Structural Analysis of Calreticulin, an Endoplasmic Reticulum-Resident Molecular Chaperone.

Calreticulin (Calr) is an endoplasmic reticulum (ER) chaperone involved in protein quality control, Ca²⁺ regulation and other cellular processes. The structure of Calr is unusual, reflecting different functions of the protein: a proline-rich β-hairpin arm and an acidic C-terminal tail protrude from a globular core, composed of a β-sheet sandwich and an α-helix. The arm and tail interact in the presence of Ca²⁺ and cover the upper β-sheet, where a carbohydrate-binding site gives the chaperone glycoprotein affinity. At the edge of the carbohydrate-binding site is a conserved, strained disulphide bridge, formed between C¹⁰⁶ and C¹³⁷ of human Calr, which lies in a polypeptide-binding site. The lower β-sheet has several conserved residues, comprised of a characteristic triad, D¹⁶⁶-H¹⁷⁰-D¹⁸⁷, Tyr¹⁷² and the free C¹⁶³. In addition to its role in the ER, Calr translocates to the cell surface upon stress and functions as an immune surveillance marker. In some myeloproliferative neoplasms, the acidic Ca²⁺-binding C-terminal tail is transformed into a polybasic sequence.