Calreticulin

• OMIM: 109091
• UniProt: P27797

Calreticulin ( CALR ) is a protein that is part of a protein complex in the lumen of the endoplasmic reticulum ( ER), which is eukaryotic. Calreticulin acts together with calnexin during folding of glycoproteins in the endoplasmic reticulum chaperone. For this purpose, it binds to glycoproteins with a terminal glucose residue which characterizes the protein folded as not correct, thus protecting it against influences from the environment, so that it can fold properly.

In addition to the quality control of the proper glycoprotein folding and securing of calcium homeostasis in the ER CALR has numerous functions outside the ER, such as in the cytoplasm, on the cell surface and in the extracellular matrix and affect cell proliferation, apoptosis, phagocytosis and the immune response. CALR can activate the JAK-STAT signaling in hematopoietic cells.

Additionally, it binds to another co-factor ( ERp57 ), which promotes the formation of disulfide bridges.

The CALR peptide consists of three main structural domains. At the N -terminus is a lectin -binding domain, with intermediate proline-rich domain, and the C-terminus is an acidic domain, with a number of calcium - binding sites and the KDEL sequence, which is typical for ER- peptides and their back- transfer from facilitates the Golgi apparatus into the ER

Mutation

In 2013, mutations in the CALR gene in patients with Essential Thrombocythemia (ET) and primary myelofibrosis described ( PMF). This CALR mutations were found in about 70 to 84% of ET and PMF cases which had no JAK2 mutation. The pathogenetic role of CALR mutations in the development of this myeloproliferative neoplasms is not yet understood in detail.

All mutations found so far are located in the last coding exon of CALR and lead durchGen insertions or deletions in a shift of the reading frame (frame shift ) in translation and thereby a change of the Carboxy-/C-Terminus calreticulin protein. This C -terminal protein domain is usually highly acidic and contains numerous calcium - binding sites as well as a recognition sequence ( KDEL ), which is typical for proteins that remain in the endoplasmic reticulum. The mutated C-terminal domain, however, is basic, and it lacks the calcium - binding sites and the KDEL sequence.