The mitochondria-targeted peptide SS-31 binds lipid bilayers and modulates surface electrostatics as a key component of its mechanism of action
The mitochondria-targeted peptide SS-31 binds lipid bilayers and modulates surface electrostatics as a key component of its mechanism of action
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DOI：
10.1074/jbc.ra119.012094
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发表时间：
2020-05-22
影响因子：
4.8
通讯作者：
Alder, Nathan N.
中科院分区：
文献类型：
--
作者：
Mitchell, Wayne;Ng, Emily A.;Alder, Nathan N.
线粒体功能障碍是许多遗传性疾病、获得性病理和与衰老相关的健康下降的基础。司徒？Schiller（SS）肽包括一类两亲性四肽，其对广泛的线粒体病症有效，并且被认为靶向线粒体膜，因为它们富含阴离子磷脂心磷脂（CL）。然而，关于SS肽如何与脂质双层相互作用或改变脂质双层的物理性质知之甚少。在这项研究中，使用生物物理和计算方法，我们分析了铅化合物SS-31（elamipretide）与模型和线粒体膜的相互作用。我们的研究结果表明，这种多元肽分区成膜界面区域的亲和力和脂质结合密度，直接关系到表面电荷。我们发现，SS-31结合不稳定的层状双层，即使在最高的结合浓度，但是，它确实导致脂质包装的饱和改变。最值得注意的是，SS-31调制模型和线粒体膜的表面静电。我们提出了非排他性的机制，表面电荷的调谐可以支持SS-31的mitoprotective性能，包括改变离子和碱性蛋白质在界面上的分布，和/或调制双层的物理性质。作为一个概念的证明，我们表明，SS-31改变二价阳离子（钙）分布的界面区域内，并减少了线粒体中的钙应力的能量负担。本研究揭示的SS-31的机制细节将有助于开发具有增强功效和生物利用度的未来化合物变体。
Mitochondrial dysfunction underlies many heritable diseases, acquired pathologies, and aging-related declines in health. Szeto?Schiller (SS) peptides comprise a class of amphipathic tetrapeptides that are efficacious toward a wide array of mitochondrial disorders and are believed to target mitochondrial membranes because they are enriched in the anionic phospholipid cardiolipin (CL). However, little is known regarding how SS peptides interact with or alter the physical properties of lipid bilayers. In this study, using biophysical and computational approaches, we have analyzed the interactions of the lead compound SS-31 (elamipretide) with model and mitochondrial membranes. Our results show that this polybasic peptide partitions into the membrane interfacial region with an affinity and a lipid binding density that are directly related to surface charge. We found that SS-31 binding does not destabilize lamellar bilayers even at the highest binding concentrations; however, it did cause saturable alterations in lipid packing. Most notably, SS-31 modulated the surface electrostatics of both model and mitochondrial membranes. We propose nonexclusive mechanisms by which the tuning of surface charge could underpin the mitoprotective properties of SS-31, including alteration of the distribution of ions and basic proteins at the interface, and/or modulation of bilayer physical properties. As a proof of concept, we show that SS-31 alters divalent cation (calcium) distribution within the interfacial region and reduces the energetic burden of calcium stress in mitochondria. The mechanistic details of SS-31 revealed in this study will help inform the development of future compound variants with enhanced efficacy and bioavailability.