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. ATF4 is composed of two domains, a long transactivation domain (TAD) and a basic-leucine zipper domain (bZIP) that mediates dimerization and DNA binding. Our findings reveal that the TAD and bZip domains of ATF4 are coupled through long-range interactions that condition the efficiency of phosphorylation by kinase CK2. Furthermore, we found that in the absence of DNA, the leucine zipper region of ATF4 adopts a partially structured α-helical conformation while the basic region remains extensively disordered. It suggests that the basic region and leucine zipper region of the bZip domain are structurally and dynamically decoupled. These insights into the structural and functional dynamics of ATF4 contribute to a better understanding of the regulatory mechanisms underlying the ISR.