HDL mimetic peptide ATI-5261 forms an oligomeric assembly in solution that dissociates to monomers upon dilution.
HDL mimetic peptide ATI-5261 forms an oligomeric assembly in solution that dissociates to monomers upon dilution.
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HDL 模拟肽 ATI-5261 在溶液中形成寡聚体，稀释后解离为单体。
DOI：
10.1021/bi2002955
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发表时间：
2011
期刊：
影响因子：
2.9
通讯作者：
Bielicki,JohnK
中科院分区：
文献类型：
--
作者：
Zheng,Ying;Patel,ArtiB;Narayanaswami,Vasanthy;Hura,GregoryL;Hang,Bo;Bielicki,JohnK
ATI-5261是一种26聚肽，能高效刺激细胞胆固醇外排。尽管该肽具有两亲性α-螺旋结构和宽的非极性表面，但仍具有较高的水溶性。这些特征提示ATI-5261在溶液中可能采用特定形态，具有良好的结构特性和动力学特性。为了验证这一点，我们对ATI-5261进行了一系列生物物理研究，并将其与二级结构和活性的自关联联系起来。凝胶过滤层析和天然凝胶电泳结果表明，ti -5261在浓度为1mg /mL时呈离散的低分子量自相关形式。小角x射线散射（SAXS）验证了离散分子种的形成，进一步揭示了肽形成具有细长形状和中空核心的四聚体组装。当稀释到促进高亲和力胆固醇从细胞外排所需的浓度时，该组装体解离成单个肽链。此外，无论物理形态和浓度如何，ATI-5261的α-螺旋含量都异常高（74.1±6.8%）。总的来说，这些结果表明ATI-5261表现出与天然载脂蛋白相似的低聚行为，并在稀释后解离成高α-螺旋含量的单体。优化自结合行为和二级结构可能有助于提高载脂蛋白模拟肽的可翻译性和有效性。
ATI-5261 is a 26-mer peptide that stimulates cellular cholesterol efflux with high potency. This peptide displays high aqueous solubility, despite having amphipathic α-helix structure and a broad nonpolar surface. These features suggested to us that ATI-5261 may adopt a specific form in solution, having favorable structural characteristics and dynamics. To test this, we subjected ATI-5261 to a series of biophysical studies and correlated self-association with secondary structure and activity. Gel-filtration chromatography and native gel electrophoresis indicated ATI-5261 adopted a discrete self-associated form of low molecular weight at concentrations >1 mg/mL. Formation of a discrete molecular species was verified by small-angle X-ray scattering (SAXS), which further revealed the peptide formed a tetrameric assembly having an elongated shape and hollow central core. This assembly dissociated to individual peptide strands upon dilution to concentrations required for promoting high-affinity cholesterol efflux from cells. Moreover, the α-helical content of ATI-5261 was exceptionally high (74.1 ± 6.8%) regardless of physical form and concentration. Collectively, these results indicate ATI-5261 displays oligomeric behavior generally similar to native apolipoproteins and dissociates to monomers of high α-helical content upon dilution. Optimizing self-association behavior and secondary structure may prove useful for improving the translatability and efficacy of apolipoprotein mimetic peptides.