Heralding a major advance in the field of protein engineering, scientists at the University of California, Berkeley have designed a protein that toggles between two different structures upon binding a small molecule. The designed property is significant because many biological processes depend on a protein's ability to change its shape in response to outside signals. The scientists predict that with further refinements, their protein may one day be used to detect environmental toxins or--in a laboratory setting--act as a switch to activate genes or as a molecular zipper to join together proteins.
The newly designed structure is featured in the cover article of the June 1996 issue of Nature Structural Biology.
"This designed protein is novel because it responds to its environment by undergoing a dramatic structural change," said Dr. Tom Alber, an x-ray crystallographer and the study's lead scientist.
The scientists synthesized their own version of a common protein structure called a double-helical coiled coil. This structure is composed of two helices that wrap like grape vines around each other. The design incorporated a selective binding site such that when the researchers added a small molecule, benzene, the two helices intertwined with a third to create a triple-helical coiled coil.
This structural change could enable the protein to indicate the presence of benzene, which is a carcinogen, said Dr. Alber. Additional proteins could be designed to detect other environmental pollutants--but not quite yet. "The present design binds compounds such as benzene too weakly to beat your nose as a detection system," said Dr. Alber.
Manipulation of coiled coils may also allow scientists to attach specific proteins together. In nature, coiled coils "zip" together two or more subunits of a protein. To take advantage of this functionality, scientists would fuse one protein to a coiled coil and fuse another protein to a loose helix, then add benzene to drive the formation of a triple helix. One example of such an application is to bring together a DNA-binding protein and a gene-activating protein to create a "switch" that targets and activates a specific gene.
The goal of protein engineers is to design and build proteins with desired three-dimensional shapes, which are crucial to protein function. Predicting the shape of a designed protein is a daunting task, because scientists don't fully understand how proteins fold into their final structure. To confront this difficulty, the Berkeley group started with a protein whose structure is known. Using their knowledge of protein architecture, they determined how to generate the desired structure--a triple helix. After synthesizing this newly designed protein, the scientists used x-ray crystallography to determine its three-dimensional shape. The result confirmed, with a clarity unusual in the field, that they had successfully predicted the final structure.
Beyond any potential applications, this study helps increase general understanding of coiled coils. These structures are found in hundreds of proteins and are essential to processes as diverse as gene transcription, muscle contraction, viral attack, and cell division.
Please acknowledge partial funding for this work from the National Institute of General Medical Sciences (NIGMS), a component of the National Institutes of Health dedicated to the support of basic research and training.
Dr. Tom Alber, (510) 642-8758Associate Professor, Department of Molecular and Cell BiologyUniversity of California, Berkeley
Gonzalez L Jr, Plecs J, Alber T. An Engineered Allosteric Switch in Leucine Zipper Oligomerization. Nature Structural Biology 1996;3:510-15.
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8/9/2018 4:40 PM
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