Ca-Dependent Folding of Human Calumenin

Human calumenin (hCALU) is a six EF-hand protein belonging to the CREC family. As other members of the family, it is localized in the secretory pathway and regulates the activity of SERCA2a and of the ryanodine receptor in the endoplasmic reticulum (ER). We have studied the effects of Ca(2+) binding to the protein and found it to attain a more compact structure upon ion binding. Circular Dichroism (CD) measurements suggest a major rearrangement of the protein secondary structure, which reversibly switches from disordered at low Ca(2+) concentrations to predominantly alpha-helical when Ca(2+) is added. SAXS experiments confirm the transition from an unfolded to a compact structure, which matches the structural prediction of a trilobal fold. Overall our experiments suggest that calumenin is a Ca(2+) sensor, which folds into a compact structure, capable of interacting with its molecular partners, when Ca(2+) concentration within the ER reaches the millimolar range.