A contiguous stretch of methionine residues mediates the energy-dependent internalization mechanism of a cell-penetrating peptide

Recently we characterized an unusual switch in the internalization mechanism of the monomeric and dimeric forms of the cell-penetrating peptide RDLWEMMMVSLACQY. Here, we observed both energy-dependent and energy-independent modes of peptide uptake by the target B-lymphocytes WI-L2-729HF2, suggesting that higher-order structure might modulate the action of this novel cell-penetrating peptide. In the present work, we propose a possible internalization mechanism for the dimeric peptide which involves an initial interaction with the cell membrane, followed by an energy-dependent internalization process which requires the contiguous Met(6-8) sequence.