We are Family!

As mentioned on the Introduction page the Bcl-2 family of proteins play a key role in regulating the release of cytochrome c from the mitochondria, where the Bcl-2 proteins are situated. This family has many members which are organised in two distinctive groups that have different functions in relation to the release of cytochrome c, these groups are pro-apoptotic and anti-apoptotic proteins and they stimulate and inhibit the release of cytochrome c, respectively _[8].

FUN FACT: Originally this family of proteins was discoveed as an oncogene in the B-cell lymphoma that was overexpressed due to chromosomal locations_[9].

Good Cop, Bad Cop

As described there are two different types of Bcl-2 proteins within the family theser groups are called pro and anti apoptotic.

• Anti-apoptotic:

  • Bcl-2, Bcl-X_L, Bcl-w, Bfl-1, BHRF and Mcl-1

  • These proteins suppress apoptosis, if activated they will work to inhibit apoptosis

  • This can go seriously wrong and too much apoptosis inhibition can cause disease such as cancer and therefore causes increased proliferation.

• Pro-apoptotic:

  • Bax, Bad, Bak, Bid, Bim, Blk and Hrk

  • These proteins stimulate apoptosis by inhibiting the action of anti-apoptotic proteins _{[10][11][12][13]}.

• Heterodimerisation is key to the regulation of apoptosis. As when a pro-apoptotic protein binds to an anti-apoptotic protein they inhibit each other's functions.

  • They bind together by attaching to a specific region on their structure that enables interaction and therefore form a secure dimer_[14].

Sequence and Structure

This family of proteins has been extensively studied in terms of mutational aspects and sequence alignment analyses. This information has brought to light how the different members of this family are related by sequence and structure and therefore their function.

• Homology has been discovered in most of the proteins in certain regions of the sequence.
• These homologous regions are Bcl-2 Homology regions and 4 have been discovered (BH1-4) _[15].
• BH1-3 have been discovered to function as the binding site for other Bcl-2 family members.
• BH4 however has not been found to function this way.
  • This suggests that the Bcl-2 family have many area of interaction in order to bind with many partners _[16].

Apoptosis and Bcl-2

This pathway has many stimuli cytotoxic damage and DNA damage are just two of the many that activate the Bcl-2 mediated pathway (external pathway).

Anti-apoptotic members of this protein family focus on the homeostasis of the mitochondrial structure. Their function is to prevent pro-apoptotic member such as Bak and Bax from causing damage to the mitochondria.

If damage is caused BH3-only proteins are activated to inhibit the anti-apoptotic proteins and therefore the inhibition of these anti-apoptotic members is ceased. This leads to their oligomerisation and proceed to form pH-dependent ion channels in the mitochondrial membranes.

These channels are used to transport cytochrome c out into the cytosol, where it will then partner with APAF-1 and ATP to form a recruitment platform for procaspase-9 activation, known as the apoptosome. This step connect the external and internal pathways to guide apoptosis to completion _[17].