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A more recent version of this article appeared on March 1, 2002
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Submitted on May 31, 2001
Revised on November 13, 2001
Accepted on November 26, 2001
1 Dana-Farber Cancer Institute and Department of Pathology, Harvard Medical School, Boston, MA 02115
2 Dana-Farber Cancer Institute and Department of Pathology, Harvard Medical School, Boston, MA 02115
3 Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA 02115
4 Dana-Farber Cancer Institute, Rm D-1430, and Department of Pathology, Harvard Medical School, Boston, MA 02115
* Corresponding author. E-mail address: Martin_Hemler{at}DFCI.Harvard.EDU.
Here we demonstrate that multiple tetraspanin (TM4SF) proteins are palmitoylated, either in the Golgi or a post-Golgi compartment. Using CD151 as a model tetraspanin, intracellular N-terminal and C-terminal cysteine palmitoylation sites were identified and mutated. Simultaneous mutations of C11, C15, C242, and C243 (each to serine) eliminated over 90% of CD151 palmitoylation. Notably, palmitoylation had minimal influence on the density of tetraspanin protein complexes, did not promote tetraspanin localization into detergent resistant microdomains, and was not required for CD151-
3ß1 integrin association. However, the CD151 tetra-mutant showed markedly diminished associations with other cell surface proteins, including other TM4SF proteins (CD9, CD63). Thus, palmitoylation may be critical for assembly of the large network of cell surface tetraspanin-protein interactions sometimes called the "tetraspanin-web".
Also, compared to wild type CD151, the tetra-mutant was much more diffusely distributed, and showed markedly diminished stability during biosynthesis. Finally, expression of the CD151 tetra-mutant profoundly altered 3 integrin-deficient kidney epithelial cells, such that they converted from a dispersed, elongated morphology to an epithelial-like cobblestone clustering. These results point to novel biochemical and biological functions for tetraspanin palmitoylation.
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