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SCIENCE
In the increasingly active field of chemical genetics, small organic molecules are used to alter the function of proteins. Chemical genetics has generally involved finding compounds that affect proteins by binding to them or by causing changes in protein conformation. Researchers have now devised a third form of chemical genetics, in which small molecules influence the function of proteins by changing their sequence. The compounds do this by initiating protein splicing--a process in which the primary sequence of a precursor protein is edited by removal of an internal segment. The new technique was developed by postdoc Henning D. Mootz and professor and lab head Tom W. Muir of the synthetic protein chemistry lab at Rockefeller University [J. Am. Chem. Soc., published online July 11, http://dx.doi.org/10.1021/ja026769o]. Potential applications include syntheses of toxic, oncogenic, or therapeutic proteins from premade precursors at desired points in time. The approach might also be used to study signal transduction processes. "Protein splicing has great potential for controlling protein function since the process results in a dramatic change in protein sequence, which is intimately linked to function," Muir tells C&EN. "The problem has been that protein splicing is not naturally regulated--it is a spontaneous process, which prevents it being exploited for protein regulation. It is this shortcoming that we have addressed in this paper." In the new technique, each of two protein fragments is derivatized with a protein-splicing construct--one-half of an "intein" linked to a protein that can bind a dimerizer ligand. An intein is an intervening protein domain that pops spontaneously out of any protein in which it's found, causing the flanking protein fragments (exteins) to become joined through a conventional peptide bond. A dimerizer is a matchmaking bifunctional ligand that can cross-link two ligand-binding proteins. The method is a hybrid of protein trans-splicing and ligand-induced dimerization, techniques introduced earlier by other groups. When Mootz and Muir introduced the ligand rapamycin to a model system, the ligand induced dimerization, the intein halves combined, the intein popped out, and two protein fragments were joined. In theory, the technique could be used to edit the sequence of any protein, since inteins are happy to pop out of any set of exteins. "This should be contrasted with most other chemical genetics approaches, where a new molecule has to be identified either by screening or rational design for every new protein of interest," Muir says. "We believe this difference is quite significant and will make our approach extremely useful for studying and manipulating protein function both in vitro and in vivo." It's "a very clean and beautiful study on a model protein, showing that the idea works," comments Timothy P. Clackson, senior vice president of science and technology at Ariad Pharmaceuticals. "The key next stage will be to move this into a cell. If you can show that this chemistry and biochemistry functions in the very complex environment of the intracellular milieu, then it really will be a potentially useful genetic tool. The likelihood is that that will be possible."
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