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Originally published In Press as doi:10.1074/jbc.M006278200 on September 11, 2000

J. Biol. Chem., Vol. 275, Issue 48, 37462-37468, December 1, 2000
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Post-translational Disruption of the Delta F508 Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)-Molecular Chaperone Complex with Geldanamycin Stabilizes Delta F508 CFTR in the Rabbit Reticulocyte Lysate*

William FullerDagger and Alan W. Cuthbert§

From the Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QJ, United Kingdom

The Delta F508 mutation of cystic fibrosis transmembrane conductance regulator (CFTR) is a trafficking mutant, which is retained and degraded in the endoplasmic reticulum by the ubiquitin-proteasome pathway. The mutant protein fails to reach a completely folded conformation that is no longer a substrate for ubiquitination ("stable B"). Wild type protein reaches this state with 25% efficiency. In this study the rabbit reticulocyte lysate with added microsomal membranes has been used to reproduce the post-translational events in the folding of wild type and Delta F508 CFTR. In this system wild type CFTR does not reach the stable B form if the post-translational temperature is 37 °C, whereas at 30 °C the behavior of both wild type and mutant proteins mimics that observed in the cell. Geldanamycin stabilizes Delta F508 CFTR with respect to ubiquitination only when added post-translationally. The interaction of wild type and mutant CFTR with the molecular chaperones heat shock cognate 70 (hsc70) and heat shock protein 90 (hsp90) has been assessed. Release of wild type protein from hsc70 coincides with the cessation of ubiquitination and formation of stable B. Geldanamycin immediately prevents the binding of hsp90 to Delta F508 CFTR, and after a delay releases it from hsc70. Release of mutant protein from hsc70 also coincides with the formation of stable B Delta F508 CFTR.

* This work was supported by Grant 044441/Z/95/Z from the Wellcome Trust (to W. F.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Present address: Dept. of Cardiovascular Research, The Rayne Inst., St. Thomas' Hospital, Lambeth Palace Rd., London SE1 7EH, UK. Tel.: 44 20 7928 9292 (ext. 2749); Fax: 44 20 7928 0658; E-mail: will.fuller@kcl.ac.uk.

§ To whom correspondence should be addressed: Dept. of Medicine, Level 5 (Box 157), Addenbrooke's Hospital, Hills Rd., Cambridge CB2 2QQ, UK. Tel.: 44 1223 336853; Fax: 44 1223 336846; E-mail: awc1000@cam.ac.uk.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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