Translocation of penetratin-like peptides involving calcium-dependent interactions between glycosaminoglycans and phosphocholine headgroups of the membrane lipid bilayer

IF 3.1 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Bingwei He, Sonia Khemaissa, Sébastien Cardon, Rodrigue Marquant, Françoise Illien, Delphine Ravault, Fabienne Burlina, Emmanuelle Sachon, Astrid Walrant and Sandrine Sagan
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Abstract

Cell-penetrating peptides (CPPs) can internalize ubiquitously in cells. To explore the specific targeting issue of CPPs, we used glycosaminoglycan (GAG)-binding peptides previously identified in Otx2 and En2 homeoproteins (HPs). The Otx2 sequence preferentially recognizes highly sulfated chondroitin (CS) and the En2 one, heparan sulfates (HS) GAGs. The two HPs internalize in specific cells thanks to their GAG-targeting sequence. We studied the capacity of chimeric peptides containing a GAG-targeting and a penetratin-like sequences to enter into various cell lines known to express different levels and types of GAGs. Since GAGs are found at the vicinity the membrane lipid bilayer, we also analyzed the putative binary and ternary interactions between heparin (HI), (4S,6S)-CS (CS-E), zwitterionic phosphocholine (PC) model membranes and those chimeric peptides. Altogether, our results demonstrate the existence of Ca2+-dependent interactions between GAGs and PC lipid bilayers, the major phospholipid headgroup found in animal cell plasma membrane. In addition, the interaction of CS-E (but not HI), with PC favors the binding of the chimeric CS-E-recognition motif-penetratin-like peptide and its subsequent crossing of the lipid membrane to access directly to the cytosol of cells. Altogether, this study brings further understanding of translocation mechanism of CPPs, which requires specific GAGs at the cell-surface. It also shed light on the role of GAGs in the cell transfer specificity and paracrine activity of HPs.

Abstract Image

涉及膜脂双分子层的糖胺聚糖和磷脂头群之间钙依赖性相互作用的穿透蛋白样肽的易位。
细胞穿透肽(CPPs)可以在细胞内普遍存在。为了探索CPPs的特异性靶向问题,我们使用了先前在Otx2和En2同源蛋白(HPs)中发现的糖胺聚糖(GAG)结合肽。Otx2序列优先识别高硫酸软骨素(CS)和En2 1硫酸肝素(HS) gag。由于它们的gag靶向序列,这两种hp在特定细胞中内化。我们研究了含有gag靶向和穿透蛋白样序列的嵌合肽进入已知表达不同水平和类型的gag的各种细胞系的能力。由于在膜脂双分子层附近发现了gag,我们还分析了肝素(HI)、(4S,6S)-CS (CS-E)、两性离子磷脂胆碱(PC)模型膜与这些嵌合肽之间的二元和三元相互作用。总之,我们的研究结果表明,在动物细胞膜中发现的主要磷脂头群——GAGs和PC脂质双分子层之间存在Ca2+依赖的相互作用。此外,CS-E(而不是HI)与PC的相互作用有利于嵌合CS-E识别基序穿透蛋白样肽的结合,并随后穿过脂质膜直接进入细胞的细胞质。总之,该研究进一步了解了CPPs的易位机制,这需要细胞表面的特异性gag。这也揭示了GAGs在hp的细胞转移特异性和旁分泌活性中的作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
6.10
自引率
0.00%
发文量
128
审稿时长
10 weeks
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