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J Biol Chem, Vol. 274, Issue 31, 21873-21877, July 30, 1999
From the Program in Cell Biology and Lung Gene Therapy, Defective cAMP-stimulated chloride conductance of the
plasma membrane of epithelial cell is the hallmark of cystic fibrosis (CF) and results from mutations in the cystic fibrosis transmembrane conductance regulator, CFTR. In the majority of CF patients, mutations in the CFTR lead to its misfolding and premature degradation at the
endoplasmic reticulum (ER). Other mutations impair the
cAMP-dependent activation or the ion conductance of CFTR
chloride channel. In the present work we identify a novel mechanism
leading to reduced expression of CFTR at the cell surface, caused by
C-terminal truncations. The phenotype of C-terminally truncated CFTR,
representing naturally occurring premature termination and frameshift
mutations, were examined in transient and stable heterologous
expression systems. Whereas the biosynthesis, processing, and
macroscopic chloride channel function of truncated CFTRs are
essentially normal, the degradation rate of the mature,
complex-glycosylated form is 5- to 6-fold faster than the wild type
CFTR. These experiments suggest that the C terminus has a central role
in maintaining the metabolic stability of the complex-glycosylated CFTR
following its exit from the ER and provide a plausible explanation for
the severe phenotype of CF patients harboring C-terminal truncations.
C-terminal Truncations Destabilize the Cystic Fibrosis
Transmembrane Conductance Regulator without Impairing Its
Biogenesis
A NOVEL CLASS OF MUTATION
, and Department of Pharmacology, University
of Toronto, Toronto, Ontario M5S 1A8, Canada
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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