Multiple endocytic signals in the C-terminal tail of the cystic fibrosis transmembrane conductance regulator - PubMed (original) (raw)

Multiple endocytic signals in the C-terminal tail of the cystic fibrosis transmembrane conductance regulator

W Hu et al. Biochem J. 2001.

Abstract

The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-dependent protein kinase (PKA)-activated chloride channel that is localized to the plasma membrane and endosomal compartment. Endosomal targeting of CFTR is attributed to the Tyr(1424)-based internalization signal, identified in the C-terminal tail of the channel. Mutation of the Tyr(1424) residue could partly inhibit the endocytosis of CFTR and its association with the adapter protein AP-2. To reveal additional endosomal targeting signals, site-directed mutagenesis of both a chimaera, composed of a truncated form of interleukin 2 receptor alpha chain (TacT) and the C-terminal tail of CFTR (Ct), and the full-length CFTR was performed. Morphological and functional assays revealed the presence of multiple internalization motifs at the C-terminus, consisting of a phenylalanine-based motif (Phe(1413)) and a bipartite endocytic signal, comprising a tyrosine (Tyr(1424)) and a di-Leu-based (Leu(1430)-Leu) motif. Whereas the replacement of any one of the three internalization motifs with alanine prevented the endocytosis of the TacT-Ct chimaera, mutagenesis of Phe(1413)-Leu impaired the biosynthetic processing of CFTR, indicating that Phe(1413) is indispensable for the native structure of CFTR. In contrast, replacement of Leu(1430)-Leu- and Tyr(1424)-based signals with alanine increased the cell-surface density of both the chimaeras and CFTR in an additive manner. These results suggest that the internalization of CFTR is regulated by multiple endocytic sorting signals.

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References

1. Nature. 1991 Aug 15;352(6336):628-31 - PubMed
1. Cell. 1983 May;33(1):273-85 - PubMed
1. J Biol Chem. 1994 Mar 18;269(11):8296-302 - PubMed
1. J Cell Sci. 1994 Jul;107 ( Pt 7):2021-32 - PubMed
1. Am J Physiol Cell Physiol. 2000 Aug;279(2):C375-82 - PubMed

Multiple endocytic signals in the C-terminal tail of the cystic fibrosis transmembrane conductance regulator - PubMed (original) (raw)