In Proteins, Function Follows Form
Human cells are fantastically busy. Each one contains thousands of miniature "machines" called ribosomes that are continuously stringing together amino acids to create proteins, the fundamental building materials of life. Cells can make hundreds of these every minute. Once these strings of amino acids "fold" and take a three-dimensional shape, they can perform their roles as antibodies, enzymes, or hormones, and interact with other molecules in the body. Structural biologists -- researchers who study proteins, their structures, and their interactions with other molecules and cells in the body -- now have access to new, extremely powerful technological tools to study molecules and are at work illuminating protein structure.
Members of Sloan-Kettering Institute's Structural Biology group study biochemical systems or pathways that are altered in cancer. They focus on the pathways that control the growth and multiplication of cells, which may be altered in cancer, leading to the unchecked division of tumor cells. The Structural Biology group works to understand what growth-regulatory proteins do in cancer cells, how they can contribute to cancer -- and how they might be controlled or targeted by chemotherapeutic compounds.
Chris Lima, a nationally recognized leader in the study of the enzymes involved in protein modification and RNA metabolism, recently joined SKI's Structural Biology group. Dr. Lima and members of his lab are currently studying a pathway called SUMO (for "small ubiquitin-like modifier"), which is known to play a part in the control of cell division and is believed to modify hundreds and possibly thousands of proteins in the cell. Using the tools of structural biology and collaborating with other researchers at Memorial Sloan-Kettering and other institutions, they are working to determine what this pathway does and to discover if it plays a role in cell growth and the development of cancer.
Using a technique called X-ray crystallography, Dr. Lima and his colleagues shine brilliant and highly focused X-rays through proteins that have been crystallized to reveal their structure and atomic details. "We look at the fine details of individual proteins or nucleic acids at a very high magnification, and can visualize every amino acid." Crystallographers now have access to X-ray sources that allow them to magnify molecules to a level that is "equivalent to you being able to see the date on a dime that's on the surface of the moon," says Dr. Lima. New X-ray sources, such as the Advanced Photon Source at Argonne National Laboratory in Illinois, are so powerful, says Dr. Lima, that "we can now do things in a matter of hours that used to take scientists days or months, sometimes years, to complete."
Dr. Lima and his colleagues are "very much at the early stages of understanding the function of SUMO," he says. "But any process that seems or appears to regulate cell division is probably very important in the progression of cancer. Cancer cells no longer know when to stop dividing, so studying proteins or systems that control the cell cycle is relevant to cancer biology."
Structural biologists are simultaneously developing the tools to create drugs designed to modify the pathways they are studying. "This is where almost all chemotherapeutics arise -- from studying a simple pathway and asking whether or not you can find a compound that affects it," explains Dr. Lima. In looking for potentially therapeutic molecules, researchers look for those that "get into the cell easily and are not quickly metabolized. We would then try to refine these compounds and make them more and more specific to the pathway to avoid potential side-effects."
Dr. Lima's work with SUMO complements the work of Nikola Pavletich, head of Memorial Sloan-Kettering's Structural Biology program. Dr. Pavletich studies ubiquitin, which is very similar to SUMO. "We use the same mechanism but target a different set of proteins for different outcomes. Our work is very complimentary to Dr. Pavletich's work," Dr. Lima says.
