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MBC in Press, published online ahead of print March 12, 2008
Mol. Biol. Cell 10.1091/mbc.E07-10-1055

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Submitted on October 19, 2007
Revised on February 19, 2008
Accepted on March 5, 2008

Lectin-deficient Calreticulin Retains Full Functionality as a Chaperone for Class I Histocompatibility Molecules

Breanna S. Ireland,*{dagger} Ulf Brockmeier,*{dagger} Christopher M. Howe,{ddagger} Tim Elliott,{ddagger} and David B. Williams*

*Departments of Biochemistry and Immunology, University of Toronto, Toronto M5S 1A8, Canada; {ddagger}Cancer Sciences Division and CRC Medical Oncology Unit, University of Southampton School of Medicine, Southampton SO16 6YD, United Kingdom

Monitoring Editor: Benjamin Glick

Calreticulin is a molecular chaperone of the endoplasmic reticulum that utilizes both a lectin site specific for Glc1Man5–9GlcNAc2 oligosaccharides and a polypeptide binding site to interact with nascent glycoproteins. The latter mode of substrate recognition is controversial. To examine the relevance of polypeptide binding to protein folding in living cells we prepared lectin-deficient mutants of calreticulin and examined their abilities to support the assembly and quality control of mouse class I histocompatibility molecules. In cells lacking calreticulin, class I molecules exhibit inefficient loading of peptide ligands, reduced cell surface expression and aberrantly rapid export from the endoplasmic reticulum. Remarkably, expression of calreticulin mutants that are completely devoid of lectin function fully complemented all of the class I biosynthetic defects. We conclude that calreticulin can utilize nonlectin-based modes of substrate interaction to effect its chaperone and quality control functions on class I molecules in living cells. Furthermore, pulse-chase coimmunoisolation experiments revealed that lectin-deficient calreticulin bound to a similar spectrum of client proteins as wild type calreticulin and dissociated with similar kinetics, suggesting that lectin-independent interactions are commonplace in cells and they appear to be regulated during client protein maturation.

{dagger}These authors contributed equally to this work.

Address correspondence to: David B. Williams (david.williams{at}utoronto.ca)






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