The role of proline in the membrane re-entrant helix of caveolin-1

One third of the human genome codes for membrane proteins and they are targets of approximately 80% of prescription drugs. We study a particular cell membrane protein, Caveolin-1 (Cav1), and its functions in relation to its membrane topology. Cav1 has a segment of hydrophobic amino acids comprising approximately residues 103 to 122. We have performed an in silico analysis of the conformational preference of this segment of Cav1 using PepLook. We find that there is one main group of stable conformations corresponding to a hydrophobic U bent model that would not traverse the membrane. Furthermore, the calculations predict that substituting the Pro110 residue with an Ala will change the conformation to a straight hydrophobic helix that would traverse the membrane. We demonstrate this prediction with model peptides. Furthermore, we are able to alter the membrane insertion of the protein by mutating a single Pro residue to an Ala. We demonstrate that the multiple activities of Cav1 are a consequence of the topology- and compartment-specific cellular localization of this protein.