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The Bcl-2 family of proteins: A life or death situation

christie cade

Christie Cade I'm on ScienceSeeker-Microscope

If you’ve taken a biochemistry class, you’ve probably heard the structure-function paradigm for proteins: amino acid sequence dictates how the protein will be folded, and the ordered 3D structure of the protein is necessary for function.(1) For example, proper formation of an active site is necessary for an enzyme to be able to carry out catalysis. You may have heard some of the models for how proteins fit with their binding partners. For example, the lock-and-key model assumes that the protein and its binding partner are rigid, and this rigid shape determines how well they interact. These models can be useful, but they tend to leave out an important group of proteins: those whose function depends on disorder. Based on sequence analysis, it is estimated that more than 30% of proteins in cells have disordered regions of greater than or equal to 50 consecutive residues.

One family of proteins which relies on disorder for function is the Bcl-2 family of proteins.(2) These proteins can be split into two groups based on their function: pro-apoptotic (when they are activated they lead to cell death) or pro-survival (also called anti-apoptotic). An imbalance between these two groups of proteins can lead to neurodegenerative diseases (too much cell death) or cancer (not enough cell death).

Bcl Protein

Structure of Bcl-w, a pro-survival protein (2)

Based mainly on structure, there are two groups of pro-apoptotic Bcl-2 proteins: BH3-only and multi-motif.(2) The BH3-only pro-apoptotic proteins are disordered in solution but undergo a disorder-to-order transition to form a helix when they are bound to another protein. The multi-motif pro-apoptotic proteins, on the other hand, have similar structures to the pro-survival proteins: their core structure is made up of 9 helices.

When they receive a cellular signal, the BH3-only proteins bind to a groove in the pro-survival Bcl-2 proteins.(2) This interaction releases the multi-motif pro-apoptotic proteins to form channels in the mitochondria for the release of cytochrome c, which leads to activation of caspases and therefore cell death.

Bcl2 in apoptosis

Involvement of Bcl-2 family in apoptosis (2)

The BH3-only proteins are not the only members of the Bcl-2 family to have disorder.(2) Although the pro-survival and multi-motif pro apoptotic proteins generally contain nine helices, the loop regions between helices can be disordered. For example, Bcl-2, one of the pro-survival proteins, has a disordered loop that is 60 residues long. Additionally, the binding of the BH3-only proteins to the pro-survival proteins displaces their C-terminal helix from its binding groove and causes it to become disordered in solution.

BH3-only protein

Binding of pro-apoptotic BH3-only proteins to pro-survival proteins result in a disorder-to-order transition (2).

The disordered regions of these proteins are important for their regulation. For example, the disordered regions can be sites for phosphorylation, ubiquitylation, or protease digestion.(2) Additionally, the 60-residue disordered loop of Bcl-2 was found to bind the anti-cancer drug paclitaxel (Taxol).(3) It was originally thought that the effect of Taxol on the Bcl-2 proteins was only indirect, through binding of the drug to β-tubulin in microtubules, which leads to cellular signals that eventually activate the Bcl-2 family pro-apoptotic proteins. However, it was found that Taxol actually binds Bcl-2 directly and that this causes Bcl-2 to switch from being pro-survival to being pro-apoptotic. It was also found that Taxol mimics the protein Nur77 in the way that it binds to Bcl-2 and β-tubulin.(4) Therefore, Nur77 may play a role in homeostasis (balancing cell death and survival).

In conclusion, the balance between Bcl-2 family members can determine whether a cell lives or dies. Misregulation of these proteins can lead to neurodegenerative disorders or cancer. The regulation of these proteins, including the binding of the anti-cancer drug Taxol, occurs mainly in the disordered regions of the Bcl-2 family. Therefore, the disorder of the Bcl-2 family of proteins can make the difference between life and death.

References:

1. Dunker, A.K., Lawson, J.D., Brown, C.J., Williams, R.M., Romero, P., Oh, J.S., Oldfield, C.J., Campen, A.M., Ratliff, C.M., Hipps, K.W. & (2001). Intrinsically disordered protein, Journal of Molecular Graphics and Modelling, 19 (1) 59. DOI: 10.1016/S1093-3263(00)00138-8

2. Rautureau, G.J.P., Day, C.L. & Hinds, M.G. (2010). Intrinsically Disordered Proteins in Bcl-2 Regulated Apoptosis, International Journal of Molecular Sciences, 11 (4) 1824. DOI: 10.3390/ijms11041808

3. Rodi, D.J., Janes, R.W., Sanganee, H.J., Holton, R.A., Wallace, B.A. & Makowski, L. (1999). Screening of a library of phage-displayed peptides identifies human Bcl-2 as a taxol-binding protein, Journal of Molecular Biology, 285 (1) 203. DOI: 10.1006/jmbi.1998.2303

4. Ferlini, C., Cicchillitti, L., Raspaglio, G., et al. (2009) Paclitaxel directly binds to Bcl-2 and functionally mimics activity of Nur77. Cancer Res 69 (17) 6906. DOI: 10.1158/0008-5472.CAN-09-0540