CALR

CALR

CALR (Calreticulin) is a multifunctional protein that plays a critical role in various cellular processes, including calcium homeostasis, protein folding, and immune response regulation. It is encoded by the CALR gene located on chromosome 19 in humans.

Structure

Calreticulin is a highly conserved protein consisting of approximately 400 amino acids. It is primarily located in the endoplasmic reticulum (ER) but can also be found in the cytoplasm and on the cell surface. The protein has three distinct domains:

• The N-terminal domain, which is involved in calcium binding and has a high capacity but low affinity for calcium ions.
• The central P-domain, which is proline-rich and forms a hairpin loop structure that interacts with other proteins.
• The C-terminal domain, which contains the KDEL sequence, a retention signal for ER localization.

Function

Calreticulin serves several important functions within the cell:

• Calcium Homeostasis: Calreticulin acts as a major calcium-binding chaperone in the ER, helping to regulate intracellular calcium levels and ensuring proper calcium signaling.
• Protein Folding: It assists in the folding of newly synthesized glycoproteins by acting as a molecular chaperone, ensuring that proteins achieve their correct conformation.
• Immune Response: Calreticulin is involved in the presentation of antigens to the immune system and can modulate immune responses. It is also implicated in the "eat-me" signal for phagocytosis of apoptotic cells.

Clinical Significance

Mutations in the CALR gene have been associated with certain myeloproliferative neoplasms (MPNs), such as essential thrombocythemia and primary myelofibrosis. These mutations often result in the production of a mutant calreticulin protein that contributes to the pathogenesis of these diseases by altering normal cellular signaling pathways.

Myeloproliferative Neoplasms

In MPNs, CALR mutations are typically found in the exon 9 region of the gene. These mutations lead to a frameshift and the generation of a novel C-terminal peptide, which is thought to drive the disease process by activating the thrombopoietin receptor (MPL) in a cytokine-independent manner.

Research and Therapeutic Implications

Understanding the role of calreticulin in disease has opened new avenues for research and potential therapeutic interventions. Targeting the mutant calreticulin or its downstream signaling pathways may offer new treatment strategies for patients with MPNs.

See Also

• Endoplasmic reticulum
• Calcium signaling
• Myeloproliferative neoplasm

External Links

• CALR Gene - NCBI
• Calreticulin - UniProt