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Caveolar Endocytosis and Microdomain Association of a Glycosphingolipid Analog Is Dependent on Its

Caveolar Endocytosis and Microdomain Association of a Glycosphingolipid Analog Is Dependent on Its,Raman Deep Singh,Yidong Liu,Christine L. Wheatley,E

Caveolar Endocytosis and Microdomain Association of a Glycosphingolipid Analog Is Dependent on Its  
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analogs via caveolae. We found that whereas the LacCer ana- log with the natural (D-erythro) sphingosine stereochemistry is internalized mainly via caveolae, the non-natural (L-threo) LacCer analog is taken up via clathrin-, RhoA-, and Cdc42- dependent mechanisms and largely excluded from uptake via caveolae. Unlike the D-erythro-LacCer analog, the L-threo analog did not cluster in membrane microdomains when added at higher concentrations (5-20 M). In vitro studies using small unilamellar vesicles and giant unilamellar vesi- cles demonstrated that L-threo-LacCer did not undergo a concentration-dependent excimer shift in fluorescence emis- sion such as that seen with BODIPYTM-sphingolipids with natural stereochemistry. Molecular modeling studies suggest that in D-erythro-LacCer, the disaccharide moiety extends above and in the same plane as the sphingosine hydrocarbon chain, while in L-threo-LacCer the carbohydrate group is nearly perpendicular to the hydrocarbon chain. Together, these results suggest that the altered stereochemistry of the sphingosine group in L-threo-LacCer results in a perturbed structure, which is unable to pack closely with natural mem- brane lipids, leading to a reduced inclusion in plasma mem- brane microdomains and decreased uptake by caveolar endo- cytosis. These findings demonstrate the importance of the sphingolipid stereochemistry in the formation of membrane microdomains.
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