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Bcl-2 family
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Bcl-2 family
The Bcl-2 family (TC# 1.A.21) 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.
Members of the BCL-2 family regulate apoptosis in mammals, reptiles, amphibs, fish, and other phyla of metazoan life, with exception of nematodes and insects. Their molecular structure and function, as well as their protein dynamics, are highly conserved over hundreds of millions of years in tissue forming life forms.
Bcl-2 family proteins have a general structure that consists of a hydrophobic α-helix surrounded by amphipathic α-helices. Some members of the family have transmembrane domains at their c-terminus which primarily function to localize them to the mitochondrion.
Bcl-x(L) is 233 amino acyl residues (aas) long and exhibits a single very hydrophobic putative transmembrane α-helical segment (residues 210-226) when in the membrane. Homologues of Bcl-x include the Bax (rat; 192 aas) and Bak (mouse; 208 aas) proteins, which also influence apoptosis. The high resolution structure of the monomeric soluble form of human Bcl-x(L) has been determined by both x-ray crystallography and NMR.
The structure consists of two central primarily hydrophobic α-helices surrounded by amphipathic helices. The arrangement of the α-helices in Bcl-X(L) resembles that for diphtheria toxin and the colicins. Diphtheria toxin forms a transmembrane pore and translocates the toxic catalytic domain into the animal cell cytoplasm. The colicins similarly form pores in lipid bilayers. Structural homology therefore suggests that Bcl-2 family members that contain the BH1 and BH2 domains (Bcl-X(L) Bcl-2 and Bax) function similarly.
The members of the Bcl-2 family share one or more of the four characteristic domains of homology entitled the Bcl-2 homology (BH) domains (named BH1, BH2, BH3 and BH4) (see figure). The BH domains are known to be crucial for function, as deletion of these domains via molecular cloning affects survival/apoptosis rates. The anti-apoptotic Bcl-2 proteins, such as Bcl-2 and Bcl-xL, conserve all four BH domains. The BH domains also serve to subdivide the pro-apoptotic Bcl-2 proteins into those with several BH domains (e.g. Bax and Bak) or those proteins that have only the BH3 domain (e.g. Bim Bid and BAD)
All proteins belonging to the Bcl-2 family contain either a BH1, BH2, BH3 or BH4 domain. All anti-apoptotic proteins contain BH1 and BH2 domains, some of them contain an additional N-terminal BH4 domain (Bcl-2, Bcl-x(L) and Bcl-w), which is also seen in some pro-apoptotic proteins like Bcl-x(S), Diva, Bok-L and Bok-S. On the other hand, all pro-apoptotic proteins contain a BH3 domain necessary for dimerization with other proteins of Bcl-2 family and crucial for their killing activity, some of them also contain BH1 and BH2 domains (Bax and Bak). The BH3 domain is also present in some anti-apoptotic protein, such as Bcl-2 or Bcl-x(L). The three functionally important Bcl-2 homology regions (BH1, BH2 and BH3) are in close spatial proximity. They form an elongated cleft that may provide the binding site for other Bcl-2 family members.
Regulated cell death (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.
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Bcl-2 family
The Bcl-2 family (TC# 1.A.21) 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.
Members of the BCL-2 family regulate apoptosis in mammals, reptiles, amphibs, fish, and other phyla of metazoan life, with exception of nematodes and insects. Their molecular structure and function, as well as their protein dynamics, are highly conserved over hundreds of millions of years in tissue forming life forms.
Bcl-2 family proteins have a general structure that consists of a hydrophobic α-helix surrounded by amphipathic α-helices. Some members of the family have transmembrane domains at their c-terminus which primarily function to localize them to the mitochondrion.
Bcl-x(L) is 233 amino acyl residues (aas) long and exhibits a single very hydrophobic putative transmembrane α-helical segment (residues 210-226) when in the membrane. Homologues of Bcl-x include the Bax (rat; 192 aas) and Bak (mouse; 208 aas) proteins, which also influence apoptosis. The high resolution structure of the monomeric soluble form of human Bcl-x(L) has been determined by both x-ray crystallography and NMR.
The structure consists of two central primarily hydrophobic α-helices surrounded by amphipathic helices. The arrangement of the α-helices in Bcl-X(L) resembles that for diphtheria toxin and the colicins. Diphtheria toxin forms a transmembrane pore and translocates the toxic catalytic domain into the animal cell cytoplasm. The colicins similarly form pores in lipid bilayers. Structural homology therefore suggests that Bcl-2 family members that contain the BH1 and BH2 domains (Bcl-X(L) Bcl-2 and Bax) function similarly.
The members of the Bcl-2 family share one or more of the four characteristic domains of homology entitled the Bcl-2 homology (BH) domains (named BH1, BH2, BH3 and BH4) (see figure). The BH domains are known to be crucial for function, as deletion of these domains via molecular cloning affects survival/apoptosis rates. The anti-apoptotic Bcl-2 proteins, such as Bcl-2 and Bcl-xL, conserve all four BH domains. The BH domains also serve to subdivide the pro-apoptotic Bcl-2 proteins into those with several BH domains (e.g. Bax and Bak) or those proteins that have only the BH3 domain (e.g. Bim Bid and BAD)
All proteins belonging to the Bcl-2 family contain either a BH1, BH2, BH3 or BH4 domain. All anti-apoptotic proteins contain BH1 and BH2 domains, some of them contain an additional N-terminal BH4 domain (Bcl-2, Bcl-x(L) and Bcl-w), which is also seen in some pro-apoptotic proteins like Bcl-x(S), Diva, Bok-L and Bok-S. On the other hand, all pro-apoptotic proteins contain a BH3 domain necessary for dimerization with other proteins of Bcl-2 family and crucial for their killing activity, some of them also contain BH1 and BH2 domains (Bax and Bak). The BH3 domain is also present in some anti-apoptotic protein, such as Bcl-2 or Bcl-x(L). The three functionally important Bcl-2 homology regions (BH1, BH2 and BH3) are in close spatial proximity. They form an elongated cleft that may provide the binding site for other Bcl-2 family members.
Regulated cell death (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.
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