also includes Bcl-x, Bcl-w and Mcl-1, are described by their similarity to Bcl-2 protein, a member of the pro-survival Bcl-2 subfamily []. Full-length Bcl-2 proteins feature all four BH domains, seven α-helices, and a C-terminal hydrophobic motif that targets the protein to the outer mitochondrial membrane, ER and nuclear envelope.
B cell CLL/lymphoma-2 (Bcl-2) and related proteins comprise the Bcl-2 family. Bcl-2 proteins are central regulators of caspase activation, and play a key role in cell death by regulating the integrity of the mitochondrial and endoplasmic reticulum (ER) membranes []. Though originally characterised with respect to their roles in controlling outer mitochondrial membrane integrity and apoptosis, the members of the Bcl-2 family are involved in numerous cellular pathways [].Bcl-2 and its relatives are functionally classified as either antiapoptoticor proapoptotic. All members contain at least one of four conserved motifs, termed Bcl-2 Homology (BH) domains. Antiapoptotic BCL-2 proteins contain four Bcl-2 homology domains (BH1-4). The major antiapoptotic proteins are Bcl-2-related gene A1 (A1), Bcl-2, Bcl-2-related gene, long isoform (Bcl-xL), Bcl-w, and myeloid cell leukemia 1 (MCL-1). They preserve outer mitochondrial membrane (OMM) integrity by directly inhibiting the proapoptotic Bcl-2 proteins [].The proapoptotic Bcl-2 members are divided into the effector proteins and the BH3-only proteins. The effector proteins Bcl-2 antagonist killer 1 (BAK) and Bcl-2-associated x protein (BAX) were originally described to contain only BH1-3; however, structure-based alignments revealed a conserved BH4 motif []. Upon activation BAK and BAX homo-oligomerise into proteolipid pores within the OMM to promote MOMP (mitochondrial outer membrane permeabilisation). The BH3-only proteins function in distinct cellular stress scenarios and are subdivided based on their ability to interact with the antiapoptotic or both the antiapoptotic and the effector proteins [].This entry represents the Bcl2 family and related proteins, including E1B 19K protein (also known as E1B protein, small T-antigen), which is a putative adenovirus Bcl-2 homologue that inhibits E1A induced apoptosis and hence prolongs the viability of the host cell.
Apoptosis, or programmed cell death (PCD), is a common and evolutionarily conserved property of all metazoans []. In many biological processes, apoptosis is required to eliminate supernumerary or dangerous (such as pre-cancerous) cells and to promote normal development. Dysregulation of apoptosis can, therefore, contribute to the development of many major diseases including cancer, autoimmunity and neurodegenerative disorders. In most cases, proteins of the caspase family execute the genetic programme that leads to cell death.Bcl-2 proteins are central regulators of caspase activation, and play a key role in cell death by regulating the integrity of the mitochondrial and endoplasmic reticulum (ER) membranes []. At least 20 Bcl-2 proteins have been reported in mammals, and several others have been identified in viruses. Bcl-2 family proteins fall roughly into three subtypes, which either promote cell survival (anti-apoptotic) or trigger cell death (pro-apoptotic). All members contain at least one of four conserved motifs, termed Bcl-2 Homology (BH) domains. Bcl-2 subfamily proteins, which contain at least BH1 and BH2, promote cell survival by inhibiting the adapters needed for the activation of caspases.Pro-apoptotic members potentially exert their effects by displacing the adapters from the pro-survival proteins; these proteins belong either to the Bax subfamily, which contain BH1-BH3, or to the BH3 subfamily, which mostly only feature BH3 []. Thus, the balance between antagonistic family members is believed to play a role in determining cell fate. Members of the wider Bcl-2 family, which also includes Bcl-x, Bcl-w and Mcl-1, are described by their similarity to Bcl-2 protein, a member of the pro-survival Bcl-2 subfamily []. Full-length Bcl-2 proteins feature all four BH domains, seven α-helices, and a C-terminal hydrophobic motif that targets the protein to the outer mitochondrial membrane, ER and nuclear envelope. This entry represents the N-terminal region of several mammal specific Bim proteins. The Bim protein is one of the BH3-only proteins, members of the Bcl-2 family that have only one of the Bcl-2 homology regions, BH3.
Bcl-2 proteins are central regulators of caspase activation, and play a key role in cell death by regulating the integrity of the mitochondrial and endoplasmic reticulum (ER) membranes []. At least 20 Bcl-2 proteins have been reported in mammals, and several others have been identified in viruses. Bcl-2 family proteins fall roughly into three subtypes, which either promote cell survival (anti-apoptotic) or trigger cell death (pro-apoptotic). All members contain at least one of four conserved motifs, termed Bcl-2 Homology (BH) domains. Bcl-2 subfamily proteins, which contain at least BH1 and BH2, promote cell survival by inhibiting the adapters needed for the activation of caspases.Pro-apoptotic members potentially exert their effects by displacing the adapters from the pro-survival proteins; these proteins belong either to the Bax subfamily, which contain BH1-BH3, or to the BH3 subfamily, which mostly only feature BH3 []. Thus, the balance between antagonistic family members is believed to play a role in determining cell fate. Members of the wider Bcl-2 family, which also includes Bcl-x, Bcl-w and Mcl-1, are described by their similarity to Bcl-2 protein, a member of the pro-survival Bcl-2 subfamily []. Full-length Bcl-2 proteins feature all four BH domains, seven α-helices, and a C-terminal hydrophobic motif that targets the protein to the outer mitochondrial membrane, ER and nuclear envelope. BID is a member of the Bcl-2 superfamily of proteins that are key regulators of programmed cell death, hence this family is related to the Apoptosis regulator Bcl-2 protein BH domain. BID is a pro-apoptotic member of the Bcl-2 superfamily and as such posses the ability to target intracellular membranes and contains the BH3 death domain. The activity of BID is regulated by a Caspase 8-mediated cleavage event, exposing the BH3 domain and significantly changing the surface charge and hydrophobicity, which causes a change of cellular localisation [].
Apoptosis, or programmed cell death (PCD), is a common and evolutionarily conserved property of all metazoans []. In many biological processes, apoptosis is required to eliminate supernumerary or dangerous (such as pre-cancerous) cells and to promote normal development. Dysregulation of apoptosis can, therefore, contribute to the development of many major diseases including cancer, autoimmunity and neurodegenerative disorders. In most cases, proteins of the caspase family execute the genetic programme that leads to cell death.Bcl-2 proteins are central regulators of caspase activation, and play a key role in cell death by regulating the integrity of the mitochondrial and endoplasmic reticulum (ER) membranes []. At least 20 Bcl-2 proteins have been reported in mammals, and several others have been identified in viruses. Bcl-2 family proteins fall roughly into three subtypes, which either promote cell survival (anti-apoptotic) or trigger cell death (pro-apoptotic). All members contain at least one of four conserved motifs, termed Bcl-2 Homology (BH) domains. Bcl-2 subfamily proteins, which contain at least BH1 and BH2, promote cell survival by inhibiting the adapters needed for the activation of caspases.Pro-apoptotic members potentially exert their effects by displacing the adapters from the pro-survival proteins; these proteins belong either to the Bax subfamily, which contain BH1-BH3, or to the BH3 subfamily, which mostly only feature BH3 []. Thus, the balance between antagonistic family members is believed to play a role in determining cell fate. Members of the wider Bcl-2 family, which also includes Bcl-x, Bcl-w and Mcl-1, are described by their similarity to Bcl-2 protein, a member of the pro-survival Bcl-2 subfamily []. Full-length Bcl-2 proteins feature all four BH domains, seven α-helices, and a C-terminal hydrophobic motif that targets the protein to the outer mitochondrial membrane, ER and nuclear envelope. This group represents the Bcl-2-like protein 11 which can induce apoptosis.
Apoptosis, or programmed cell death (PCD), is a common and evolutionarily conserved property of all metazoans []. In many biological processes, apoptosis is required to eliminate supernumerary or dangerous (such as pre-cancerous) cells and to promote normal development. Dysregulation of apoptosis can, therefore, contribute to the development of many major diseases including cancer, autoimmunity and neurodegenerative disorders. In most cases, proteins of the caspase family execute the genetic programme that leads to cell death.Bcl-2 proteins are central regulators of caspase activation, and play a key role in cell death by regulating the integrity of the mitochondrial and endoplasmic reticulum (ER) membranes []. At least 20 Bcl-2 proteins have been reported in mammals, and several others have been identified in viruses. Bcl-2 family proteins fall roughly into three subtypes, which either promote cell survival (anti-apoptotic) or trigger cell death (pro-apoptotic). All members contain at least one of four conserved motifs, termed Bcl-2 Homology (BH) domains. Bcl-2 subfamily proteins, which contain at least BH1 and BH2, promote cell survival by inhibiting the adapters needed for the activation of caspases.Pro-apoptotic members potentially exert their effects by displacing the adapters from the pro-survival proteins; these proteins belong either to the Bax subfamily, which contain BH1-BH3, or to the BH3 subfamily, which mostly only feature BH3 []. Thus, the balance between antagonistic family members is believed to play a role in determining cell fate. Members of the wider Bcl-2 family, which also includes Bcl-x, Bcl-w and Mcl-1, are described by their similarity to Bcl-2 protein, a member of the pro-survival Bcl-2 subfamily []. Full-length Bcl-2 proteins feature all four BH domains, seven α-helices, and a C-terminal hydrophobic motif that targets the protein to the outer mitochondrial membrane, ER and nuclear envelope. In healthy cells, Bcl-w resides in the cytoplasm, and becomes membrane-associated in response to cytotoxic insults. Its 3D structure comprises a bundle of five amphipathic α-helices surrounding two central hydrophobic helical regions. A hydrophobic groove, formed by residues from BH1-BH3, is capable of binding the BH3 α-helix from a pro-apoptotic BH3-only family member [].
