PAS domain receptor photoactive yellow protein is converted to a molten globule state upon activation

Biological signaling generally involves the activation of a receptor protei n by an external stimulus followed by protein-protein interactions between the activated receptor and its downstream signal transducer. The current pa radigm for the relay of signals along a signal transduction chain is that i t occurs by highly specific interactions between fully folded proteins. How ever, recent results indicate that many regulatory proteins are intrinsical ly unstructured, providing a serious challenge to this paradigm and to the nature of structure-function relationships in signaling. Here we study the structural changes that occur upon activation of the blue light receptor ph otoactive yellow protein (PYP). Activation greatly reduces the tertiary str ucture of PYP but leaves the level secondary structure largely unperturbed. In addition, activated PYP exposes previously buried hydrophobic patches a nd allows significant solvent penetration into the core of the protein. The se traits are the distinguishing hallmarks of molten globule states, which have been intensively studied for their role in protein folding. Our result s show that receptor activation by light converts PYP to a molten globule a nd indicate stimulus-induced unfolding to a partially unstructured molten g lobule as a novel theme in signaling.