| Category | Item | Evidence-backed notes | Key citations |
|---|---|---|---|
| Protein feature | Identity and ER-targeting motifs | Human CALR (UniProt P27797) is a 417-aa soluble endoplasmic reticulum protein with an N-terminal signal peptide (~17 aa) that targets it to the secretory pathway and a C-terminal KDEL retrieval motif that supports ER residency via Golgi-to-ER retrieval. Loss of KDEL is therefore a major functional consequence of pathogenic exon 9 frameshift mutations. | (pqac-00000012, pqac-00000010, pqac-00000007) |
| Protein feature | Domain architecture | CALR contains an N-domain, a proline-rich P-domain, and an acidic C-domain. The N-domain mediates glycan/polypeptide interactions, the P-domain binds co-chaperones including PDIA3/ERp57, and the acidic C-domain provides major low-affinity, high-capacity Ca2+ binding/storage functions. | (pqac-00000012, pqac-00000010, pqac-00000011) |
| Canonical function/pathway | Lectin chaperone in the calnexin/calreticulin cycle | CALR is a lectin-like chaperone that recognizes monoglucosylated N-glycans on newly synthesized glycoproteins. In the ER quality-control cycle, CALR works with calnexin, UGGT1, and ERp57/PDIA3 to promote oxidative folding, reglucosylation of incompletely folded substrates, and routing of terminally misfolded proteins toward ER-associated degradation. | (pqac-00000010, pqac-00000009) |
| Canonical function/pathway | ER Ca2+ buffering and gatekeeping | CALR is a major ER luminal Ca2+ buffer/store, with reports that it binds a large fraction of ER Ca2+ and acts as a Ca2+ sensor/gatekeeper for luminal processes. This Ca2+-dependent role is tightly coupled to its chaperone functions and to ER homeostasis under stress. | (pqac-00000012, pqac-00000011, pqac-00000003) |
| Canonical function/pathway | UPR and ER-stress linkage | CALR function is integrated with ER proteostasis and unfolded protein response signaling. In particular, type 1 mutant CALR, which loses more acidic Ca2+-binding residues than type 2 mutant, directly impairs Ca2+ binding, depletes ER Ca2+, and activates the IRE1α/XBP1 arm of the UPR; pharmacologic or genetic IRE1α/XBP1 inhibition selectively impairs type 1 mutant CALR-driven disease models. | (pqac-00000007) |
| Localization | Primary localization: ER lumen | The principal site of CALR action is the ER lumen, where it supports glycoprotein folding and Ca2+ homeostasis. Its KDEL motif explains retention/retrieval to the ER despite trafficking through the early secretory pathway. | (pqac-00000012, pqac-00000010) |
| Localization | Non-ER localization under stress | CALR is not confined to the ER: it can relocalize to the cell surface, extracellular space, and other compartments under stress or in specific contexts. Cell-surface association is notable because CALR lacks a transmembrane helix and instead depends on partner-mediated membrane association or noncanonical trafficking routes. | (pqac-00000003, pqac-00000002) |
| Disease/immune relevance | Ecto-CALR in immunogenic cell death (ICD) | During immunogenic cell death, stressed tumor cells expose CALR on their surface before or during apoptosis, converting an ER chaperone into a damage-associated molecular pattern and potent pro-phagocytic “eat-me” signal. Recent reviews emphasize ecto-CALR as a core ICD hallmark used to judge whether radiotherapy, chemotherapy, or nanomedicine regimens are immunogenic. | (pqac-00000002, pqac-00000003) |
| Disease/immune relevance | LRP1/CD91 receptor axis | Surface-exposed CALR promotes engulfment by professional antigen-presenting cells through interaction with LRP1/CD91, especially on dendritic cells and macrophages. This CALR–LRP1 axis is central to cross-priming and anti-tumor immunity in ICD frameworks. | (pqac-00000002) |
| Disease/clinical relevance | Exon 9 frameshift mutations in MPNs | Somatic CALR driver mutations in myeloproliferative neoplasms are exon 9 insertions/deletions that create a +1 frameshift, replacing the normal acidic C-terminus with a shared, novel basic tail and removing KDEL. Across recent reviews, CALR mutations are reported in ~25–30% of essential thrombocythemia, ~20% of MPN overall, or ~40% of ET/PMF in some disease-focused summaries; type 1 (52-bp deletion) and type 2 (5-bp insertion) account for ~80% of CALR-mutant cases, with type 1 ~50% and type 2 ~30%. | (pqac-00000011, pqac-00000007, pqac-00000006) |
| Disease/clinical relevance | MPL binding and JAK–STAT activation | Mutant CALR acquires a neomorphic interaction with the thrombopoietin receptor MPL: the N-domain recognizes MPL N-glycans while the mutant basic C-terminus contributes pathogenic receptor engagement/stabilization. This drives ligand-independent MPL activation and downstream JAK2/STAT, ERK, and AKT signaling, explaining the megakaryocytic bias of CALR-mutant disease. | (pqac-00000006, pqac-00000008, pqac-00000005, pqac-00000007) |
| Disease/clinical relevance | Mutant trafficking, secretion, and surface display | Loss of KDEL facilitates secretion and abnormal trafficking of mutant CALR, although mutant proteins can still be detected in ER/Golgi compartments. Mutant CALR also appears on the cell surface and in circulation, where recent reviews note potential immunomodulatory or immunosuppressive effects, broadening its relevance beyond cell-intrinsic MPL signaling. | (pqac-00000006, pqac-00000008, pqac-00000005) |
| Current applications/therapeutics | Diagnostics and molecular profiling | CALR exon 9 testing is now part of standard molecular workup for BCR-ABL1-negative MPNs because CALR, JAK2, and MPL mutations are largely mutually exclusive and diagnostically informative. Mutation subtype also contributes to prognostic stratification and therapeutic monitoring in contemporary MPN care. | (pqac-00000011, pqac-00000007) |
| Current applications/therapeutics | Mutant-CALR targeted therapy and trials | 2024 reviews highlight active development of mutant-CALR-targeting antibodies directed to the neo-C-terminus, exploiting the shared neoepitope created by exon 9 frameshifts. Clinical translation is underway: a CALR-mutant peptide vaccine trial is recruiting (NCT05025488), and a phase 1 study of JNJ-88549968 for CALR-mutated MPN is recruiting (NCT06150157); these programs reflect the field’s move from mechanistic insight to mutation-specific immunotherapy. | (pqac-00000006) |


*Table: This table summarizes core structural features, biological functions, localization, and disease relevance of human calreticulin (CALR), with emphasis on immunogenic cell death and CALR-mutant myeloproliferative neoplasms. It is useful as a compact evidence map linking canonical ER biology to current translational applications.*