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MBC in Press, published online ahead of print July 5, 2007
Mol. Biol. Cell 10.1091/mbc.E07-01-0046

A more recent version of this article appeared on September 1, 2007
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Submitted on January 22, 2007
Revised on June 22, 2007
Accepted on June 25, 2007

Inhibiting ERAD of Misfolded Yor1p Does Not Permit ER Export Despite the Presence of a Di-acidic Sorting Signal

Silvere Pagant,* Leslie Kung,* Mariana Dorrington, Marcus C.S. Lee,{dagger} and Elizabeth A. Miller

Department of Biological Sciences, Columbia University, New York, NY 10027-6902

Monitoring Editor: Jeffrey Brodsky

Capture of newly synthesized proteins into endoplasmic reticulum (ER)-derived COPII vesicles represents a critical juncture in the quality control of protein biogenesis within the secretory pathway. The yeast ABC transporter, Yor1p, is a pleiotropic drug pump that shows homology to the human cystic fibrosis transmembrane conductance regulator (CFTR). Deletion of a phenylalanine residue in Yor1p, equivalent to the major disease-causing mutation in CFTR, causes ER retention and degradation via ER-associated degradation (ERAD). We have examined the relationship between protein folding, ERAD and forward transport during Yor1p biogenesis. Uptake of Yor1p into COPII vesicles is mediated by an N-terminal di-acidic signal that likely interacts with the "B-site" cargo-recognition domain on the COPII subunit, Sec24p. Yor1p-{Delta}F is subjected to complex ER quality control involving multiple cytoplasmic chaperones and degradative pathways. Stabilization of Yor1p-{Delta}F by inhibiting its degradation does not permit access of Yor1p-{Delta}F to COPII vesicles. We propose that the ER quality control checkpoint engages misfolded Yor1p even after it has been stabilized by inhibition of the degradative pathway.

*These authors contributed equally to this work.

{dagger}Current address: Department of Microbiology, Columbia University, New York, NY 10027-6902.

Address correspondence to: Elizabeth A. Miller (em2282{at}columbia.edu)




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