Cysteine34 of the cytoplasmic tail of the cation-dependent mannose 6- phosphate receptor is reversibly palmitoylated and required for normal trafficking and lysosomal enzyme sorting

doi:10.1083/jcb.132.4.577

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Cysteine34 of the cytoplasmic tail of the cation-dependent mannose 6- phosphate receptor is reversibly palmitoylated and required for normal trafficking and lysosomal enzyme sorting

A Schweizer, S Kornfeld and J Rohrer
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

We have examined whether the two cysteine residues (Cys30 and Cys34) in the cytoplasmic tail of the cation-dependent mannose 6-phosphate receptor are palmitoylated via thioesters and whether these residues influence the biologic function of the receptor. To do this, mouse L cells expressing wild-type and mutant receptors were analyzed by metabolic labeling with [3H]palmitate, immunoprecipitation, and SDS- PAGE. Both Cys30 and Cys34 were found to be sites of palmitoylation and together they accounted for the total palmitoylation of the receptor. The palmitate rapidly turned over with a half-life of approximately 2 h compared to a half-life of greater than 40 h for the protein. Mutation of Cys34 to Ala resulted in the gradual accumulation of the receptor in dense lysosomes and the total loss of cathepsin D sorting function in the Golgi. A Cys30 to Ala mutation had no biologic consequences, showing the importance of Cys34. Mutation of amino acids 35-39 to alanines impaired palmitoylation of Cys30 and Cys34 and resulted in abnormal receptor trafficking to lysosomes and loss of cathepsin D sorting. These data suggest that palmitoylation of Cys30 and Cys34 leads to anchoring of this region of the cytoplasmic tail to the lipid bilayer. Anchoring via Cys34 is essential for the normal trafficking and lysosomal enzyme sorting function of the receptor.
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