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Vol. 15, Issue 10, 4556-4567, October 2004

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Conformational Defects Slow Golgi Exit, Block Oligomerization, and Reduce Raft Affinity of Caveolin-1 Mutant Proteins

Xiaoyan Ren ^*, Anne G. Ostermeyer ^*, Lynne T. Ramcharan ^*, Youchun Zeng , Douglas M. Lublin , and Deborah A. Brown ^* 

^* Department of Biochemistry and Cell Biology, State University of New York at Stony Brook, Stony Brook, NY 11794-5215; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110-1010

Submitted June 11, 2004; Revised July 14, 2004; Accepted July 16, 2004
Monitoring Editor: Jean Gruenberg

Caveolin-1, a structural protein of caveolae, is cleared unusually slowly from the Golgi apparatus during biosynthetic transport. Furthermore, several caveolin-1 mutant proteins accumulate in the Golgi apparatus. We examined this behavior further in this mutant study. Golgi accumulation probably resulted from loss of Golgi exit information, not exposure of cryptic retention signals, because several deletion mutants accumulated in the Golgi apparatus. Alterations throughout the protein caused Golgi accumulation. Thus, most probably acted indirectly, by affecting overall conformation, rather than by disrupting specific Golgi exit motifs. Consistent with this idea, almost all the Golgi-localized mutant proteins failed to oligomerize normally (even with an intact oligomerization domain), and they showed reduced raft affinity in an in vitro detergent-insolubility assay. A few mutant proteins formed unstable oligomers that migrated unusually slowly on blue native gels. Only one mutant protein, which lacked the first half of the N-terminal hydrophilic domain, accumulated in the Golgi apparatus despite normal oligomerization and raft association. These results suggested that transport of caveolin-1 through the Golgi apparatus is unusually difficult. The conformation of caveolin-1 may be optimized to overcome this difficulty, but remain very sensitive to mutation. Disrupting conformation can coordinately affect oligomerization, raft affinity, and Golgi exit of caveolin-1.

Abbreviations used: CSD, caveolin scaffolding domain; DOPC, dioleoyl phosphatidylcholine; DPPC, dipalmitoyl phosphatidylcholine; DRM, detergent-resistant membrane; FRT, Fischer rat thyroid; HRP, horseradish peroxidase; IF, immunofluorescence; OG, N-octyl--D-glucopyranoside; PBS, phosphate-buffered saline; PLAP, placental alkaline phosphatase; TX100, Triton X-100.

Corresponding author. E-mail address: deborah.brown{at}sunysb.edu.

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