LAUSR

The cyclic AMP response element binding protein (CREB) contains a basic leucine zipper motif (bZIP) that forms a coiled coil structure upon dimerization and specific DNA binding. Although this state is well characterized, key features of CREB bZIP binding and folding are not well understood. We used single‐molecule Förster resonance energy transfer (smFRET) to probe conformations of CREB bZIP subdomains. We found differential folding of the basic region and leucine zipper in response to different binding partners; a strong and previously unreported DNA‐independent dimerization affinity; folding upon binding to nonspecific DNA; and evidence of long‐range interdomain interactions in full‐length CREB that modulate DNA binding. These studies provide new insights into DNA binding and dimerization and have implications for CREB function.