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Vol. 17, Issue 11, 4748-4759, November 2006

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Dual Role of the Cysteine-String Domain in Membrane Binding and Palmitoylation-dependent Sorting of the Molecular Chaperone Cysteine-String Protein

Henry Wellcome Laboratory of Cell Biology, Division of Biochemistry and Molecular Biology, Faculty of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, United Kingdom

Submitted March 7, 2006; Revised August 14, 2006; Accepted August 18, 2006
Monitoring Editor: Sean Munro

S-palmitoylation occurs on intracellular membranes and, therefore, membrane anchoring of proteins must precede palmitate transfer. However, a number of palmitoylated proteins lack any obvious membrane targeting motifs and it is unclear how this class of proteins become membrane associated before palmitoylation. Cysteine-string protein (CSP), which is extensively palmitoylated on a "string" of 14 cysteine residues, is an example of such a protein. In this study, we have investigated the mechanisms that govern initial membrane targeting, palmitoylation, and membrane trafficking of CSP. We identified a hydrophobic 31 amino acid domain, which includes the cysteine-string, as a membrane-targeting motif that associates predominantly with endoplasmic reticulum (ER) membranes. Cysteine residues in this domain are not merely sites for the addition of palmitate groups, but play an essential role in membrane recognition before palmitoylation. Membrane association of the cysteine-string domain is not sufficient to trigger palmitoylation, which requires additional downstream residues that may regulate the membrane orientation of the cysteine-string domain. CSP palmitoylation-deficient mutants remain "trapped" in the ER, suggesting that palmitoylation may regulate ER exit and correct intracellular sorting of CSP. These results reveal a dual function of the cysteine-string domain: initial membrane binding and palmitoylation-dependent sorting.

Address correspondence to: L. Chamberlain (l.chamberlain{at}bio.gla.ac.uk)

Abbreviations used: CSP, cysteine-string protein; CFTR, cystic fibrosis transmembrane conductance regulator; ER, endoplasmic reticulum; PAT, palmitoyl transferase

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