Enhancing the activity of membrane remodeling epsin-peptide by trimerization. Issue 12 (15th June 2020)

• Record Type: Journal Article
• Authors: Hsu, Wei-Yuan; Masuda, Toshihiro; Afonin, Sergii; Sakai, Takayuki; Arafiles, Jan Vincent V.; Kawano, Kenichi; Hirose, Hisaaki; Imanishi, Miki; Ulrich, Anne S.; Futaki, Shiroh
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 12(2020)
• Publication Date: 2020-06-15
• Subjects: Epsin N-terminal segment -- Trimerization -- Membrane curvature -- Lipid packing -- Oligoarginine -- Cell-membrane penetration; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127190
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Modulating the structural dynamics of biomembranes by inducing bilayer curvature and lipid packing defects has been highlighted as a practical tool to modify membrane-dependent cellular processes. Previously, we have reported on an amphipathic helical peptide derived from the N -terminal segment (residues 1–18, EpN18) of epsin-1, which can promote membrane remodeling including lipid packing defects in cell membranes. However, a high concentration is required to exhibit a pronounced effect. In this study, we demonstrate a significant increase in the membrane-remodeling effect of EpN18 by constructing a branched EpN18 homotrimer. Both monomer and trimer could enhance cell internalization of octaarginine (R8), a cell-penetrating peptide. The EpN18 trimer, however, promoted the uptake of R8 at an 80-fold lower concentration than the monomer. Analysis of the generalized polarization of a polarity-sensitive dye (di-4-ANEPPDHQ) revealed a higher efficacy of trimeric EpN18 in loosening the lipid packing in the cell membrane. Circular dichroism measurements in the presence of lipid vesicles showed that the EpN18 trimer has a higher α-helix content compared with the monomer. The stronger ability of the EpN18 trimer to impede negative bilayer curvature is also corroborated by solid-state 31 P NMR spectroscopy. Hence, trimerizing peptides can be considered a promising approach for an exponential enhancement of their membrane-remodeling performance.