{"title":"Synergistic effects of hydrophilic residues in the transmembrane region on lipid scrambling activity of dimeric helices","authors":"Hiroyuki Nakao , Toshiki Tsujii , Hiroaki Saito , Keisuke Ikeda , Minoru Nakano","doi":"10.1016/j.colsurfb.2025.114612","DOIUrl":null,"url":null,"abstract":"<div><div>Phospholipid scramblases promote lipid transbilayer movement (flip-flop) in the plasma membrane, which is involved in a wide range of cellular functions, such as phagocytosis and blood coagulation. One structural characteristic of scramblases and model lipid scrambling peptides is the presence of hydrophilic residues in their transmembrane domains. These hydrophilic regions are considered the active sites through which lipid polar headgroups pass during the translocation process. However, how the structural arrangement of hydrophilic residues results in strong lipid scrambling activities in scramblases needs to be investigated, because the effects of a single hydrophilic residue on lipid scrambling are much lower than the activity of natural scramblases. Here, we developed double-spanning transmembrane peptides containing varying numbers of Gln residues. A combination of lipid vesicle experiments and molecular dynamics simulations indicates that lipid scrambling activities are synergistically enhanced by the proximity between planes created by Gln residues aligned parallel to the helix and that interactions between Gln and Trp residues stabilize the strongly active structures. The contribution of Gln residues to lipid scrambling activity suggests that the alignment and proximity of hydrophilic residues in the transmembrane region is one of the mechanisms of lipid scrambling by natural scramblases. This study provides clues for the energetic and structural mechanisms of lipid scrambling and for the design of artificial phospholipid scramblases.</div></div>","PeriodicalId":279,"journal":{"name":"Colloids and Surfaces B: Biointerfaces","volume":"251 ","pages":"Article 114612"},"PeriodicalIF":5.4000,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Colloids and Surfaces B: Biointerfaces","FirstCategoryId":"1","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0927776525001195","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOPHYSICS","Score":null,"Total":0}
引用次数: 0
Abstract
Phospholipid scramblases promote lipid transbilayer movement (flip-flop) in the plasma membrane, which is involved in a wide range of cellular functions, such as phagocytosis and blood coagulation. One structural characteristic of scramblases and model lipid scrambling peptides is the presence of hydrophilic residues in their transmembrane domains. These hydrophilic regions are considered the active sites through which lipid polar headgroups pass during the translocation process. However, how the structural arrangement of hydrophilic residues results in strong lipid scrambling activities in scramblases needs to be investigated, because the effects of a single hydrophilic residue on lipid scrambling are much lower than the activity of natural scramblases. Here, we developed double-spanning transmembrane peptides containing varying numbers of Gln residues. A combination of lipid vesicle experiments and molecular dynamics simulations indicates that lipid scrambling activities are synergistically enhanced by the proximity between planes created by Gln residues aligned parallel to the helix and that interactions between Gln and Trp residues stabilize the strongly active structures. The contribution of Gln residues to lipid scrambling activity suggests that the alignment and proximity of hydrophilic residues in the transmembrane region is one of the mechanisms of lipid scrambling by natural scramblases. This study provides clues for the energetic and structural mechanisms of lipid scrambling and for the design of artificial phospholipid scramblases.
期刊介绍:
Colloids and Surfaces B: Biointerfaces is an international journal devoted to fundamental and applied research on colloid and interfacial phenomena in relation to systems of biological origin, having particular relevance to the medical, pharmaceutical, biotechnological, food and cosmetic fields.
Submissions that: (1) deal solely with biological phenomena and do not describe the physico-chemical or colloid-chemical background and/or mechanism of the phenomena, and (2) deal solely with colloid/interfacial phenomena and do not have appropriate biological content or relevance, are outside the scope of the journal and will not be considered for publication.
The journal publishes regular research papers, reviews, short communications and invited perspective articles, called BioInterface Perspectives. The BioInterface Perspective provide researchers the opportunity to review their own work, as well as provide insight into the work of others that inspired and influenced the author. Regular articles should have a maximum total length of 6,000 words. In addition, a (combined) maximum of 8 normal-sized figures and/or tables is allowed (so for instance 3 tables and 5 figures). For multiple-panel figures each set of two panels equates to one figure. Short communications should not exceed half of the above. It is required to give on the article cover page a short statistical summary of the article listing the total number of words and tables/figures.