What are the different sub-classes of BCI2 proteins? Explain briefly based on structure and function

The Bcl-2 family of proteins is a very important group of regulatory proteins that play a major role in the intrinsic (mitochondrial) pathway of apoptosis, which is a kind of programmed cell death. These proteins mainly control the permeability of the mitochondrial outer membrane and thus regulate the release of apoptotic factors like cytochrome c. This family includes both pro-apoptotic proteins (which promote cell death) and anti-apoptotic proteins (which protect the cell from dying).

Sub-classes of Bcl-2 Family Proteins

These proteins are classified into different sub-classes based on the number and type of BH (Bcl-2 Homology) domains they contain, and also based on their functional role in apoptosis. There are three major sub-classes of Bcl-2 family proteins.

1. Anti-apoptotic Bcl-2 Proteins (BH1-BH4 containing proteins)

These proteins inhibit apoptosis and protect cells from death. Structurally, they have all four BH domains: BH1, BH2, BH3 and BH4. Functionally, they bind to pro-apoptotic proteins like Bax, Bak, or BH3-only proteins and neutralise their apoptotic action. By doing this, they prevent the permeabilization of the mitochondrial outer membrane, which stops the release of cytochrome c, a key step in activating caspases.

Examples:
  • Bcl-2: First identified in B-cell lymphomas. It stabilises mitochondria and prevents MOMP (mitochondrial outer membrane permeabilization).
  • Bcl-XL: Expressed in many cell types and inhibits apoptosis by binding to Bax and Bak.
  • Other proteins: Mcl-1, Bcl-w, A1/Bfl-1.

2. Pro-apoptotic Effector Proteins (BH1-BH3 containing)

These proteins help in the execution of apoptosis. They have three BH domains: BH1, BH2 and BH3, but lack BH4. Structurally, they can form homodimers or heterodimers and functionally they insert into mitochondrial membranes to form pores. These pores allow the release of cytochrome c, which then activates the downstream caspases like caspase-9.

Examples:
  • Bax: Normally present in the cytosol in inactive form. After apoptotic signals, it changes shape and moves to the mitochondria to form pores.
  • Bak: Always anchored to the mitochondrial membrane. On activation, it forms oligomers that disturb membrane integrity.
Both Bax and Bak are essential for the proper induction of intrinsic apoptosis.

3. BH3-only Pro-apoptotic Proteins

These proteins act as initiators or sensors of apoptosis. They contain only the BH3 domain and do not form pores themselves. Their main job is to activate Bax and Bak directly or to inhibit the anti-apoptotic Bcl-2 proteins, which frees Bax/Bak to do their job. These proteins are often upregulated or activated in response to cellular stress, DNA damage, or growth factor deprivation.

These BH3-only proteins work like messengers that sense damage and then pass the death signal to the main effectors (Bax/Bak).

Examples:
  • Bid: Cleaved by caspase-8 into tBid during extrinsic apoptosis. tBid then activates Bax/Bak.
  • Bad: Becomes active when dephosphorylated. It binds to Bcl-2 or Bcl-XL and frees Bax/Bak.
  • Bim: Activated under stress like growth factor withdrawal.
  • Puma and Noxa: Induced by p53 during DNA damage.





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