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Although plasma membrane domains, such as caveolae, provide an organizing principle for signaling pathways and cholesterol homeostasis in the cell, relatively little is known regarding specific mechanisms, whereby intracellular lipid-binding proteins are targeted to caveolae. Therefore, the interaction between caveolin-1 and sterol carrier protein-2 (SCP-2), a protein that binds and transfers both cholesterol and signaling lipids (e.g., phosphatidylinositides and sphingolipids), was examined by yeast two-hybrid, in vitro binding and fluorescence resonance energy transfer (FRET) analyses. Results of the in vivo and in vitro assays identified for the first time the N-terminal amino acids (aa) 1−32 amphipathic α helix of SCP-2 functionally interacted with caveolin-1. This interaction was independent of the classic caveolin-1 scaffolding domain, in which many signaling proteins interact. Instead, SCP-2 bound caveolin-1 through a new domain identified in the N-terminal domain of caveolin-1 between aa 34−40. Modeling studies suggested that electrostatic interactions between the SCP-2 N-terminal aa 1−32 amphipathic α-helical domain (cationic, positively charged face) and the caveolin-1 N-terminal aa 33−59 α helix (anionic, negatively charged face) may significantly contribute to this interaction. These findings provide new insights on how SCP-2 enhances cholesterol retention within the cell as well as regulates the distribution of signaling lipids, such as phosphoinositides and sphingolipids, at plasma membrane caveolae.


Parr, Rebecca D., Gregory G. Martin, Heather A. Hostetler, Megan E. Schroeder, Kiran D. Mir, Ann B. Kier, Judith M. Ball, and Friedhelm Schroeder. "A new N-terminal recognition domain in caveolin-1 interacts with sterol carrier protein-2 (SCP-2)." Biochemistry 46, no. 28 (2007): 8301-8314.

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