The center of this story, in more ways than one, is the Golgi apparatus (pronounced ‘goal jee’). As a crude analogy, think of the Golgi apparatus as a re-packaging operation inside of living cells. It receives packages (called vesicles, which are like tiny bubbles) of proteins from the parts of the cell where proteins are produced (primarily the endoplasmic reticulum). It empties the vesicle and analyzes the type of protein. From that it determines where in the cell, or out of it, the protein should go. If the protein is destined to leave the cell, the Golgi attaches a specialized fatty-acid molecule (a lipid) to it in a process called palmitoylation. Then the protein is attached to the outer surface of the Golgi and a new vesicle is formed and ‘aimed’ (by following actin structures in the cell) at the outer membrane. Once at the membrane, the attached fat molecule is used to anchor the protein to the membrane, either to hold it there in reserve, or to pass the vesicle through to the outside of the membrane and on to other nearby cells.
It is the fatty-acid molecule that attracted the most interest from the scientists at the Max Planck Institute of Molecular Physiology in Dortmund (Germany). They are among the first to identify and observe the action of this attached molecule with the aid of new-generation microscopic techniques. Their work, published in Cell and Nature Chemical Biology in April, 2010, explains an important principle used in the transport of proteins throughout the cell, and then applies that knowledge to a potential anti-cancer application.
They discovered that the lipid molecule is like a key that fits a lock on a membrane surface. It can be attached to any protein that has an exposed amino acid called cysteine. However the molecule is not specific to the cell’s outer membrane. It can also anchor the protein to the membranes of internal components called organelles. (The Golgi is itself one of the organelles.) Eventually, the organelle membranes would be covered with unneeded proteins; however the cell also produces enzymes (found throughout the cell fluid, or cytosol) that remove the lipid molecule, causing the protein to float free. Eventually it is drawn back into the Golgi, where it can be repackaged – and the cycle starts over.
This relatively simple process – placing a targeting molecule on a protein and aiming it at the cell membrane, but removing the molecule when the protein misses the target – has implications that can be applied to specific proteins. One in particular, known as Ras is a palmitoylated protein (it has the lipid molecule attached), which in mutated forms is strongly associated with cancer. Interestingly, the Ras protein can only function when embedded solely in the cell membrane; if it is also embedded in organelle membranes, it doesn’t function correctly. The researchers reasoned that if something could keep the Ras protein attached to organelle membranes that might be a way to hinder or stop the cancer associated with mutated Ras.
The outcome was the development of palmostatin B, which inhibits the enzyme that releases the lipid molecule. Without that enzyme, Ras remains attached to all the membranes in the cell and cannot function. This outcome is a lot better than previous techniques, which involved turning off the gene that produces Ras and has the unfortunate consequence of also killing the cell. The palmostatin B suppresses the Ras and returns the cell to normal operation.
The discovery of palmitoylation and the protein transport cycle associated with it, provides a good example of how new knowledge of a fundamental process of cell biology can lead to insights that may be helpful in treating diseases. However, it should be noted that the discovery and subsequent development of palmostatin B is a long way from entering the list of active pharmaceuticals. There are fundamental issues involved with delivery and long-term action of palmostatin B and with possible (unknown) side effects, which will only surface during long and thorough testing.