Cyclotides Insert into Lipid Bilayers to Form Membrane Pores and Destabilize the Membrane through Hydrophobic and Phosphoethanolamine-specific Interactions*
Cyclotides Insert into Lipid Bilayers to Form Membrane Pores and Destabilize the Membrane through Hydrophobic and Phosphoethanolamine-specific Interactions*
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环肽插入脂质双层形成膜孔并通过疏水性和磷酸乙醇胺特异性相互作用使膜不稳定*
DOI：
10.1074/jbc.m112.421198
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
D. Craik
中科院分区：
文献类型：
--
作者：
Conan K. Wang;H. Wacklin;D. Craik
背景：环肽类化合物是一种通过膜相互作用发挥作用的植物防御肽。结果如下：环肽类化合物特异性地结合到含磷酸乙醇胺的脂质双分子层上，并通过主要的熵驱动过程逐渐插入到含磷酸乙醇胺的脂质双分子层中。结论：由于与脂质尾部的疏水相互作用和与磷酸乙醇胺头基的特异性相互作用，环肽深深地插入到脂质双层中。意义：我们的研究拓宽了环肽如何与膜相互作用的知识。环肽类化合物是一类植物源环状蛋白，具有显著的稳定性、广泛的序列多样性和广泛的生物活性，具有潜在的治疗应用。其膜结合活性被认为是其作用机制的关键组成部分。使用等温滴定量热法，我们研究了结合的原型cyclotides kalata B1和kalata B2（和各种突变体）的十二烷基磷酸胆碱胶束和含磷酸乙醇胺的脂质双层。虽然结合主要是一个熵驱动的过程，这表明疏水力有助于显着的环肽-脂质复合物的形成，特异性结合的磷酸乙醇胺-脂质头基也是必需的，这是显而易见的，从结合的自由能的突变变化。此外，使用耗散石英晶体微天平测量和中子反射计的组合，我们阐明了该过程中，cyclotides与双层膜相互作用。最初，少量的环肽结合到膜表面，然后首先插入外膜小叶，然后渗透通过膜和孔形成。在更高浓度的环肽，膜的不稳定发生。我们的研究结果提供了显着的机制洞察如何cyclotides发挥其生物活性。
Background: Cyclotides are plant defense peptides that act via membrane interactions. Results: Cyclotides bind specifically to and progressively insert into phosphoethanolamine-containing lipid bilayers via a predominantly entropy-driven process. Conclusion: Cyclotides insert deeply into lipid bilayers due to hydrophobic interactions with lipid tails and specific interactions with the phosphoethanolamine headgroup. Significance: Our study broadens knowledge of how cyclotides interact with membranes. Cyclotides are a family of plant-derived circular proteins with potential therapeutic applications arising from their remarkable stability, broad sequence diversity, and range of bioactivities. Their membrane-binding activity is believed to be a critical component of their mechanism of action. Using isothermal titration calorimetry, we studied the binding of the prototypical cyclotides kalata B1 and kalata B2 (and various mutants) to dodecylphosphocholine micelles and phosphoethanolamine-containing lipid bilayers. Although binding is predominantly an entropy-driven process, suggesting that hydrophobic forces contribute significantly to cyclotide-lipid complex formation, specific binding to the phosphoethanolamine-lipid headgroup is also required, which is evident from the enthalpic changes in the free energy of binding. In addition, using a combination of dissipative quartz crystal microbalance measurements and neutron reflectometry, we elucidated the process by which cyclotides interact with bilayer membranes. Initially, a small number of cyclotides bind to the membrane surface and then insert first into the outer membrane leaflet followed by penetration through the membrane and pore formation. At higher concentrations of cyclotides, destabilization of membranes occurs. Our results provide significant mechanistic insight into how cyclotides exert their bioactivities.
影响因子：
2.9
作者：
Ludtke, SJ;He, K;Huang, HW
通讯作者：
Huang, HW
DOI：
10.1073/pnas.96.16.8913
发表时间：
1999-08-03
影响因子：
11.1
作者：
Tam, JP;Lu, YA;Chiu, KW
通讯作者：
Chiu, KW
影响因子：
3.1
作者：
Gould A;Ji Y;Aboye TL;Camarero JA
通讯作者：
Camarero JA