KANSAS CITY, MOMolecular geneticists call big boss proteins that switch on broad developmental or metabolic programs "master regulators," as in master regulators of muscle development or fat metabolism. One such factor, the Activating Transcription Factor 6α (ATF6α) protein, takes charge following a cellular crisis known as endoplasmic reticulum (ER) stress, which is triggered by the accumulation of misfolded and aggregated proteins.
Molecularly, the ER stress pathway is always poised for action. Inactive ATF6α is normally embedded in cellular membranes, but at the first hint of protein overload, its working end springs superman-like into the nucleus, binds DNA and kicks on a host of target genes whose job is to clear a protein logjam.
Now, in a study published in the June 29 issue of The Journal of Biological Chemistry, and selected as "Paper of the Week" by the journal's editors, a team led by Stowers investigators Ron and Joan Conaway reveal that unlike the real superman ATF6α does not work solo. Using the ATF6α target gene HSPA5 as a probe, they apply mass spectrometry analysis to show that ATF6α recruits a fleet of coactivators to assist in target activation.
"We knew that as a master regulator, ATF6α was needed to turn on downstream genes in the ER stress response," says Ron Conaway, Ph.D., who with Joan Conaway, Ph.D., is co-corresponding author of the study. "Our goal was to determine what ATF6α was bringing with it to these genes' control elements."
"By devising a clever mix of state-of-the-art mass spectrometry and good old-fashioned biochemistry, this study has revealed that ATF6α is a virtual magnet for a wide range of 'A-list' co-regulators," said Michael K. Reddy, Ph.D., who oversees transcription mechanism grants at the National Institutes of Health's National Institute of General Medical Sciences, which partly supported the work. "These co-regu
|Contact: Kristin Kessler|
Stowers Institute for Medical Research