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© The Rockefeller University Press, 0021-9525/2000//1235 $5.00
The Journal of Cell Biology, Volume 149, Number 6, , 2000 1235-1248

Cytosolic Phosphorylation of Calnexin Controls Intracellular Ca²⁺ Oscillations via an Interaction with Serca2b

^a Department of Physiology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900
^b Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900
Department of Physiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900.(210) 567-4410(210) 567-6558

camacho{at}uthscsa.edu

Calreticulin (CRT) and calnexin (CLNX) are lectin chaperones that participate in protein folding in the endoplasmic reticulum (ER). CRT is a soluble ER lumenal protein, whereas CLNX is a transmembrane protein with a cytosolic domain that contains two consensus motifs for protein kinase (PK) C/proline- directed kinase (PDK) phosphorylation. Using confocal Ca²⁺ imaging in Xenopus oocytes, we report here that coexpression of CLNX with sarco endoplasmic reticulum calcium ATPase (SERCA) 2b results in inhibition of intracellular Ca²⁺ oscillations, suggesting a functional inhibition of the pump. By site-directed mutagenesis, we demonstrate that this interaction is regulated by a COOH-terminal serine residue (S562) in CLNX. Furthermore, inositol 1,4,5-trisphosphate– mediated Ca²⁺ release results in a dephosphorylation of this residue. We also demonstrate by coimmunoprecipitation that CLNX physically interacts with the COOH terminus of SERCA2b and that after dephosphorylation treatment, this interaction is significantly reduced. Together, our results suggest that CRT is uniquely regulated by ER lumenal conditions, whereas CLNX is, in addition, regulated by the phosphorylation status of its cytosolic domain. The S562 residue in CLNX acts as a molecular switch that regulates the interaction of the chaperone with SERCA2b, thereby affecting Ca²⁺ signaling and controlling Ca²⁺-sensitive chaperone functions in the ER.

Key Words: phosphorylation • calnexin • ER lectin chaperones • Ca²⁺ ATPases • Ca²⁺ signaling

© 2000 The Rockefeller University Press

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