Cell Penetrating Peptides
Fig. 1. Representation of tetrahedral network of water channels in a porous Pn3m cubic phase of lipids induced by TAT.
The TAT protein of the HIV virus can cross cell membranes with remarkable efficiency. Its 11-amino acid protein transduction domain of TAT has been shown to deliver everything from nucleic acids to proteins to nanoparticles. The precise molecular mechanism of cellular entry is not understood. At the molecular level, it is known that TAT is not receptor mediated and its mechanism of action is related to electrostatics. However, it is also known that electrostatics alone does not explain everything since there is a drastic difference between the transduction ability of TAT compared to polypeptide TAT analogs with the same charge (such as versions with the arginine residues substituted with lysines). Recently, we show that TAT can drastically remodel membranes into a porous 'sponge-like' bicontinuous manifold. This 'double-diamond' Pn3m structure has two non-intersecting tetrahedral networks of 6nm-diameter water pores that can facilitate the direct translocation of most protein-sized objects, as well as serve as an intermediate state for higher order processes such as receptor-independent forms of endocytosis. Moreover, we show how and why TAT in particular is able to do this, while similar peptides with the same charge cannot.
We are exploring the mechanisms of other cell penetrating peptides, such as ANTP and PVEC, as well as synthetic architectures, such as block copolypeptides with arginine blocks.