Cellular Uptake and Ultrastructural Localization Underlie the Pro-apoptotic Activity of a Hydrocarbon-stapled BIM BH3 Peptide.
Cellular Uptake and Ultrastructural Localization Underlie the Pro-apoptotic Activity of a Hydrocarbon-stapled BIM BH3 Peptide.
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DOI：
10.1021/acschembio.5b00214
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发表时间：
2015-09-18
影响因子：
4
通讯作者：
Walensky LD
中科院分区：
文献类型：
--
作者：
Edwards AL;Wachter F;Lammert M;Huhn AJ;Luccarelli J;Bird GH;Walensky LD
碳氢化合物钉合已被应用于恢复和稳定生物活性肽的α-螺旋结构，用于生物化学、结构、细胞和体内研究。除了所安装的钉合物的组成和位置之外，肽序列可以显著地影响钉合肽的性质。因此，看起来相似的构造可以具有不同的功能和实用程序。在这里，我们进行了并排比较后，促凋亡BIM BH 3螺旋建模的钉合肽，以突出这些原则。我们证实，用i，i + 4烃钉取代盐桥不会损害靶结合亲和力，而是可以产生生物学和生物学增强的α-螺旋肽配体。重要的是，我们通过电子显微镜证明，钉合的BIM BH 3螺旋的促凋亡活性与其实现细胞摄取而不破坏膜的能力相关，并在机械活性的细胞器位点积累。
Hydrocarbon stapling has been applied to restore and stabilize the α-helical structure of bioactive peptides for biochemical, structural, cellular, and in vivo studies. The peptide sequence, in addition to the composition and location of the installed staple, can dramatically influence the properties of stapled peptides. As a result, constructs that appear similar can have distinct functions and utilities. Here, we perform a side-by-side comparison of stapled peptides modeled after the pro-apoptotic BIM BH3 helix to highlight these principles. We confirm that replacing a salt-bridge with an i, i + 4 hydrocarbon staple does not impair target binding affinity and instead can yield a biologically and pharmacologically enhanced α-helical peptide ligand. Importantly, we demonstrate by electron microscopy that the pro-apoptotic activity of a stapled BIM BH3 helix correlates with its capacity to achieve cellular uptake without membrane disruption and accumulate at the organellar site of mechanistic activity.
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影响因子：
14.8
作者：
Stewart ML;Fire E;Keating AE;Walensky LD
通讯作者：
Walensky LD
影响因子：
16
作者：
Barclay, Lauren A.;Wales, Thomas E.;Garner, Thomas P.;Wachter, Franziska;Lee, Susan;Guerra, Rachel M.;Stewart, Michelle L.;Braun, Craig R.;Bird, Gregory H.;Gavathiotis, Evripidis;Engen, John R.;Walensky, Loren D.
通讯作者：
Walensky, Loren D.
影响因子：
2.9
作者：
Abdiche, Yasmina;Malashock, Dan;Pons, Jaurne
通讯作者：
Pons, Jaurne
影响因子：
16
作者：
Gavathiotis E;Reyna DE;Davis ML;Bird GH;Walensky LD
通讯作者：
Walensky LD
影响因子：
64.8
作者：
Gavathiotis, Evripidis;Suzuki, Motoshi;Davis, Marguerite L.;Pitter, Kenneth;Bird, Gregory H.;Katz, Samuel G.;Tu, Ho-Chou;Kim, Hyungjin;Cheng, Emily H. -Y.;Tjandra, Nico;Walensky, Loren D.
通讯作者：
Walensky, Loren D.