Alternative subcellular localizations of calreticulin. A round trip from biophysics to cell biology
Calreticulin (CRT) is the second most abundant protein within the endoplasmic reticulum (ER), where it fulfills two basic biological roles. On one hand, thanks to its ability to recognize monoglucosylated N-glycans, CRT plays a central role in the folding quality control of glycoproteins by retaining immature species in the ER. Besides, due to its capacity to bind high amounts of calcium with low affinity, CRT is the principal calcium buffer of the ER. It was originally proposed that the lectin activity of CRT depends on calcium binding. By using a combination of biophysical techniques with cellular and molecular biology experiments, we found that both activities of CRT (lectin/chaperone and calcium buffer) are mutually independent. In addition, we found that the calcium buffering domain of CRT allows its retrotranslocation into the cytosol in a process regulated by the calcium levels of the ER. This process may be relevant for the crosstalk of different signal transduction pathways. Finally, these biophysical studies allowed us to develop a new sensor to measure macromolecular crowding in complex environments.