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

Calreticulin (Calr) is an endoplasmic reticulum (ER) chaperone involved in protein quality control, Ca 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 Ca 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 C and C of human Calr, which lies in a polypeptide-binding site. The lower β-sheet has several conserved residues, comprised of a characteristic triad, D-H-D, Tyr and the free C. 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 Ca-binding C-terminal tail is transformed into a polybasic sequence.