Calreticuline

Calreticuline is a term occasionally used to refer to calreticulin, a soluble chaperone protein localized in the lumen of the endoplasmic reticulum (ER). Calreticulin is encoded by the CALR gene and is widely expressed in animal cells, where it participates in calcium storage and homeostasis as well as the folding and quality control of glycoproteins.

The protein has a modular structure consisting of a globular N-terminal domain, a proline-rich P-domain, and an acidic C-terminal domain that contains EF-hand calcium-binding motifs. It carries an ER retention signal at its C-terminus (often KDEL in mammals), which helps keep it within the ER rather than in the secretory pathway. Calcium binding occurs mainly through the EF-hand motifs in the C-terminal region, contributing to both calcium buffering and signaling roles.

Functionally, calreticulin participates in the calnexin/calreticulin cycle, assisting glycoprotein folding by interacting with exposed glucose residues and with the folding sensor UGGT. Beyond its chaperone activity, it influences calcium homeostasis and can participate in immune signaling, antigen presentation, and cellular stress responses. Under certain conditions, extracellular calreticulin can be released or exposed on the surface of stressed or dying cells, where it can act as a damage-associated molecular pattern and promote phagocytosis through receptors such as CD91.

Clinically, CALR mutations are well described in myeloproliferative neoplasms, particularly essential thrombocythemia and primary myelofibrosis, often in JAK2/MPL-negative cases. These mutations create a novel C-terminal sequence and contribute to disease via activation of signaling pathways involving the MPL receptor. Detection of CALR mutations supports diagnosis and informs prognosis and treatment decisions.