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Vol. 18, Issue 9, 3398-3413, September 2007

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Inhibiting Endoplasmic Reticulum (ER)-associated Degradation of Misfolded Yor1p Does Not Permit ER Export Despite the Presence of a Diacidic Sorting Signal

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

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

Submitted January 22, 2007; Revised June 22, 2007; Accepted June 25, 2007
Monitoring Editor: Jeffrey Brodsky

Capture of newly synthesized proteins into endoplasmic reticulum (ER)-derived coat protomer type II (COPII) vesicles represents a critical juncture in the quality control of protein biogenesis within the secretory pathway. The yeast ATP-binding cassette 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. 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 diacidic signal that likely interacts with the "B-site" cargo-recognition domain on the COPII subunit, Sec24p. Yor1p-F is subjected to complex ER quality control involving multiple cytoplasmic chaperones and degradative pathways. Stabilization of Yor1p-F by inhibiting its degradation does not permit access of Yor1p-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.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

* These authors contributed equally to this work.

Present address: Department of Microbiology, Columbia University, New York, NY 10027-6902.

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

Abbreviations used: ABC, ATP-binding cassette; CFTR, cystic fibrosis transmembrane conductance regulator; COPII, coat protomer type II; ER, endoplasmic reticulum; ERAD, endoplasmic reticulum-associated degradation; MSD, membrane spanning domain; NBD, nucleotide binding domain; TMD, transmembrane domain.

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