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The Security Checkpoint of Cells: Stopping Bad Proteins at the Border

Mirella Bucci
Department of Biological Sciences
Stanford University
March 2002

When proteins are made within a cell, they must first pass through a checkpoint to ensure that they are made properly. When this mechanism is defective or is overloaded, proteins which are not folded properly may accumulate within cells. This is the basis of Cystic Fibrosis and several neurodegenerative diseases such as Lou Gehrig's, Alzheimers and Huntington's diseases. Our lab uses these neurodegeneration models to understand multiple features of the control mechanism including how proteins are folded, how "bad" ones are recognized and how they are disposed of. The cell seems to accomplish this by integrating the protein folding machinery with the protein degradation machinery in an extensive pathway called "quality control."

It is critical for cells to maintain a pool of proteins which are functionally and structurally efficient. Within cells, proteins are made at a rate of hundreds per second. At this speed, it is likely that errors are made with some frequency. Fortunately, cells are equipped with mechanisms to recognize and dispose of defective proteins efficiently. In fact, within the same compartment in which they are made, proteins are monitored for proper structure after they are folded. Proteins which are made or folded incorrectly or cannot function properly must be disposed of. To do this, cells have adopted a "quality control" mechanism that monitors each protein's progress.

It is not known how the quality control mechanism works to recognize misfolded proteins, especially since the chains of amino acids that constitute can fold into many diverse protein shapes. Proteins like the one responsible for cystic fibrosis have a single amino acid out of place. Because of this, the culprit protein is grossly misfolded. In cystic fibrosis, and in many other diseases caused by a "bad" protein, the protein will become recognized and degraded very rapidly. In this case, the protein is not available to carry out its normal function and therefore the cell becomes deficient in that protein, thereby allowing cystic fibrosis to occur. Perhaps in cases like this, the quality control mechanism recognizes portions of misfolded proteins which are normally not exposed in properly folded proteins.

Another problem can arise for the cell if too much misfolded protein is built up and the cell cannot dispose of them quickly enough. Normally, "bad" proteins are degraded after they leave the quality control compartment. To accomplish this, proteins are fed into barrel-shaped structures called proteasomes. Proteasomes contain specialized proteins called enzymes which chew up the "bad" proteins, thereby destroying them. If the proteasomes are not functioning properly or the cellular environment is not conducive to protein folding, a backlog or choking of the proteasome can occur. When this happens, misfolded protein can accumulate in a cellular junk pile called an inclusion body.

Inclusion bodies are a hallmark of several neurodegenerative diseases such as Huntington's and Alzheimers diseases. In these cases, special cells within the brain called neurons accumulate large inclusion bodies which cannot be removed thereby making the neurons dysfunctional. This is presumably due to the sheer volume of cell taken up by the inclusion body. To better understand the reasons for these cellular diseases, it is critical to identify the unknown features and players of the quality control pathway from the point proteins are made until the point they are degraded.

Having shown all of this, our laboratory is currently focused on the degradative pathways cells can use to destroy unwanted unfolded proteins and the ability of these pathways to function properly during the accumulation of these "bad" proteins. We are investigating the possibility of other uncharacterized pathways that cells may use to deal with these proteins. These include autophagy (from the Latin for self-eating), a mechanism used by cells to deal with stressful conditions like starvation and extreme temperatures. We believe that autophagy and the proteasomes are but two pathways that cells can use to maintain a pool of properly folded and functional proteins.