How Cells Recognize and Destroy "Problem"
My lab studies proteins called molecular chaperones. Chaperones help to shape, or fold, other proteins into their proper structure. Sometimes proteins cannot fold appropriately. This can cause problems in the cell that result in neurodegenerative diseases such as Alzheimer's' disease, Huntington's disease, and Parkinson's disease. I am studying how chaperones help identify proteins that cannot fold into their proper structure and how chaperones target misfolded proteins for destruction the cell' degradation machinery. Degradation of these "problem proteins" is one of the ways the cell can try to prevent the development of disease.
Each of the thousands of proteins found in a cell has a specific job to do. Many proteins are often required to accomplish a complex task. A few of the multitude of cellular processes in which proteins participate include controlling cell growth, protecting against DNA damage, and providing structural strength to the cell. Proteins are created when a cell translates the message encoded in a gene into a linear string of amino acids. This string must "fold" up into a very specific three-dimensional structure for the protein to be able to perform its job. Although a protein could potentially fold into an almost infinite number of different arrangements, or conformations, only one specific conformation of the protein is able to perform the job the protein was built to do. It is up to proteins called molecular chaperones to help other proteins fold into their appropriate, or "native", conformation.
Even with molecular chaperones around to help, sometimes proteins cannot fold into the native conformation. Such proteins are referred to as misfolded proteins. Protein misfolding can occur for many reasons. For example, if the DNA encoding the protein was mutated, the protein product may contain the wrong amino acids and never be able to fold appropriately. Direct damage to a protein that has already folded can also cause the protein to loose its shape. Whatever the cause, when misfolded proteins are present in the cell, the proteins must be recognized by the cell's quality control system and disposed of quickly.
If they are not detected, misfolded proteins can cause problems not only for the cell but also the organism in which the cell resides. The development of neurodegenerative diseases such as Alzheimer's' disease, Huntington's disease,and Parkinson's disease has been linked to problems that arise when misfolded proteins escape the cell's quality control system.
I am looking at the role of molecular chaperones in the disposal of misfolded proteins. Although molecular chaperones are responsible for helping to fold many proteins, they are also involved the destruction of proteins that cannot fold appropriately. It is unclear how chaperones perform this dual role. I am examining this problem by setting up an experimental system that includes misfolded model proteins, molecular chaperones, and the degradation machinery. I began by measuring the effect of changing the concentration of various molecular chaperones on the destruction of the misfolded proteins. Using this approach, I have identified a few molecular chaperones that appear to be involved in the degradation of the misfolded model proteins. However, I need to look at the contribution of these chaperones to each of step of the degradation process before I can answer specific questions about how chaperones are involved in the destruction of misfolded proteins.
The degradation machinery is a complex system with several steps. First, a misfolded protein must be picked out from its properly folded counterparts. Next, a small molecular tag is attached to the misfolded protein and marks it for destruction. There is also some opportunity for editing, in case a tag has mistakenly been attached to a correctly folded protein. The last step requires the misfolded protein to be unfolded and fed into the cell's degradation machinery. Chaperones may be involved in the degradation of misfolded proteins at any or all of these steps. For example, a protein that spends too much time with a chaperone trying to fold might be recognized as problematic and tagged for degradation.
A more complete understanding of the process by which misfolded proteins
are recognized by the cell and targeted for degradation should yield insight
as to the reasons why the quality control system sometimes fails. This
knowledge will hopefully lead to the development of drugs that increase
the efficiency and accuracy of the machinery responsible for the degradation
of misfolded proteins. These drugs would give us new tools to use in the
fight against Alzheimer's' and other neurodegenerative diseases.
|Modified 15 January 2003 * Contact Us|