Abstract: Cells face a multitude of stresses during their lifespan, including endoplasmic reticulum stress, oxidative stress, and nutrient deprivation. These stress stimuli activate the Integrated Stress Response (ISR) pathway, which result in a global halt of protein expression and the overexpression of specific transcription factors that lead cells toward survival or apoptosis. Cancer cells are known to exploit the ISR in order to proliferate, grow, migrate, and build therapeutics resistance. Activating Transcription Factor 4 (ATF4) is a key effector of the ISR that is consistently found to be over-activated in a wide range of cancers. In this study, we employ a combination of molecular dynamics simulations and solution NMR spectroscopy to determine the molecular basis of ATF4 activation and regulation.
