CSHL scientists discover new details of a gene-regulatory network governing metabolism

It was Dr. Joshua-Tor’s team at CSHL that took the step of investigating the architecture of the proteins involved in the pathway, at the level of individual atoms. Using a technique called x-ray crystallography, they discovered a “player” in the molecular cast of characters whose involvement previously had been overlooked.

The unexpected molecule is called NADP. The team discovered that when a yeast cell changes from using glucose, a simple sugar, as a nutritional source to using galactose, a more complex sugar often found in dairy products and vegetables such as sugar beets, NADP is called into action. It “docks” to a protein called Gal80p, which acts along with a gene regulating-protein called Gal4p, to adapt the metabolism of the yeast cell so that it can make use of galactose.

“Importantly, changes in cellular levels of NAD, a close relative of NADP, had previously been linked to a gene circuit that controls aging and longevity in a large number of different organisms, including yeast but also including animals,” said Professor Rolf Sternglanz of Stony Brook University in New York, a co-author of the study.

Why The Regulatory Cascade Is Important

“It is becoming increasingly clear that the metabolic state of a cell is linked to the expression of its genes in a way that impacts biological processes of many kinds, ranging from cancer to aging,” said Dr. Joshua-Tor. The biochemical cascade identified by the team is part of a complex chain of events whose object is regulation of the output of specific genes.

Not only does the team’s work help explain how links in that gene-regulatory chain are constructed. “Gene-regulatory proteins impact every property of a cell and have long been recognized as possible targets for drugs,” said Dr. Joshua-Tor. “However, these types of proteins have proven resistant to the chemistry of modern drug design. A detailed understanding of how gene regulatory proteins are controlled may offer new and unanticipated opportunities to design drugs that would impact this class of proteins.”

“NADP Regulates the Yeast GAL Induction System” appears in Science on February 22. The compete citation is as follows: P. Rajesh Kumar, Yao Yu, Rolf Sternglanz, Stephen Albert Johnston, Leemor Joshua-Tor. The paper is available online at: http://www.sciencemag.org/cgi/content/full/319/5866/1090

CSHL is a private, non-profit research and education institution dedicated to exploring molecular biology and genetics in order to advance the understanding and ability to diagnose and treat cancers, neurological diseases, and other causes of human suffering.

For more information, visit www.cshl.edu.