In this post I will attempt to make my case for why you should consider the Fas/FADD death domain complex as a strong contender for protein of the year. Unlike several of our opponents, My protein has not received any favors by presented in class... (I'm looking at you RuBisCO and Nitrogenase...). To be fair, these proteins do very novel chemistry. Without RuBisCO we would find ourselves lacking fresh air to breath and without nitrogenase we would find ourselves without plants to produce RuBisCO. However, as Prof. Arnoys said today "breathing is for the weak". Assuming this to be true I would now like to present my case for protein of the year.
Apoptosis can be initiated in two ways: either a cell fails to recieve the signal to survive or the cell recieves a signal for death. One method of actively signaling for apoptosis proceeds through the formation of a signalling complex called the Fas/FADD death domain complex. This occurs through the event of a Fas trimer bonding with a FasL trimer from a neighboring cell. However, unlike cell necrosis, apoptosis does not cause the release of cellular content and no inflammatory response is initiated.
The Fas/FADD death domain complex is formed through the boding of the FADD protein domain to the Fas Domain (initiated through the binding of Fas to FasL mentioned above. These interactions are novel as the bonds which hold these complexes together are very weak. Although this protein tends to form tetramers and higher oligomers, the complex is only held together through hydrophobic interactions as can be seen below.
This results in a highly oligomeric product which signals cell apoptosis in the following steps.
1.Fas trimer's on the surface of a cell bind with Fas-Ligands on the exterior of a neighboring cell.
2. The Death induced signaling complex (DISC) is formed through the incorporation of FADD.
4. signaling molecules are released (more shazam)
5. A lot more intercellular-activity that was imitated through the DISC formation
OR, for the not weak of heart, the complicated explanation:
1. A Fas Trimer associates with the adapter protein: Fas-Ligand
2. The DISC (death induced signaling complex) is formed
3. The adapter protein FADD, Fas associated death domain, binds its death domain to the death domain of the Fas
4. The DED, death effector domain, of FADD binds the DED of procaspase 8 into the DISC
5. Procaspace 8 is activated and caspase 8 dissociates from the DISC moving into the cytoplasm
6. Caspase 8 cleaves procaspase 3 into active caspase 3
7. Caspase 3 cleaves I-CAD, enabling the activity of CAD which enters the nucleus and begins to destroy DNA
Although the Fas/FADD death domain begins the process of cell apoptosis, the enzyme lacks a specific interaction site. There is no well defined active site and as such, ligands and signalling molecules bind only through being incorporated into or forming additional clusters with the DISC.
As one might imagine, a protein which can induec cellular death has potential to be employed as killer of virally infected cells. Cytotoxic T cells can kill a virally infected cell in two ways: one, through the release of toxic perforins and granzymes and two, through the association of a T cell Fas-Ligand With a Fas trimer on the infected cell. The T-cells identify a infected cell, and when the FasL bound to the T-cell binds to the Fas trimer on the surface of the infected cell the DISC forms. This then causes the cell to commit apoptosis, that is cellular death without the release inner cellular content. This then would cause the "death" of the infected cell without releasing the virus to simply move on and infect the closest target.
To recount the reasons why this protein is cool:
1. Initiates apoptosis through binding of a ligand
2. No active site. All signaling molecules released from this protein must be formed from substrates incorporated into the DISC cluster.
3. It has an awesome name
4. Can function as a way to destroy virally infected cells.
5. It has an awesome name
6. The DISC cluster is held together only through hydrophobic interactions
7. It has an awesome name